Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study.

BACKGROUND: There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy. OBJECTIVES: To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy. METHODS: We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality. RESULTS: One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21). CONCLUSIONS: While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.

Impact of Preoperative Neutrophil to Prealbumin Ratio Index (NPRI) on Short-Term Complications and Long-Term Prognosis in Patients Undergoing Laparoscopic Radical Surgery for Colorectal Cancer.

Objective: This study aims to evaluate the impact and predictive value of the preoperative NPRI on short-term complications and long-term prognosis in patients undergoing laparoscopic radical surgery for colorectal cCancer (CRC). Methods: A total of 302 eligible CRC patients were included, assessing five inflammation-and nutrition-related markers and various clinical features for their predictive impact on postoperative outcomes. Emphasis was on the novel indicator NPRI to elucidate its prognostic and predictive value for perioperative risks. Results: Multivariate logistic regression analysis identified a history of abdominal surgery, prolonged surgical duration, CEA levels ≥5 ng/mL, and NPRI ≥ 3.94 × 10-2 as independent risk factors for postoperative complications in CRC patients. The Clavien--Dindo complication grading system highlighted the close association between preoperative NPRI and both common and severe complications. Multivariate analysis also identified a history of abdominal surgery, tumor diameter ≥5 cm, poorly differentiated or undifferentiated tumors, and NPRI ≥ 2.87 × 10-2 as independent risk factors for shortened overall survival (OS). Additionally, a history of abdominal surgery, tumor maximum diameter ≥5 cm, tumor differentiation as poor/undifferentiated, NPRI ≥ 2.87 × 10-2, and TNM Stage III were determined as independent risk factors for shortened disease-free survival (DFS). Survival curve results showed significantly higher 5-year OS and DFS in the low NPRI group compared to the high NPRI group. The incorporation of NPRI into nomograms for OS and DFS, validated through calibration and decision curve analyses, attested to the excellent accuracy and practicality of these models. Conclusion: Preoperative NPRI independently predicts short-term complications and long-term prognosis in patients undergoing laparoscopic colorectal cancer surgery, enhancing predictive accuracy when incorporated into nomograms for patient survival.

Identification of new endocrine disruptive transthyretin ligands in polluted waters using pull-down assay coupled to non-target mass spectrometry.

Surface and treated wastewater are contaminated with highly complex mixtures of micropollutants, which may cause numerous adverse effects, often mediated by endocrine disruption. However, there is limited knowledge regarding some important modes of action, such as interference with thyroid hormone (TH) regulation, and the compounds driving these effects. This study describes an effective approach for the identification of compounds with the potential to bind to transthyretin (TTR; protein distributing TH to target tissues), based on their specific separation in a pull-down assay followed by non-target analysis (NTA). The method was optimized with known TTR ligands and applied to complex water samples. The specific separation of TTR ligands provided a substantial reduction of chromatographic features from the original samples. The applied NTA workflow resulted in the identification of 34 structures. Twelve compounds with available standards were quantified in the original extracts and their TH-displacement potency was confirmed. Eleven compounds were discovered as TTR binders for the first time and linear alkylbenzene sulfonates (LAS) were highlighted as contaminants of concern. Pull-down assay combined with NTA proved to be a well-functioning approach for the identification of unknown bioactive compounds in complex mixtures with great application potential across various biological targets and environmental compartments.

Evaluation of Laboratory Parameters as Predictors of Mortality.

BACKGROUND: Evaluation of biomarkers as risk factors for mortality may provide early intervention and treatment for fatal diseases. We aimed to determine the usability of inexpensive and easily measurable tests in the differentiation of critically ill patients by investigating their relationship with mortality. METHODS: This study was executed by examining the sixth, third, and first month examinations of patients registered to the home health care services unit in 2022 before mortality due to any reason. This study was conducted by including 1,060 patients. All parameters were distributed non-parametrically. The difference between the dependent groups was evaluated with Friedman's two-way analysis of variance, and p < 0.05 was considered statistically significant. RESULTS: When the patients' premortem one-month, three-month, and six-month results were examined, there was an increase in mean platelet volume (MPV) values over time. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) also increased. In these two parameters, the difference between the first and third months and between the first and sixth months was statistically significant. Given the C-Reactive Protein (CRP)/Albumin Ratio (CAR) and CRP/Prealbumin results, a significant increase was observed in both ratios. A more than four-fold increase was observed in the CAR between the premortem first and sixth month results, which increased gradually over time and was statistically significant. Conclusions: NLR, PLR, MPV, CAR and CRP/Prealbumin values were statistically associated with mortality.

Poor diet quality is associated with biochemical parameters of protein nutritional status after Roux-en-Y gastric bypass.

OBJECTIVE: To assess diet quality and its association with body and biochemical parameters in patients who underwent Roux-en-Y gastric bypass (RYGB). METHODS: Prospective observational study with individuals of both sexes subjected to RYGB. Body composition, biochemical parameters, and diet quality were assessed before and six months after RYGB. Diet quality was assessed by the Healthy Eating Index (HEI). Data were analyzed by the paired t-test or Wilcoxon signed-rank test, with a significance level of 5%. Spearman's correlation and simple linear regression were performed between variables. RESULTS: The final sample included 34 patients. Their diet was classified as poor before and 6 mo after RYGB. BMI, fat mass, fat-free mass, waist perimeter, serum total protein, transthyretin, alpha-1-acid glycoprotein, and C-reactive protein decreased significantly (P < 0.05). Variations in the HEI score and caloric intake were associated with serum albumin and transthyretin (P < 0.05). CONCLUSION: Poor diet quality was present before and six months after RYGB, and the study data suggest that poor diet quality is associated to a risk of loss of lean body mass and visceral protein six months after RYGB.

Plasmalogens Alter the Aggregation Rate of Transthyretin and Lower Toxicity of Transthyretin Fibrils.

Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine. This severe pathology is known as transthyretin amyloid cardiomyopathy. Numerous experimental studies indicated that the aggregation rate and toxicity of TTR fibrils could be altered by the presence of lipids; however, the role of plasmalogens in this process remains unknown. In this study, we investigate the effect of choline plasmalogens (CPs) with different lengths and saturations of fatty acids (FAs) on TTR aggregation. We found that CPs with saturated and unsaturated FAs strongly suppressed TTR aggregation. We also found that CPs with saturated FAs did not change the morphology of TTR fibrils; however, much thicker fibrillar species were formed in the presence of CPs with unsaturated FAs. Finally, we found that CPs with C16:0, C18:0, and C18:1 FAs substantially lowered the cytotoxicity of TTR fibrils that were formed in their presence.

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer's Amyloid-ß Fibrillogenesis with High Blood Brain Barrier Crossing Capability.

The design of a potent amyloid-ß protein (Aß) inhibitor plays a pivotal role in the prevention and treatment of Alzheimer's disease (AD). Despite endogenous transthyretin (TTR) being recognized as an Aß inhibitor, the weak inhibitory and blood brain barrier (BBB) crossing capabilities hinder it for Aß aggregation inhibition and transport. Therefore, we have herein designed a recombinant TTR by conjugating a cationic cell penetrating peptide (penetratin, Pen), which not only enabled the fusion protein, TTR-Pen (TP), to present high BBB penetration but also greatly enhanced the potency of Aß inhibition. Namely, the protein fusion made TP positively charged, leading to a potent suppression of Aß40 fibrillization at a low concentration (1.5 µM), while a TTR concentration as high as 12.5 µM was required to gain a similar function. Moreover, TP could mitigate Aß-induced neuronal death, increase cultured cell viability from 72% to 92% at 2.5 µM, and extend the lifespan of AD nematodes from 14 to 18 d. Thermodynamic studies revealed that TP, enriched in positive charges, presented extensive electrostatic interactions with Aß40. Importantly, TP showed excellent BBB penetration performance, with a 10 times higher BBB permeability than TTR, which would allow TP to enter the brain of AD patients and participate in the transport of Aß species out of the brain. Thus, it is expected that the fusion protein has great potential for drug development in AD treatment.

Cardiac Amyloidosis Due to Transthyretin Protein: A Review.

Importance: Systemic amyloidosis from transthyretin (ATTR) protein is the most common type of amyloidosis that causes cardiomyopathy. Observations: Transthyretin (TTR) protein transports thyroxine (thyroid hormone) and retinol (vitamin A) and is synthesized predominantly by the liver. When the TTR protein misfolds, it can form amyloid fibrils that deposit in the heart causing heart failure, heart conduction block, or arrhythmia such as atrial fibrillation. The biological processes by which amyloid fibrils form are incompletely understood but are associated with aging and, in some patients, affected by inherited variants in the TTR genetic sequence. ATTR amyloidosis results from misfolded TTR protein deposition. ATTR can occur in association with normal TTR genetic sequence (wild-type ATTR) or with abnormal TTR genetic sequence (variant ATTR). Wild-type ATTR primarily manifests as cardiomyopathy while ATTR due to a genetic variant manifests as cardiomyopathy and/or polyneuropathy. Approximately 50 000 to 150 000 people in the US have heart failure due to ATTR amyloidosis. Without treatment, heart failure due to ATTR amyloidosis is associated with a median survival of approximately 5 years. More than 130 different inherited genetic variants in TTR exist. The most common genetic variant is Val122Ile (pV142I), an allele with an origin in West African countries, that is present in 3.4% of African American individuals in the US or approximately 1.5 million persons. The diagnosis can be made using serum free light chain assay and immunofixation electrophoresis to exclude light chain amyloidosis combined with cardiac nuclear scintigraphy to detect radiotracer uptake in a pattern consistent with amyloidosis. Loop diuretics, such as furosemide, torsemide, and bumetanide, are the primary treatment for fluid overload and symptomatic relief of patients with ATTR heart failure. An ATTR-directed therapy that inhibited misfolding of the TTR protein (tafamidis, a protein stabilizer), compared with placebo, reduced mortality from 42.9% to 29.5%, reduced hospitalizations from 0.7/year to 0.48/year, and was most effective when administered early in disease course. Conclusions and Relevance: ATTR amyloidosis causes cardiomyopathy in up to approximately 150 000 people in the US and tafamidis is the only currently approved therapy. Tafamidis slowed progression of ATTR amyloidosis and improved survival and prevented hospitalization, compared with placebo, in people with ATTR-associated cardiomyopathy.

Composite of KLVFF-Transthyretin-Penetratin and Manganese Dioxide Nanoclusters: A Multifunctional Agent against Alzheimer's ß-Amyloid Fibrillogenesis.

Design of amyloid ß-protein (Aß) inhibitors is considered an effective strategy for the prevention and treatment of Alzheimer's disease (AD). However, the limited blood-brain barrier (BBB) penetration and poor Aß-targeting capability restricts the therapeutic efficiency of candidate drugs. Herein, we have proposed to engineer transthyretin (TTR) by fusion of the Aß-targeting peptide KLVFF and cell-penetrating peptide Penetratin to TTR, and derived a fusion protein, KLVFF-TTR-Penetratin (KTP). Moreover, to introduce the scavenging activity for reactive oxygen species (ROS), a nanocomposite of KTP and manganese dioxide nanoclusters (KTP@MnO2) was fabricated by biomineralization. Results revealed that KTP@MnO2 demonstrated significantly enhanced inhibition on Aß aggregation as compared to TTR. The inhibitory effect was increased from 18%, 33%, and 49% (10, 25, and 50 µg/mL TTR, respectively) to 52%, 81%, and 100% (10, 25, and 50 µg/mL KTP@MnO2). In addition, KTP@MnO2 could penetrate the BBB and target amyloid plaques. Moreover, multiple ROS, including hydroxyl radicals, superoxide radicals, hydrogen peroxide, and Aß-induced-ROS, which cannot be scavenged by TTR, were scavenged by KTP@MnO2, thus resulting in the mitigation of cellular oxidative damages. More importantly, cell culture and in vivo experiments with AD nematodes indicated that KTP@MnO2 at 50 µg/mL increased the viability of Aß-treated cells from 66% to more than 95%, and completely cleared amyloid plaques in AD nematodes and extended their lifespan by 7 d. Overall, despite critical aspects such as the stability, metabolic distribution, long-term biotoxicity, and immunogenicity of the nanocomposites in mammalian models remaining to be investigated, this work has demonstrated the multifunctionality of KTP@MnO2 for targeting Aß in vivo, and provided new insights into the design of multifunctional nanocomposites of protein-metal clusters against AD.

Higher serum prealbumin levels are associated with higher graft take and wound healing in adult burn patients: A prospective observational trial.

INTRODUCTION: Nutritional support is essential in burn care. There are few studies investigating the effect of nutrition on burn healing. The purpose of this study was to determine the relationship between perioperative serum prealbumin levels and the probability of autologous skin graft take in burned patients. MATERIALS AND METHODS: A prospective observational study was carried out with burned adults recruited consecutively from April 2019 until September 2021. Serum prealbumin was determined perioperatively. The percentage of graft take was evaluated over the first 5 postoperative dressing changes. Time until full epithelialization (absence of wounds) was also registered. RESULTS: A total of 60 patients were recruited, mostly middle-aged people with moderate flame burns. Serum prealbumin levels and graft take had a weak-moderate, nonlinear, statistically significant correlation. They were also an independent predictor of full epithelialization on the fifth dressing change, together with burn depth. Higher perioperative serum prealbumin levels were significantly associated with a reduction in time until full epithelialization. CONCLUSIONS: Perioperative serum prealbumin levels are significantly correlated with the probability of split-thickness skin autograft take in burned patients and with a reduced time to achieve complete epithelialization. They were an independent predictor of full graft take.

Multiorgan Dysfunction and Associated Prognosis in Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis. METHODS AND RESULTS: This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; P=0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; P=0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; P=0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; P=0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; P<0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; P<0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; P=0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; P=0.01). CONCLUSIONS: Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.

Rare c.302C>T TTR Variant Associated with Transthyretin Amyloidosis.

Background and Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a rare disease caused by pathogenic variants in the transthyretin (TTR) gene. More than 140 different disease-causing variants in TTR have been reported. Only a few individuals with a rare TTR variant, c.302C>T, p.(Ala101Val) (historically known as p.(Ala81Val)), primarily associated with cardiac ATTRv, have been described. Therefore, our aim was to analyze the clinical characteristics of individuals with the identified c.302C>T TTR variant at our center. Materials and Methods: We analyzed data from individuals with ATTRv who were diagnosed and treated at Vilnius University Hospital Santaros Klinikos. ATTRv was confirmed by negative hematological analysis for monoclonal protein, positive tissue biopsy or bone scintigraphy and a pathogenic TTR variant. Results: During 2018-2021, the TTR NM_000371.3:c.302C>T, NP_000362.1:p.(Ala101Val) variant was found in one individual in a homozygous state and in three individuals in a heterozygous state. The age of onset of symptoms ranged from 44 to 74 years. The earliest onset of symptoms was in the individual with the homozygous variant. A history of carpal tunnel syndrome was identified in two individuals. On ECG, three individuals had low QRS voltage in limb leads. All individuals had elevated NT-proBNP and hsTroponine I levels on baseline laboratory tests and concentric left ventricular hypertrophy on transthoracic echocardiography. The individual with the homozygous c.302C>T TTR variant had the most pronounced polyneuropathy with tetraparesis. Other patients with the heterozygous variant had more significant amyloid cardiomyopathy. When screening family members, the c.302C>T TTR variant was identified in two phenotypically negative relatives at the ages of 33 and 47 years. Conclusions: c.302C>T is a rare TTR variant associated with ATTRv cardiomyopathy. The homozygous state of this variant was not reported before, and is associated with earlier disease onset and neurological involvement compared to the heterozygote state.

Inhibitors of Transthyretin Amyloidosis: How to Rank Drug Candidates Using X-ray Crystallography Data.

Amyloidosis is a group of protein misfolding diseases, which include spongiform encephalopathies, Alzheimer's disease and transthyretin (TTR) amyloidosis; all of them are characterized by extracellular deposits of an insoluble fibrillar protein. TTR amyloidosis is a highly debilitating and life-threatening disease. Patients carry less stable TTR homotetramers that are prone to dissociation into non-native monomers, which in turn rapidly self-assemble into oligomers and, ultimately, amyloid fibrils. Liver transplantation to induce the production of wild-type TTR was the only therapeutic strategy until recently. A promising approach to ameliorate transthyretin (TTR) amyloidosis is based on the so-called TTR kinetic stabilizers. More than 1000 TTR stabilizers have already been tested by many research groups, but the diversity of experimental techniques and conditions used hampers an objective prioritization of the compounds. One of the most reliable and unambiguous techniques applied to determine the structures of the TTR/drug complexes is X-ray diffraction. Most of the potential inhibitors bind in the TTR channel and the crystal structures reveal the atomic details of the interaction between the protein and the compound. Here we suggest that the stabilization effect is associated with a compaction of the quaternary structure of the protein and propose a scoring function to rank drugs based on X-ray crystallography data.

Transthyretin-derived amyloid (ATTR) and sarcoidosis: Does ATTR deposition cause a granulomatous inflammatory response in older adults with sarcoidosis?

This study aimed to assess the frequency and association between transthyretin-derived (ATTR) amyloidosis and sarcoidosis in a large autopsy cohort including many cases of sudden cardiac death (SCD). We identified 73 sporadic ATTR amyloidosis cases and 11 sarcoidosis cases, among which we found two cases with concomitant ATTR amyloidosis and sarcoidosis (2.4% of all cases; 2.7% within the sporadic ATTR group). The first case involved a 92-year-old man who experienced SCD. In this patient's heart, we observed ATTR deposition and noncaseating epithelioid granulomas consistent with sarcoidosis. Focally, ATTR deposits and granulomas co-localized, with histiocyte phagocytosis of transthyretin-immunoreactive fragments. However, in most lesions, they were distributed independently. The second case was that of an 86-year-old woman who also experienced SCD. In this patient, we detected ATTR deposition in the heart and lung, while noncaseating epithelioid granulomas were only observed in the lung, liver, kidney, and thyroid. Furthermore, no co-localization of the two lesions was observed. Based on these findings, we concluded that the coexistence of ATTR amyloidosis and sarcoidosis was likely coincidental. Nevertheless, despite the rarity of the combination of these two diseases, it should be recognized as a potential cause of SCD, especially among elderly people.

Breakthrough advances enhancing care in ATTR amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has been traditionally considered a rare and inexorably fatal condition. ATTR-CM now is an increasingly recognized cause of heart failure (HF) and mortality worldwide with effective pharmacological treatments. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have transformed the diagnosis of ATTR-CM, which is now possible without recourse to endomyocardial biopsy in ≈70 % of cases. Many patients are now diagnosed at an earlier stage. Echocardiography and cardiac magnetic resonance have enabled identification of patients with possible ATTR-CM and more accurate prognostic stratification. Although radionuclide scintigraphy with 'bone' tracers has an established diagnostic value, the diagnostic performance of the bone tracers validated for non-invasive confirmation of ATTR-CM may not be equal. Characterising the wider clinical phenotype of patients with ATTR-CM has enabled identification of features with potential for earlier diagnosis such as carpal tunnel syndrome. Therapies able to slow or halt ATTR-CM progression and increase survival are now available and there is also evidence that patients may benefit from specific conventional HF medications. Cutting-edge research in the field of antibody-mediated removal of ATTR deposits compellingly suggest that ATTR-CM is a truly reversible disorder, bringing hope for patients even with advanced disease. A wide horizon of possibilities is unfolding and awaits discovery.

Development and validation of prealbumin-bilirubin score (preALBI score) for predicting long-term survival after hepatectomy for hepatocellular carcinoma: A multicenter analysis versus ALBI score.

BACKGROUND: The Albumin-Bilirubin (ALBI) score, widely used in predicting long-term prognosis for patients with hepatocellular carcinoma (HCC), has limitations due to serum albumin variability. This study aimed to develop and validate the Prealbumin-Bilirubin (preALBI) score as a reliable alternative. METHODS: A multicenter cohort of HCC patients who underwent hepatectomy was randomly divided into the training and validation cohorts. The preALBI score was developed using Cox regression models within the training cohort, incorporating serum prealbumin and bilirubin levels as crucial determinants. The survival predictive accuracy was evaluated and compared between the preALBI score with two other staging systems, including the ALBI score and the Child-Pugh grade. RESULTS: A total of 2409 patients were enrolled. In the training cohort, the preALBI score demonstrated superior performance in predicting long-term survival after hepatectomy. The preALBI score was associated with the best monotonicity of gradients (linear trend χ2: 72.84) and homogeneity (likelihood ratio χ2: 74.69), and the highest discriminatory ability (the areas under curves for 1-, 3-, and 5-year mortality: 0.663, 0.654, and 0.644, respectively). In addition, the preALBI was the most informative staging system in predicting survival (Akaike information criterion: 11325.65).The results remained consistent in both training and validation cohorts, indicating its reliable performance across different populations. CONCLUSION: The preALBI score, leveraging the stability of prealbumin, represents a promising tool for better patient stratification, providing more accurate prognostic predictions than the ALBI score and the Child-Pugh grade.

Bioaccumulation and thyroid endcrione disruption of 2-ethylhexyl diphenyl phosphate at environmental concentration in zebrafish larvae.

2-ethylhexyl diphenyl phosphate (EHDPP) strongly binds to transthyretin (TTR) and affects the expression of genes involved in the thyroid hormone (TH) pathway in vitro. However, it is still unknown whether EHDPP induces endocrine disruption of THs in vivo. In this study, zebrafish (Danio rerio) embryos (< 2 h post-fertilization (hpf)) were exposed to environmentally relevant concentrations of EHDPP (0, 0.1, 1, 10, and 100 µg·L-1) for 120 h. EHDPP was detected in 120 hpf larvae at concentrations of 0.06, 0.15, 3.71, and 59.77 µg·g-1 dry weight in the 0.1, 1, 10, and 100 µg·L-1 exposure groups, respectively. Zebrafish development and growth were inhibited by EHDPP, as indicated by the increased malformation rate, decreased survival rate, and shortened body length. Exposure to lower concentrations of EHDPP (0.1 and 1 µg·L-1) significantly decreased the whole-body thyroxine (T4) and triiodothyronine (T3) levels and altered the expressions of genes and proteins involved in the hypothalamic-pituitary-thyroid axis. Downregulation of genes related to TH synthesis (nis and tg) and TH metabolism (dio1 and dio2) may be partially responsible for the decreased T4 and T3 levels, respectively. EHDPP exposure also significantly increased the transcription of genes involved in thyroid development (nkx2.1 and pax8), which may stimulate the growth of thyroid primordium to compensate for hypothyroidism. Moreover, EHDPP exposure significantly decreased the gene and protein expression of the transport protein transthyretin (TTR) in a concentration-dependent manner, suggesting a significant inhibitory effect of EHDPP on TTR. Molecular docking results showed that EHDPP and T4 partly share the same mode of action of binding to the TTR protein, which might result in decreased T4 transport due to the binding of EHDPP to the TTR protein. Taken together, our findings indicate that EHDPP can cause TH disruption in zebrafish and help elucidate the mechanisms underlying EHDPP toxicity.

Sex differences in transthyretin cardiac amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to cardiac dysfunction. Recent evidence suggests that sex differences may play a significant role in various steps of ATTR-CA, including clinical presentation, diagnostic challenges, disease progression, and treatment outcomes. ATTR-CA predominantly affects men, whereas women are older at presentation. Women generally present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. When indexed, left ventricular (LV) wall thickness is equal, or even increased, than men. Women also have smaller LV cavities, more preserved ejection fractions, and apparently a slightly worse right ventricular and diastolic function. Given the under-representation on women in clinical trials, no data regarding sex influence on the treatment response are currently available. Finally, it seems there are no differences in overall prognosis, even if premenopausal women may have a certain level of myocardial protection. Genetic variations, environmental factors, and hormonal changes are considered as potential contributors to observed disparities. Understanding sex differences in ATTR-CA is vital for accurate diagnosis and management. By considering these differences, clinicians can improve diagnostic accuracy, tailor treatments, and optimize outcomes for both sexes with ATTR-CA.

Drug Repositioning for Amyloid Transthyretin Amyloidosis by Interactome Network Corrected by Graph Neural Networks and Transcriptome Analysis.

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.

Dapagliflozin treatment and cardiovascular outcome in RBP4/TTRVal30Met (transthyretin cardiac amyloidosis) mice.

AIMS: Whether sodium-glucose co-transporter 2 inhibitors are effective for heart failure caused by ATTR-CA (transthyretin cardiac amyloidosis) remains uncertain. The aim of this study is to investigate the cardiovascular prognosis in ATTR-CA mice model with dapagliflozin treatment. METHODS AND RESULTS: Humanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1 mg/kg/day, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test, and plasma brain natriuretic peptide (BNP) concentration were measured at Day 0, Week 2, and Week 4. BNP, transforming growth factor-beta (TGF-ß), collagen type I alpha 1 (COL1A1) protein levels, and Cola1, TGFß1, TNFα, IL-1ß, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter were measured at Week 4 after treatment procedure. All 18 mice completed the experiment. The baseline characteristics were balanced among three treatment groups. In placebo-treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice (RBP4[KI/KI], TTR [KI/KI]: 0.72 ± 0.46, RBP4[KI/KI], TTRVal50Met [KI/KI]: 1.44 ± 0.60, P = 0.043), indicating more significant heart failure progression in ATTR-CA mice than normal mice. In ATTR-CA mice, the cardiovascular prognosis measurements including heart failure (plasma BNP concentration and relative quantities of BNP), cardiac inflammation (relative quantities of Cola1, TGFß1, TNFα, and IL-1ß), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between those under dapagliflozin and placebo treatment. CONCLUSIONS: Dapagliflozin did not improve cardiovascular prognosis including the progression of heart failure, cardiac inflammation, and pathological changes in ATTR-CA mice compared with placebo. The results of this study were not in support of dapagliflozin's therapeutic effects for ATTR-CA. More pre-clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.