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Lijing Wang,1 Hongjun Zhao,2,* Indu Raman,3 Mei Yan,3 Qiong Chen,1 Quan-Zhen Li3,* 1Departments of Geriatrics, Respiratory Medicine, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 2Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China; 3Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA*These authors contributed equally to this workCorrespondence: Quan-Zhen Li, Department of Immunology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, 75390, USA, Tel +1 214-645-6071, Fax +1 214-645-6074, Email quan.li@utsouthwestern.eduIntroduction: The mechanisms underlying chronic obstructive pulmonary disease (COPD) remain unclear. Genetic and genomic changes may play a significant role in the pathogenesis of COPD. Identification of differentially expressed genes and miRNAs and their regulatory mechanisms at the whole-genome level will provide a comprehensive understanding of the development of COPD.Methods: Peripheral blood mononuclear cells (PBMCs) from 12 patients with COPD and 12 normal controls were examined at the miRNA and mRNA expression levels using Affymetrix GeneChip. Microarray data were analyzed with Affymetrix Transcriptome Analysis Console 2.0 and GeneSpring software. Gene interaction pathways of the differentially expressed genes and miRNA-mRNA regulation were analyzed using the Ingenuity Pathway Analysis software. Four differentially expressed genes and one miRNA were further confirmed using RT-qPCR.Results: One hundred and thirty-three upregulated and 973 downregulated genes were identified in PBMCs of patients with COPD. Pathway analysis on the differentially expressed genes in COPD revealed significant enrichment in IL-8 signaling and iCOS-iCOSL signaling in T helper cells. Seventy-seven upregulated miRNAs and 43 downregulated miRNAs were differentially expressed between PBMCs from patients with COPD and normal controls. Among these 120 differentially expressed miRNAs, 42 miRNAs targeting 28 upregulated genes and 69 miRNAs targeting 498 downregulated genes were identified. The expression of CXCR1, HBEGF, TREM-1, and hsa-miR-148a-3p was more elevated in patients with COPD than in normal controls, whereas NFAT5 was decreased.Conclusion: miRNAs and mRNAs are differentially expressed in PBMCs of patients with COPD, compared with normal controls. miRNAs regulate the expression of mRNAs, and thus play a role in the pathogenesis of COPD. Investigating these relationships may provide further insight into the mechanisms of COPD.Keywords: COPD, whole-genome transcription, gene, miRNA, peripheral blood mononuclear cells

Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

Background and Aims: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis., Methods: Molecular (Prognostic Liver Secretome signature with alpha-fetoprotein) and clinical (aMAP score) variable-based scores were integrated to develop PAaM, which was subsequently validated in two phase 3 biomarker validation studies: the statewide Texas HCC Consortium (THCCC) and nationwide HCC Early Detection Strategy (HEDS) prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation (PRoBE) design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events., Results: Of 2,156 cirrhosis patients in THCCC, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared to low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios (sHRs) for incident HCC of 7.51 (95% confidence interval [CI], 4.42-12.8) and 4.20 (95%CI, 2.52-7.01), respectively. Of 1,328 cirrhosis patients in HEDS, PAaM identified 201 (15%) high-risk, 540 (41%) intermediate-risk, and 587 (44%) low-risk patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate risk groups were associated with sHRs for incident HCC of 6.54 (95%CI, 3.85-11.1) and 1.77 (95%CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cured hepatitis C infection., Conclusion: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Sjögren's Disease (SjD) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands (LG). The LG produces the protein-rich aqueous component of tears, and SjD-associated autoimmune dacryoadenitis (AD) may thus alter tear autoantibody composition., Methods: The presence of tertiary lymphoid structures (TLS) in LG from two murine models of SjD-associated AD, male NOD and male NOR mice, were evaluated using immunofluorescence. IgG and IgA reactivity in serum and tears from these models were probed in three studies against a panel of 80-120 autoantigens using autoantibody microarrays relative to serum and tears from healthy male BALB/c mice. Data were analyzed by R package Limma., Results: Analysis of immunofluorescence in LG sections from both SjD models showed TLS. Only one autoantibody was significantly elevated in tears and serum in both SjD models across all studies. Three autoantibodies were significantly elevated in serum but not in tears in both SjD models across all studies. Conversely, six IgG and thirteen IgA autoantibodies (6 sharing the same autoantigen) were significantly elevated in tears but not serum in both SjD models., Conclusion: NOD and NOR mice with SjD-associated AD have distinct autoantibody profiles in tears and serum. Tear IgA isotype autoantibodies showed a greater diversity than tear IgG autoantibodies. TLS observed in LG are a likely source of the tear autoantibodies.

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.

The current study set out to examine the influence of AoA on word recall and recognition tasks in 30 Alzheimer's patients and 28 healthy ageing control group. Each participant was presented with 20 words that critically varied on AoA. A subtest of WAIS-R was employed to establish the vocabulary capacity of participants together with the Mini-Mental State Examination. The pattern of results showed that healthy ageing adults outperformed Alzheimer's patients in recall and recognition tasks and that overall early acquired words had an advantage over late acquired words. The results have implications for developing assessment tools and are discussed within the current theories of age of acquisition and the impact of the neurodegenerative loss of memory in Alzheimer's disease on lexicosemantic processing.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1 + dendritic cells and dysfunctional CD8 + T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

Cirrhosis is the terminal stage of progressive liver fibrosis, affecting 1%-2% of the global population and accounting for 1.3 million deaths annually. 1 , 2 Median survival for persons with compensated cirrhosis is approximately 12 years, compared with only 2 years for those with hepatic decompensation. Accurate prediction of hepatic decompensation is an unmet need to enable identification of patients with cirrhosis who could benefit from close monitoring and timely medical interventions. Besides, risk stratification of patients with cirrhosis could help inform patient selection for trials evaluating therapies to prevent hepatic decompensation. Although various clinical scores, such as the albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4) indices (ALBI-FIB4 score) have been proposed to predict long-term risk of hepatic decompensation, 3 external validation has often shown suboptimal prognostic capability and revealed room for improvement. 4 ., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression., Methods: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122)., Results: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients., Conclusion: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability., Methods: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients., Results: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices., Conclusions: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Polycythemia vera is a Philadelphia negative myeloproliferative neoplasm characterized by erythrocytosis in which the major cause of morbidity and mortality is thrombosis. Aspirin and hematocrit reduction by venesection or cytoreductive therapy are at the cornerstone of management. First line cytoreductive therapy in high-risk patients is hydroxyurea; however, its use is associated with toxicities and resistance in a significant proportion of patients. In a disease with a long overall survival with appropriate treatment, it is imperative that other treatment options do not accelerate the risk of progression to acute leukemia. The following review will appraise the evidence of interferon, ruxolitinib, and other agents in management of hydroxyurea resistant or intolerant polycythemia vera.

Background: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need., Methods: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection., Findings: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively)., Conclusions: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening., Competing Interests: DECLARATION OF INTERESTS Y.H. serves as an advisory board member for Helio Health and founding shareholder for Alentis Therapeutics, and received a research funding from Morphic Therapeutics. T.F.B. serves as advisor and is a founding shareholder or Alentis Therapeutics. R.T received a lecture fee from Bayer, Chugai, Eisai, Takeda and Wako/Fujifilm. N.P. has served as a consultant for Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome. A.G.S. has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest.

Drug-induced liver injury (DILI) sometimes presents with an autoimmune hepatitis-like phenotype (AI-DILI), and it is challenging to distinguish it from de novo autoimmune hepatitis (AIH). We conducted a study to identify autoantibodies unique to AI-DILI by profiling serum autoantibodies. Autoantibodies were quantified using an autoantigen array containing 94 autoantigens from four groups: AI-DILI (n = 65), DILI controls (n = 67), de novo AIH (n = 17), and healthy controls (HCs; n = 30). In 37 patients with AI-DILI, samples were also collected 6 months after presentation. AI-DILI and de novo AIH had similar anti-neutrophil antibody and anti-smooth muscle antibody prevalence. Compared to HCs, de novo AIH had an increase in many immunoglobulin G (IgG; 35 [46.1%]) and IgM (51 [70%]) autoantibodies, whereas AI-DILI had an increase of IgM (40 [54.8%]) but not IgG autoantibodies. DILI controls had a similar IgG and IgM profile compared to HCs. Comparing de novo AIH to AI-DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in de novo AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI-DILI and de novo AIH were common; however, AI-DILI induced by different drugs showed different frequencies of IgM autoantibodies, with nitrofurantoin-related AI-DILI showing a higher number of increased IgM autoantibodies. AI-DILI autoantibody levels at diagnosis and at 6 months showed a significant decline in 37 IgM autoantibodies. A model with highly correlated IgG and IgM was fitted into multivariate logistic regression and revealed an area under the curve of 0.87 (95% confidence interval, 0.79-0.95) to distinguish de novo AIH from AI-DILI. Conclusion: The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI-DILI from de novo AIH., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)