The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising sharply, yet treatment options remain inadequate. To uncover new therapeutic targets for MASLD, we conducted a comprehensive proteome-wide Mendelian randomization (MR) and phenome-wide association study (PheWAS).

Discovery MR utilized protein quantitative trait loci (pQTL) data on 4907 plasma protein levels from 35,559 individuals, alongside genome-wide association study (GWAS) on MASLD from the Million Veteran Program (68,725 cases / 95,482 controls). Validation comprised five pairwise combinations of these discovery datasets with three additional datasets: pQTL data for 2923 proteins from the UK Biobank, and liver biopsy-confirmed MASLD GWAS (1483 cases/17,781 controls) and MRI-liver fat GWAS (31,377 subjects) (excluding discovery pair). Candidate proteins underwent druggability assessment and on-target side effect evaluation via PheWAS.

We identified 26 proteins associated with MASLD after Bonferroni correction (P < 1.16 × 10-5), with 19 of them showing no significant reverse association. Interleukin-6 (IL-6), alpha-1-antitrypsin (α1-antitrypsin), 5-hydroxytryptamine receptor 7 (5-HT7R), ephrin-B1 (EFNB1), and protein MENT (CA056) were replicated. Notably, IL-6 (OR = 2.02; 95 % CI 1.54-2.64), 5-HT7R (OR = 2.73; 95 % CI 1.96-3.80), and EFNB1 (OR = 1.82; 95 % CI 1.59-2.08) were positively associated with MASLD risk, whereas α1-antitrypsin (OR = 0.84; 95 % CI 0.78-0.90) and CA056 (OR = 0.90; 95 % CI 0.86-0.94) appeared protective. Among these, IL-6, 5-HT7R, and α1-antitrypsin were druggable. PheWAS identified potential cardiovascular side effects for 5-HT7R and α1-antitrypsin.

The integrative study identified several plasma proteins associated with MASLD. IL-6, α1-antitrypsin, 5-HT7R, EFNB1 and CA056 deserve further investigation as potential drug targets for MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a type of fat accumulation in the liver that can lead to cirrhosis and chronic liver disease. MASLD is recognized as the most frequent of liver-associated deaths worldwide. The SERPINA1 gene encodes a serine protease protein that plays a pivotal role in the pathogenesis of liver deficiencies. In this study, we aimed to evaluate the genetic association between rs6647 (M1), rs709932 (M2), and rs1303 (M3) variants in the SERPINA1 gene and the risk of MASLD in an Iranian population.

In this case-control study, 120 patients affected by MASLD and 120 healthy subjects participated. The Nephelometry system measured serum levels of α1-antitrypsin (A1AT). Biochemical tests were conducted to assess serum levels of blood parameters using commercially available kits. DNA extraction was performed using the salting-out method, followed by the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method for genotyping. Statistical analysis was performed by SPSS v16.0.

The findings showed that the rs6647 G allele significantly increased the risk of MASLD. The G allele in codominant, dominant, and over-dominant models caused an increase in the risk of MASLD. Additionally, the rs709932 T allele was more frequent among patients compared to healthy subjects and significantly enhanced the risk of MASLD. The T allele in the codominant and recessive models indicated a high risk for MASLD in our population. The G allele of rs1303 caused an enhancement in the mean serum levels of A1AT in the MASLD group.

Our results show an association between SERPINA1 gene variants and the risk of MASLD. The rs6647 (M1) and rs709932 (M2) variants of the SERPINA1 gene increased the risk of disorder in our population.

The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.

Most thyroid nodules can be diagnosed preoperatively by ultrasonography and fine-needle aspiration biopsy. However, accurately differentiating between benign nodules or indolent thyroid tumors and aggressive thyroid cancers remains a significant clinical challenge when the biopsy results are indeterminate. In this study, we aim to explore a novel biomarker to determine the malignancy of thyroid nodules. Fifteen tissue samples from patients with Stage I&II papillary thyroid carcinoma (PTC) and benign thyroid nodule (BTN) were analyzed by EPIC Methylation 850 K and RNA-Sequencing. Altered and inversely correlated methylation and expression in SERPINA1 gene in PTC was found in the discovery study. PTC-associated SERPINA1 hypomethylation was further verified by mass spectrometry in case-control studies from two clinical centers (Validation I: 140 PTCs vs. 182 BTNs, ORs ≥ 2.48, and Validation II: 224 PTCs vs. 217 BTNs, ORs ≥ 2.04; P ≤ 3.07E-15, for all measurable CpG sites). Moreover, SERPINA1 methylation had an outstanding clinical application value to differentiate PTC from BTN (the AUC combining Validation I and Validation II was 0.92). Our study also revealed that the upregulated SERPINA1 could promote cell proliferation, migration and invasion in the PTC cell lines, and thereby facilitate the malignant progression of PTC. Mechanistically, SERPINA1 activated the AKT/mTOR pathway via binding to MAPK6. Intervention targeting either SERPINA1 or MAPK6 has a significant impact on the malignancy of PTC cells. Together, we identified SERPINA1 methylation as a functional and effective diagnostic marker for PTC and provided a novel epigenetic insight into the etiology of PTC.

Mutants of members of the serpin superfamily can undergo nonamyloid aggregation to form polymeric chains that are associated with disease. This is typified by Z alpha-1-antitrypsin (Glu342Lys) that accumulates as polymers within hepatocytes to cause cirrhosis. We have used ion mobility mass spectrometry and electron-capture dissociation to directly observe and characterize novel intermediates formed during polymerization. Our data are congruent with an ensemble of conformations that are monomeric but maintained in a partially misfolded metastable state in which ∼12% of the molecule at the C-terminus is displaced. The application of these techniques to Z alpha-1-antitrypsin polymers isolated from human liver revealed a molecular species most consistent with a polymer mediated by an intermolecular C-terminal domain insertion. These findings establish a previously unobserved progression of pathogenic structural changes and thereby extend the mechanism of alpha-1-antitrypsin polymerization. They additionally demonstrate the strengths of native top-down ion mobility mass spectrometry in characterizing misfolding intermediates and proteins isolated from human tissue.

There is a dearth of population-based studies on the association between the diversity of the oral microbiome and the risk of chronic obstructive pulmonary disease (COPD). The study aims to investigate the association between oral microbiome diversity and COPD.

In this cross-sectional study, data from the National Health and Nutrition Examination Survey (NHANES 2009-2012) were analyzed. The association between the oral microbiome α-diversity and COPD risk was examined via multivariable logistic regression, with Restricted cubic splines revealing potential non-linear trends. The β-diversity disparities between COPD and non-COPD groups were delineated using Principal Coordinate Analysis (PCoA) and Permutational Multivariate Analysis of Variance (PERMANOVA).

A total of 6061 participants were included in this study. For α-diversity, the observed ASVs were significantly associated with COPD risk (OR = 0.964, 95%CI: 0.936-0.993, P = 0.016). Similarly, Faith's phylogenetic Diversity showed a significant association with COPD risk (OR = 0.955, 95%CI: 0.919-0.993, P = 0.020). The Shannon-Weiner index was also associated with COPD risk (OR = 0.829, 95%CI: 0.702-0.981, P = 0.029). For β-diversity, PCoA and PERMANOVA analysis showed statistically significant differences in Bray-Curtis, unweighted, and weighted UniFrac distances (all P < 0.01) between the COPD and non-COPD groups.

Significant differences in oral microbiome α-diversity and β-diversity were found between COPD and non-COPD populations, with α-diversity (observed ASVs, Faith's Phylogenetic Diversity, Shannon-Weiner index) being negatively associated with the risk of COPD.

Alpha-1 antitrypsin deficiency (AATD) can manifest at any age, including the perinatal period. Its manifestations include obstructive lung disease, which can be severe and for which current therapies are of limited benefit. We sought to determine whether the transamniotic route could be a viable alternative for administering AAT mRNA to the fetus. Twelve pregnant dams underwent volume-matched intra-amniotic injections in all their fetuses (n = 139) of either a suspension of human AAT (hAAT) mRNA encapsulated by a synthetic cationic polymer-based composite, lipopolyplex (mRNA group; n = 99) or of lipopolyplex free of mRNA (controls; n = 40), on gestational day 17 (E17; term = E21). Fetal lung and liver samples were procured daily thereafter until term to screen for hAAT by ELISA. Liver function panels were performed at term. Statistical analysis included median regression (p < 0.05). Fetal survival was 79% (110/139), significantly higher in the mRNA group (p = 0.012). Controlled by mRNA-free injections, hAAT was found in the fetal lungs at all time points (p = 0.005 to < 0.001) but in the liver only at E20, suggesting interspecies homology manifesting at that site. The term liver function panels were comparable between groups. Encapsulated exogenous mRNA encoding for human alpha-1 antitrypsin protein can be incorporated and translated by fetal lung cells following simple intra-amniotic injection in a healthy rat model. Fetal hepatic incorporation and translation remain to be determined in a model with minimal to no human homology. Transamniotic mRNA delivery could become a novel strategy for the perinatal management of alpha-1 antitrypsin deficiency.

Although several SERPINA1 genetic variants have been reported for their pathogenicity to induce liver disorders through phenotype-driven approaches, data regarding genotype-driven approaches of the SERPINA1 locus remain unavailable. This study aimed to characterize the clinical and liver biological profiles of patients harboring nonbenign SERPINA1 variants.

We conducted a retrospective, exome-based genotype-first reverse phenotyping study using structured electronic health record data from consecutive patients from January 1, 2015, to January 31, 2022. Statistical associations were assessed using frequentist and Bayesian models, with validation in the UK Biobank cohort.

Among 1377 patients analyzed, 15 SERPINA1 variants classified as nonbenign were identified in 217 (15.7%) patients. Data were available for 126 patients (median age, 41.5 years; 52.4% male). Liver disease, hyperferritinemia, and pulmonary emphysema were observed in 32.5% (41/126), 23% (29/126), and 5.6% (7/126) of the patients, respectively. The median follow-up duration was 1.3 years and encompassed 1085 biological observations. We confirmed associations with well-documented variants of SERPINA1 (p.Glu366Lys, p.Pro393Ser, p.Ala308Ser, p.Glu288Val, and p.Phe76del). We identified three novel genetic associations with liver markers: c.*10G > A, c.1065 + 10C > T, and p.Arg63Cys. The UK Biobank data confirmed significant gene- and variant-level associations, notably for the variants identified in our study, which ranked in the top decile of statistical associations.

This study supports the utility of a genotype-first approach in characterizing hepatic manifestations of nonbenign SERPINA1 variants. The findings highlight novel genotype-biomarker associations and suggest a role for SERPINA1 genetic testing in patients with unexplained liver abnormalities.

Serpins, protease inhibitors whose regulated conformational instability renders them susceptible to mutations that cause misfolding, represent a system for the study of non-amyloid protein aggregation. The E342K "Z" variant of α-1-antitrypsin (AAT) undergoes oligomeric self-assembly into polymer chains that are associated with liver and lung pathologies in AAT deficiency. Structural characterization of polymers from human tissue has been limited by their heterogeneity and flexibility; here, we have studied their internal structure, which provides insights into the molecular linkage and the pathway by which they are formed. NMR spectra of heat-induced 13C-ILV-methyl-labeled polymers, and 1H-methyl spectra of liver-derived polymers, show equivalence to that of AAT in a post-protease-encounter conformation. This is corroborated by x-ray crystallography, which reveals a cryptic epitope recognized by the conformationally selective 2C1 antibody, common to both forms. These data definitively preclude most models of polymerization and are compatible with sequential intermolecular donation of the carboxyl terminus of one molecule into the next during polymer formation.

Alpha-1 antitrypsin deficiency (AATD) constitutes an inborn disorder arising due to mutations in alpha-1 antitrypsin (AAT), a secreted protease inhibitor produced primarily in hepatocytes. It leads to diminished serum AAT levels, and this loss-of-function predisposes to chronic obstructive pulmonary disease and lung emphysema. The characteristic Pi*Z mutation results in hepatic Z-AAT accumulation. In its homozygous form (Pi*ZZ genotype), it is responsible for the majority of severe AATD cases and can cause both pediatric and adult liver disease, while the heterozygous form (Pi*MZ) is considered a disease modifier that becomes apparent primarily in the presence of other comorbidities or risk factors. In the current review, we collate conditions associated with AATD, introduce typical AAT variants, and discuss our understanding of disease pathogenesis. We present both cross-sectional and longitudinal data informing about the natural disease history and noninvasive tools that can be used for disease stratification as well as a basis for disease monitoring. Given that AATD-associated liver disease is highly heterogeneous, we discuss the risk factors affecting disease progression. While the loss-of-function lung disease is treated by weekly intravenous administration of purified AAT, recombinant modified AAT and oral protease inhibitors are currently in clinical trials. Among the liver candidates, small interfering RNA fazirsiran efficiently suppresses AAT production and is currently in phase 3 clinical trial, while several other genetic approaches, such as RNA editing, are at earlier stages. In summary, AATD represents a systemic disorder increasingly seen in the hepatologic routine and requiring thorough interdisciplinary care, since the currently ongoing clinical trials often address only one of the organs it affects.

The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ's functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or 'liver' organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.

Protein misfolding diseases, including α1-antitrypsin deficiency (AATD), pose substantial health challenges, with their cellular progression still poorly understood1-3. We use spatial proteomics by mass spectrometry and machine learning to map AATD in human liver tissue. Combining Deep Visual Proteomics (DVP) with single-cell analysis4,5, we probe intact patient biopsies to resolve molecular events during hepatocyte stress in pseudotime across fibrosis stages. We achieve proteome depth of up to 4,300 proteins from one-third of a single cell in formalin-fixed, paraffin-embedded tissue. This dataset reveals a potentially clinically actionable peroxisomal upregulation that precedes the canonical unfolded protein response. Our single-cell proteomics data show α1-antitrypsin accumulation is largely cell-intrinsic, with minimal stress propagation between hepatocytes. We integrated proteomic data with artificial intelligence-guided image-based phenotyping across several disease stages, revealing a late-stage hepatocyte phenotype characterized by globular protein aggregates and distinct proteomic signatures, notably including elevated TNFSF10 (also known as TRAIL) amounts. This phenotype may represent a critical disease progression stage. Our study offers new insights into AATD pathogenesis and introduces a powerful methodology for high-resolution, in situ proteomic analysis of complex tissues. This approach holds potential to unravel molecular mechanisms in various protein misfolding disorders, setting a new standard for understanding disease progression at the single-cell level in human tissue.

The development of portal hypertension (PH) is a key prognostic factor in patients with compensated advanced chronic liver disease (cACLD). The gold standard for assessing PH is the hepatic venous pressure gradient measurement. However, noninvasive tools have gained significant importance in recent years, mainly liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE). Spleen stiffness measurement (SSM) by VCTE using a dedicated 100-Hz module has emerged as a promising non-invasive diagnostic tool, although data on its prognostic value remain limited. This study aimed to evaluate the accuracy of SSM, as measured by transient elastography, in predicting the risk of liver decompensation.

A prospective study was conducted including patients with cACLD followed at a tertiary center from January 2020 to April 2024. All patients underwent liver and spleen VCTE (utilizing the 100-Hz module) performed by the same blinded operator. Patients were subsequently monitored at the same institution for the development of PH complications.

The study included 242 patients with cACLD, with a mean age of 63.0 ± 10.5 years and who were 78.5% male. The most common etiology was alcoholic liver disease (62.0%). The median LSM value was 21.9 kPa (interquartile range [IQR], 15.0-34.0 kPa), and the median SSM value was 38.9 kPa (IQR, 28.0-58.0 kPa). The median follow-up period was 501.5 days (IQR, 343.0-725.3 days). During this time, 28 patients (11.6%) developed liver decompensations, with 20 requiring hospital admission. SSM demonstrated good predictive capacity for the risk of liver decompensation (area under the curve, 0.823; 95% confidence interval, 0.742-0.904). Alongside LSM, SSM was an effective predictor of liver decompensation, with a cutoff of 50.0 kPa indicating a significantly increased risk of hepatic decompensation.

Noninvasive assessment using SSM may serve as an excellent tool for predicting the risk of liver-related complications and risk-stratifying patients with cACLD, thereby improving their management.

Primary liver cancers (PLCs) remain a major challenge to global health and an escalating threat to human life, with a growing incidence worldwide. PLCs are composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and mixed HCC-CCA, accounting for 85 %, 10 %, and 5 % of cases, respectively. Among the numerous identified risk factors associated with liver cancers, Alpha 1-AntiTrypsin Deficiency (AATD) genetic disease emerges as an intriguing one. AATD-related liver disease may lead to chronic hepatitis, cirrhosis, and PLCs in adulthood. Although our knowledge about the natural history of AATD-liver disease has improved recently, liver cancers associated with AATD remain poorly understood and explored, while this specific population is at a 20 to 50 times higher risk of developing PLC. Thus, we review here current knowledge about AATD-associated PLCs, describing the impact of AATD genotypes on their occurrence. We also discuss emerging hypotheses regarding the AATD PiZZ genotype-related hepatic carcinogenesis process. Finally, we perform an updated analysis of the United Kingdom Biobank database that highlights and confirms AATD PiZZ genotype as an important HCC risk factor.

Neutrophil elastase (NE) is released by activated neutrophils during an inflammatory response and exerts proteolytic activity on elastin and other extracellular matrix components. This protease is rapidly inhibited by the plasma serine protease inhibitor alpha-1-antitrypsin (AAT), and the importance of this protective activity on lung tissue is highlighted by the development of early onset emphysema in individuals with AAT deficiency. As a serpin, AAT presents a surface-exposed reactive centre loop (RCL) whose sequence mirrors the target protease specificity. Following binding of NE in a 'Michaelis' encounter complex, cleavage of the RCL results in an irreversible complex between the two molecules. Here, the structure of the AAT-NE encounter complex was studied by molecular dynamics, mutagenesis and enzyme kinetics. Exploration of the geometry of interaction between the two molecules revealed the possibility that the interaction interface extends beyond the RCL; a persistent feature of the simulations was the interaction between a region located upstream of β-strand 4C of AAT, comprising three acidic residues (Asp202, Glu199 and Glu204), and Arg147 of NE. Mutation of the acidic residues to either alanine or serine, or a D202R substitution, resulted in a reduced rate of association between recombinant AAT and NE. Addition of salt to the buffer had little effect for these mutants but substantially reduced the rate of interaction of the wild-type protein. These data are consistent with a role for this acidic region on AAT as an exosite that contributes to an optimal interaction with its physiological protease target.

Colon adenocarcinoma (COAD) is characterized by high mortality and poor prognosis. Endoplasmic reticulum stress-related gene (ERSG) plays an indispensable role in the progression and immunotherapy of COAD. In this study, we evaluated the prognostic value of ERSGs in COAD.

We constructed and validated the ERSG-related prognostic signature based on public databases using univariate Cox analysis, Kaplan-Meier survival analysis, the LASSO method, and multivariate Cox analysis. In addition, TCGA-COAD, the Human Protein Atlas, and quantitative real-time PCR (q-PCR) were used to detect the mRNA and protein expressions of ERSGs in normal and cancer tissues/cells. The immunotherapeutic cohort was used to evaluate the predictive value of the ERSG signature for immunotherapeutic sensitivity.

The ERSG signature, consisted of HSPA1A, SERPINA1, and DAPK1, could predict the prognosis of patients with COAD. Clinicopathologic characteristics were significantly correlated with risk scores. There were significant differences in the proportion of tumor-infiltrating immune cells, the TP53 mutation rate, the expression of immune checkpoint-related genes, and IC50 of the chemotherapeutic drugs between the low- and high-risk groups. Compared with normal tissues, the mRNA and protein expressions of three ERSGs were decreased in cancer tissues. Compared with NCM460, the mRNA levels of HSPA1A and DAPK1 were decreased in the majority of COAD cell lines, whereas the mRNA level of SERPINA1 was increased in HCT116 and SW480, and reduced in SW620. The ERSG signature could be used as a predictor of immunotherapeutic outcomes.

The ERSG signature has a predictive value in the prognosis and immunotherapeutic sensitivity in COAD, helping guide the personalized treatment.

The severe alpha-1 antitrypsin deficiency (AATD) genotype Pi*ZZ increases the risk of liver disease (AATD-LD) and lung disease. While non-invasive tests (NITs) are widely used for fibrosis stage and monitoring of all liver diseases, the consensus for use in AATD-LD is limited. A Delphi panel study was conducted to address this need.

Healthcare providers who managed at least two patients with AATD-LD in the past two years participated. Two iterative surveys were developed and administered. The second survey clarified the results from the first and provided deeper feedback. As follow-up, a real-time consensus-building exercise focused on survey topics without consensus. Controlled feedback was anonymous.

A total of 20 AATD experts (hepatology [n = 9], pulmonology [n = 6], transplant hepatology [n = 3], gastroenterology [n = 1], and hepatology and transplant hepatology [n = 1]) completed the study. A strong consensus was achieved around the use and evaluation of NITs for risk stratification and monitoring. All panelists agreed that vibration-controlled transient elastography (VCTE) is the preferred NIT for the initial assessment of AATD-LD owing to its accessibility and reliability. Magnetic resonance elastography and enhanced liver fibrosis tests were also considered valuable. Most (85%) agreed that VCTE < 8 kPa could indicate no or mild fibrosis and VCTE ≥ 8 kPa could indicate clinically significant fibrosis, which may correspond to fibrosis stage ≥ F2 on the METAVIR scale. Most (85%) agreed that VCTE ≥ 13 kPa may indicate cirrhosis.

Utilizing the Delphi technique, this study identified a clinically applicable framework for the diagnosis and monitoring of AATD-LD. A high level of agreement emerged regarding preferred NITs and their usage, risk stratification and monitoring in the context of AATD-LD management. The results provide a foundation for future efforts into NIT validation and the development of clinical guidelines for AATD-LD.

Demographic studies have revealed a strong association between exposure to high ambient temperatures during pregnancy and increased risks of preterm birth (PTB). The mechanism underlying this association is unclear, but it is plausible that altered placental function may contribute to it. In this study, we conducted differential gene expression analysis, gene set enrichment analysis (GSEA), and gene ontology (GO) analysis on bulk RNA-seq data from human placentas delivered at term and preterm during the warmer months compared to placentas delivered at term and preterm during the colder months in the UK. We detected 48 differentially expressed genes in preterm placentas delivered during the warmer months compared to preterm placentas delivered during the colder months, the majority of which were inflammatory cytokines and chemokines, including SERPINA1, IL1B, CCL3, CCL3L3, CCL4, CCL4L2, CCL20, and CXCL8. The GSEA positively enriched 17 signalling pathways, including the NF-κB, IL17, Toll-like receptor, and chemokine signalling pathways in preterm placentas delivered during warmer months. These results were not observed in the placentas delivered at term during the same times of the year. The GO analysis revealed several enhanced biological processes, including neutrophil, granulocyte, monocyte, and lymphocyte chemotaxis, as well as inflammatory and humoral immune responses in preterm placentas, but not in placentas delivered at term in the summer. We conclude that maternal exposure to warm environmental temperatures during pregnancy likely alters the placental transcriptomes towards inflammation and immune regulation, potentially leading to PTB.

As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.

Homozygous Pi∗Z mutation in alpha-1 antitrypsin (Pi∗ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only 1 organ, we systematically evaluated an international, multicenter, longitudinal, Pi∗ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints.

Cohort 1 recruited 737 Pi∗ZZ individuals from 25 different centers without known liver comorbidities who received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least 6 months. Cohort 2 consisted of 135 Pi∗ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least 2 years later, both including LSM.

During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. Forty-one Pi∗ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, that is, LSM (24 vs 5 kPa, P < .001) and aspartate aminotransferase-to-platelet ratio index (1.1 vs 0.3 units, P < .001). Liver-related endpoints within 5 years were most accurately predicted by LSM (area under the curve 0.95) followed by aspartate aminotransferase-to-platelet ratio index (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within 5 years (forced expiratory volume in the first second area under the curve 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors.

Noninvasive liver fibrosis surrogates accurately stratify liver-related risks in Pi∗ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi∗ZZ patients.

Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder most commonly due to a single G to A point mutation (E342K), leading to debilitating lung and/or liver disorders and is associated with increased mortality. The E342K point mutation causes a conformational change of the AAT protein resulting in its retention in liver hepatocytes. This reduces AAT secretion into the serum resulting in higher protease activities due to the lack of inhibition from AAT, causing damage to healthy lung tissue. The current standard of care for lung manifestations involves weekly IV augmentation therapy and is considered suboptimal for these patients. Furthermore, there is currently no approved treatment for liver manifestations. The unmet medical need for patients with AAT deficiency remains high, and new treatment options are needed to treat the underlying disease etiology.

Advances in genomic medicines may enable treatment by editing the DNA or RNA sequence to produce wild-type AAT instead of the mutated AAT caused by the E342K mutation. One approach can be achieved by directing endogenous adenosine deaminases that act on RNA to the E342K RNA site, where they catalyze adenosine to inosine conversion through a process known as RNA editing. The A-I RNA change will be read as a G during protein translation, resulting in an altered amino acid and restoration of wild-type AAT secretion and function.

In this review, we will discuss the pathophysiology of AAT deficiency and emerging treatment options with particular focus on RNA editing as a disease-modifying treatment for both liver and lung disease.

Alpha-1-antitrypsin (AAT), a circulating serine protease inhibitor, is an acute inflammatory response protein with anti-inflammatory functions. The C-terminal peptides of AAT are found in various tissues and have been proposed as putative bioactive peptides with multiple functions, but its mechanism of action remains unclear. We previously reported that a mouse AAT C-terminal peptide of 35 amino acids (mAAT-C1-35) penetrates plasma membrane and associates guanine nucleotide-binding protein subunit alpha 13 (Gα13). Here, we show that mAAT-C1-35 binds directly to the guanosine diphosphate (GDP)-bound form of Gα13 through the N-terminal region (mAAT-C1-17), thereby facilitating the interaction of Gα13・GDP with its effector proteins. The minimal sequence (mAAT-C3-16) and essential amino acid residue (Phe11) of mAAT-C1-17 were identified as being necessary for this effect. A molecular dynamics simulation for the Gα13・GDP-mAAT-C1-17 complex model showed that binding of mAAT-C1-17 to the region surrounded by switch regions of Gα13 stabilizes the flexible switch II and III regions, thereby maintaining their active conformation. In addition, mAAT-C1-35 activates the Gα13 signaling pathway in cells where Phe11 is required. Our study reveals the structure-based mechanism of action of AAT-C peptides in the regulation of Gα13 and demonstrates that AAT-C peptides represent a biological peptide capable of activating G protein signals in a manner that is independent of G-protein-coupled receptors.

For patients with alpha-1 antitrypsin (AAT) deficiency, AAT augmentation therapy can be an important part of care. However, for those who require a lung transplant (LT), there is currently only limited information to guide the use of AAT augmentation therapy post-LT.

We identified all LT recipients from 2011-2021 in the Scientific Registry of Transplant Recipients with an AAT deficiency diagnosis. We categorized recipients by use of AAT augmentation therapy post-LT and compared their baseline characteristics using Fisher's exact test and Wilcoxon rank-sum tests. We used Kaplan-Meier analyses and estimated the average treatment effect (ATE) of post-LT AAT augmentation therapy on mortality and all-cause graft failure (ACGF). The ATE measures the observed effect we would see if everyone in the population received the intervention as opposed to just a subset.

Among the 447 recipients with AAT deficiency, 109 used AAT augmentation therapy pre-LT, of which 32 (29.4%) continued post-LT. Recipients who used augmentation therapy post-LT were younger (56.5 [53-59.75] vs 57 [53.75-63], p = 0.04) and had shorter ischemia time (mean 311 vs 363 minutes, p = 0.03) than those who did not. The age-adjusted ATE estimate of post-LT augmentation therapy use on time to death and ACGF was +1.69 and +1.48 years, respectively. Post-LT augmentation therapy use was associated with a mortality reduction in the top quartile bilirubin subgroup (p = 0.02, log-rank test).

In our study, the use of augmentation therapy post-LT was associated with improved survival. Confirmatory prospective studies should be considered to inform post-LT AAT therapy guidelines.

The lack of in vivo accurate human liver models hinders the investigation of liver-related diseases, injuries, and drug-related toxicity, posing challenges for both basic research and clinical applications. Traditional cellular and animal models, while widely used, have significant limitations in replicating the liver's complex responses to various stressors. Liver organoids derived from human pluripotent stem cells, adult stem cells primary cells, or tissues can mimic diverse liver cell types, major physiological functions, and architectural features. Recent advancements in the field have shown that some liver organoids have sufficient accuracy to replicate specific aspects of the human liver's complexity. This review highlights recent progress in liver organoid research, with a particular emphasis on their potential for toxicity assessment and disease modeling. The intrinsic advantages of liver organoids include higher sensitivity and suitability for long-term studies, which enhance the predictive value in drug and nanomaterial toxicity testing. The integration of liver organoids with microfluidic devices enables the simulation of the liver microenvironment and facilitates high-throughput drug screening. The liver organoids also serve as ideal platforms for studying liver diseases such as hepatitis, liver fibrosis, viral liver diseases, and monogenic diseases. Additionally, this review discusses the advantages and limitations of liver organoids along with potential avenues for future research.

Despite the increasing body of evidence that mitochondrial activities implicate in chronic obstructive pulmonary disease (COPD), we are still far from a causal-logical and mechanistic understanding of the mitochondrial malfunctions in COPD pathogenesis.

Differential expression genes (DEGs) from six publicly available bulk human lung tissue transcriptomic datasets of COPD patients were intersected with the known mitochondria-related genes from MitoCarta3.0 to obtain mitochondria-related DEGs associated with COPD (MitoDEGs). The 32 hub MitoDEGs identified from protein-protein interaction (PPI) networks demonstrated superior overall diagnostic efficacy to non-hub MitoDEGs. Random forest (RF) analysis, least absolute shrinkage and selection operator (LASSO) regression, and Mendelian Randomization (MR) analysis of hub MitoDEGs further nominated NDUFS2, CAT, and MRPL2 as causal MitoDEGs for COPD, whose predominate expressions in pulmonary macrophages were revealed by an independent single-cell transcriptomic dataset of COPD human lungs. Finally, NDUFS2 was evaluated as the top-ranked contributor to COPD in the nomogram model and its downregulation in pulmonary macrophages could result in pro-inflammatory secretion, enhanced intercellular communications, whereas depressed phagocytosis of macrophages as revealed by gene set variation analysis (GSVA) and cell-cell interaction (CCI) analysis of single-cell transcriptomic dataset of COPD human lungs, which was later confirmed in COPD mouse model and macrophage cell lines.

Our study established the causal linkage between mitochondrial malfunctions and COPD, providing a potential therapeutic avenue to alleviate pulmonary inflammation accounting for COPD by targeting mitochondria-related genes. NDUFS2, a canonical component of mitochondrial electron respiratory chain, was highlighted instrumental for the susceptibility of risk-exposed individuals to COPD.

CRISPR-based gene editing technology theoretically allows for precise manipulation of any genetic target within living cells, achieving the desired sequence modifications. This revolutionary advancement has fundamentally transformed the field of biomedicine, offering immense clinical potential for treating and correcting genetic disorders. In the treatment of most genetic diseases, precise genome editing that avoids the generation of mixed editing byproducts is considered the ideal approach. This article reviews the current progress of base editors and prime editors, elaborating on specific examples of their applications in the therapeutic field, and highlights opportunities for improvement. Furthermore, we discuss the specific performance of these technologies in terms of safety and efficacy in clinical applications, and analyze the latest advancements and potential directions that could influence the future development of genome editing technologies. Our goal is to outline the clinical relevance of this rapidly evolving scientific field and preview a roadmap for successful DNA base editing therapies for the treatment of hereditary or idiopathic diseases.

Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer worldwide. More than 90% of cases occur in cirrhotic patients, with the degree of fibrosis being the main risk factor for the development of HCC. Liver biopsy is the gold-standard for fibrosis assessment, but it is an invasive procedure. Liver stiffness measurement (LSM) has shown high accuracy for diagnosing liver cirrhosis, as well as for predicting decompensation and HCC development. More recently, spleen stiffness measurement (SSM) has presented excellent results for ruling in/out high-risk varices and the presence of clinical significant portal hypertension. The aim of our study was to evaluate the relationship between LSM and SSM and the risk of hepatocellular carcinoma.

A prospective study on cirrhotic patients was performed in a tertiary center from January 2020 to May 2024. All patients were submitted to liver and spleen elastography (with a new probe of 100 Hz) by the same blinded operator and were treated in the same institution for the development of hepatocellular carcinoma.

We included 299 cirrhotic patients, 75.9% male, with a mean age of 61.8 years (±10.0). The median value of LSM was 25.7 kPa [4.5-75.0] and that of SSM was 44.6 kPa [7.9-100.0]. The median follow-up time was 505 days [114.0-1541.0]. During this period, 18 patients developed HCC, with a median time to HCC diagnosis after LSM and SSM of 321 days [63.0-1227.0]. LSM was the only factor associated with the development of HCC (p = 0.002) with an AUC of 0.715. On the other hand, SSM was not associated with the development of HCC.

We found that the risk of developing HCC is associated with liver fibrosis but not with portal hypertension (assessed using SSM).

Thyroid-associated ophthalmopathy (TAO) is one of the most complex autoimmune diseases in endocrinology areas. Autophagy-related genes may be involved in the pathophysiology of TAO. This study aims to reveal key genes associated with autophagy in the pathogenesis and the potential diagnostic markers for TAO.

We obtained autophagy-related differential genes (AR-DEGs) and their expression in TAO patients and controls. Gene ontology analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to perform the enrichment analysis of AR-DEGs. LASSO regression, support vector machine recursive feature elimination, and random forest were performed to screen for disease signature genes (DSGs), which were further validated in another independent validation dataset. We used the receiver operating characteristic for the evaluation of the diagnostic efficacy of DSGs and also established a nomogram. The relative proportion of immune infiltration was calculated using the CIBERSORT algorithm, and the relationship between the identified gene markers and the level of infiltrating immune cells was explored.

We identified 24 AR-DEGs, which were primarily enriched in cellular catabolic regulation, autophagosome membrane, and ubiquitin protein ligase binding in GO analysis, while KEGG analysis highlighted autophagy as the main enriched pathway. Six DSGs were identified by three algorithms. They were validated in another independent validation dataset. The combined six-gene model also showed good diagnostic efficacy (AUC = 0.948). We further plotted the nomogram with better diagnostic efficacy. Immuno-infiltration analysis and correlation analysis demonstrated that six DSGs were significantly correlated with the infiltrating immune cells.

We identified several biological processes and pathways for the enrichment of AR-DEGs. Six DSGs were identified, which showed great potential to become critical molecules in the diagnosis of TAO, and these DSGs showed a correlation with infiltrating immune cells.

α1-Antitrypsin deficiency is characterized by elevated elastase activity and excessive elastin degradation, which may impact cancer development and progression. We tested the hypothesis that individuals with α1-antitrypsin deficiency have increased susceptibility to cancer in the Danish population.

In a nationwide nested study, we identified 2702 individuals with α1-antitrypsin deficiency and 26,750 control subjects without α1-antitrypsin deficiency matched on age, sex, and municipality. We recorded admissions due to cancer as outcomes during a median follow-up of 62 years.

Individuals with α1-antitrypsin deficiency versus control subjects had an increased hazard of skin cancer (2.18, 95%CI: 1.81-2.63), leukemia (1.76, 1.12-2.79), liver cancer (3.91, 2.23-6.85), and cancer overall (1.25, 1.13-1.38). Corresponding hazard ratios when the entire Danish population was used as control group were 3.02 (2.55-3.58), 1.83 (1.19-2.81), 4.46 (2.74-7.28), and 1.45 (1.31-1.59). When the analysis was stratified according to comorbidities, the hazard for skin cancer was higher in those with chronic obstructive pulmonary disease (COPD) (3.59, 2.60-4.95) and skin disease (2.93, 2.19-3.92) but remained elevated in those without any of these diseases. Hazards for skin cancer in individuals with α1-antitrypsin deficiency were similar when stratified by liver cirrhosis and ischemic heart disease (ps for interaction: ≥0.76). Hazards for liver cancer in individuals with α1-antitrypsin deficiency versus control subjects were similar when stratified according to liver cirrhosis, COPD, skin disease, and ischemic heart disease (ps for interaction: ≥0.13).

Individuals with α1-antitrypsin deficiency have increased risks of skin cancer, leukemia, and liver cancer in the Danish population.

The course of adults with ZZ alpha-1-antitrypsin deficiency (AATD) liver disease is unpredictable. The utility of markers, including liver biopsy, is undefined.

A prospective cohort, including protocol liver biopsies, was enrolled to address these questions.

We enrolled 96 homozygous ZZ AATD adults prospectively at three US sites with standardized clinical evaluations, and protocol liver biopsies. Fibrosis was scored using Ishak (stages 0-6). Also, 51% of the 96 subjects had Ishak score >1 fibrosis (49% Ishak 0-1, 36% Ishak 2-3 and 15% ≥4). Elevated aspartate aminotransferase (AST) more than alanine aminotransferase (ALT), high body mass index (BMI), obesity, AST platelet ratio index and elevated serum Z alpha 1 antitrypsin (AAT) polymer levels were associated with increased fibrosis. Steatosis did not correlate to fibrosis. Increased fibrosis was associated with increased mutant Z polymer globular inclusions (p = .002) and increased diffuse cytoplasmic Z polymer on biopsy (p = .0029) in a direct relationship. Increased globule Z polymer was associated with increased serum AST (p = .007) and increased periportal inflammation on histopathology (p = .004), but there was no relationship of Z polymer hepatocellular accumulation with ALT, gamma glutamine transferase, inflammation in other parts of the lobule, necrosis or steatosis. Serum Z polymer levels were directly correlated to hepatic Z protein polymer content. Lung function, smoking and alcohol consumption patterns were not associated with fibrosis.

In AATD high BMI, obesity and elevated AST are associated with increased fibrosis. Liver biopsy features are correlated to some serum tests. Serum Z AAT polymer levels could be a future biomarker to detect fibrosis early and is directly correlated to liver Z content.

Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium.

Reported alcohol consumption was evaluated in two cohorts: (i) the community-based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non-carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate-deficient transferrin (CDT).

In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma-glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease.

Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption.

Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes.

CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody.

CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT.

These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Secondary pneumothorax due to early-onset emphysema can be a presenting feature of filamin A mutation. https://bit.ly/3ycAeCs.

Inflammation drives COPD pathogenesis and exacerbations. Although the conceptual framework and major players in the inflammatory milieu of COPD have been long established, the nuances of cellular interactions and the etiological differences that create heterogeneity in inflammatory profiles and treatment response continue to be revealed. This wealth of data and understanding is not only a boon to the researcher but also provides guidance to the clinician, moving the field closer to precision medicine. It is through this lens that this review seeks to describe the inflammatory processes at play in COPD, relating inflammation to pathological and functional changes, identifying patient-specific and disease-related factors that may influence clinical observations, and providing current insights on existing and emerging anti-inflammatory treatments and treatment targets, including biological therapies and phosphodiesterase (PDE) inhibitors.