EBioMedicine最新文献

Background: Pulmonary fibrosis is a challenging clinical problem with lung pathology featuring immune cell infiltrates, fibroblast expansion, and matrix deposition. Molecular analysis of diseased lungs and preclinical models have uncovered C-C chemokine receptor type 2 (CCR2)+ monocyte egress from the bone marrow into the lung, where they acquire profibrotic activities. Current drug treatment is focused on fibroblast activity. Alternatively, therapeutic targeting and monitoring CCR2+ cells may be an effective patient management strategy.

Methods: Inhibition of CCR2+ cells and, as a benchmark, the clinical antifibrotic agent, nintedanib, were used in mouse lung fibrosis models. Lungs were evaluated directly for CCR2+ cell infiltration and by non-invasive CCR2+ positron emission tomography imaging (CCR2-PET).

Findings: Lung CCR2+ cells were significantly elevated in the bleomycin model as determined by tissue evaluation and CCR2-PET imaging. A protective treatment protocol with an oral CCR2 inhibitor was compared to oral nintedanib. While we expected disparate effects on CCR2+ cells, each drug similarly decreased lung CCR2+ cells and fibrosis. Chemotaxis assays showed nintedanib indirectly inhibited C-C motif chemokine 2 (CCL2)-mediated migration of CCR2+ cells. Even delayed therapeutic administration of nintedanib in bleomycin and the silicosis progressive fibrosis models decreased the accumulation of CCR2+ lung cells. In these treatments early CCR2-PET imaging predicted the later development of fibrosis.

Interpretation: The inhibition of CCR2+ cell egress is likely a critical controller for stabilising lung fibrosis, as provided by nintedanib. Imaging with CCR2-PET may be useful to monitor nintedanib treatment responses, guide decision-making in the treatment of patients with progressive pulmonary fibrosis, and as a biomarker for drug development.

Funding: National Institutes of Health (NIH), R01HL131908 (SLB), R35HL145212 (YL), P41EB025815 (YL), K01DK133670 (DHK); Barnes Jewish Hospital Foundation (SLB).

Background: Despite successes in multiple sclerosis (MS) drug development, the effectiveness of animal studies in predicting successful bench-to-bedside translation is uncertain. Our goal was to identify predictors of successful animal-to-human translation for MS by systematically comparing animal studies of approved disease-modifying therapies (DMTs) with those that failed in clinical trials due to efficacy or safety concerns.

Methods: Systematic review of animal studies testing MS DMTs, identified from searches in PubMed and EMBASE. A random effect meta-analysis was fitted to the data to compare outcome effect sizes for approved versus failed DMTs. Effect sizes and testing under diverse experimental conditions were assessed as potential predictors for successful translation.

Findings: We included 497 animal studies, covering 15 approved and 11 failed DMTs, tested in approximately 30'000 animals. DMTs were tested in a small repertoire of experimental parameters: about 86% of studies used experimental autoimmune encephalomyelitis (EAE), 80% used mice, and 76% used female animals. There was no association between animal study outcomes or testing DMTs under varied conditions (e.g., different laboratories or models) and successful approval. Surprisingly, 91% of animal studies were published after first-in-MS trial and 91% after official regulatory approval.

Interpretation: Our findings emphasize the complexity in carrying drugs from animals to clinical practice. Specific challenges include limited experimental methods in animal research and a disconnect between preclinical and clinical research. We advocate for efforts to streamline drug development for MS to improve animal research's relevance for patients.

Funding: NIH, Swiss National Science Foundation, Universities Federation for Animal Welfare.

Background: The liver is a key metabolic organ, acting as a hub to metabolically connect various tissues. Spinal muscular atrophy (SMA) is a neuromuscular disorder whereby patients have an increased susceptibility to developing dyslipidaemia and liver steatosis. It remains unknown whether fatty liver is due to an intrinsic or extrinsic impact of survival motor neuron (SMN) protein depletion.

Methods: Using an adeno-associated viral vector with a liver specific promoter (albumin), we restored SMN protein levels in the liver alone in Smn^2B/- mice, a model of SMA. Experiments assessed central and peripheral impacts using immunoblot, immunohistochemistry, and electron microscopy techniques.

Findings: We demonstrate that AAV9-albumin-SMN successfully expresses SMN protein in the liver with no detectable expression in the spinal cord or muscle in Smn^2B/- mice. Liver intrinsic rescue of SMN protein was sufficient to increase survival of Smn^2B/- mice. Fatty liver was ameliorated while key markers of liver function were also restored to normal levels. Certain peripheral pathologies were rescued including muscle size and pancreatic cell imbalance. Only a partial CNS recovery was seen using a liver therapeutic strategy alone.

Interpretation: The fatty liver phenotype is a direct impact of liver intrinsic SMN protein loss. Correction of SMN protein levels in liver is enough to restore some aspects of disease in SMA. We conclude that the liver is an important contributor to whole-body pathology in Smn^2B/- mice.

Funding: This work was funded by Muscular Dystrophy Association (USA) [grant number 963652 to R.K.]; the Canadian Institutes of Health Research [grant number PJT-186300 to R.K.].

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups.

Findings: We examined two high-risk omics-defined groups in non-overlapping test sets (n = 1133 NHW COPDGene, n = 299 African American (AA) COPDGene, n = 468 ECLIPSE). We defined "high activity" (low PRS, high TRS) and "severe risk" (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. "High activity" but not "severe risk" participants had greater prospective FEV₁ decline (COPDGene: -51 mL/year; ECLIPSE: -40 mL/year) and proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors.

Interpretation: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.

Funding: National Institutes of Health.

Background: To date, global priorities for new vaccine R&D have not been systematically identified for endemic pathogens. As part of Immunisation Agenda 2030 (IA2030), we have systematically identified priority endemic pathogens for new vaccine R&D based on country and regional stakeholder values to address this need.

Methods: MCDA surveys targeting policy makers and immunisation stakeholders in each World Health Organization (WHO) region were used to weight eight criteria for prioritisation. Applying those weights to regional pathogen data yielded regional top ten pathogen lists, which are intended to inform regional deliberations on R&D priorities. The regional top ten lists were combined into an IA2030 global priority list. To inform R&D, use cases for new vaccines and monoclonal antibodies were identified, then categorized in terms of the activities needed to accelerate progress.

Findings: In five out of six WHO regions, Annual deaths in children under five and Contribution to antimicrobial resistance were the most heavily weighted criteria. How participants weighted the criteria was not associated with their region, biographical characteristics, or areas of expertise. Five pathogens were common priorities across all regions: M tuberculosis, HIV-1, K pneumoniae, S aureus, and Extra-intestinal pathogenic E coli. Six pathogens were priorities in single regions. Combining regional top ten lists provided a global list of 17 priority pathogens for new vaccine R&D. Thirty-four distinct use cases were identified for new products targeting these pathogens. While most are in the "Advance product development" category, ten are in the "Research" category and seven are in the "Prepare to implement" category.

Interpretation: These priorities for new vaccine R&D will help stakeholders better respond to regional and country needs. The use cases will inform R&D and enable monitoring of R&D under IA2030.

Funding: The work was funded by a Bill and Melinda Gates Foundation grant to WHO (INV-005318).

Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ₄₀, Aβ₄₂, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ₄₀, Aβ₄₂, tau, ptau181, and NfL) and amyloid and tau PET data.

Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ₄₀ and Aβ₄₂ concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia.

Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted.

Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873).

Background: Cancer cell plasticity is the ability of neoplastic cells to alter their identity and acquire new biological properties under microenvironmental pressures. In prostate cancer (PCa), lineage plasticity often results in therapy resistance and trans-differentiation to neuroendocrine (NE) lineage. However, identifying the cancer cells harboring lineage plasticity-related status remains challenging.

Methods: Based on 13 multi-center human PCa bulk transcriptomic cohorts (samples = 3314) and 9 bulk transcriptomic datasets derived from PCa experimental models, we established an integrated lineage plasticity-related gene signature, termed LPSig. Leveraging this gene signature, AUCell enrichment analysis was applied to identify the cell population with high lineage plasticity from a comprehensive single-cell RNA-sequencing (scRNA-seq) meta-atlas assembled by us, which consisted of 10 public human PCa scRNA-seq datasets (samples = 93, cells = 222,529). Moreover, additional scRNA-seq dataset of human PCa, multiplex immunohistochemistry staining for human PCa tissues, in vitro and in vivo functional experiments, as well as qPCR and Western blot analyses were employed to validate our findings.

Findings: We found that LPSig could finely capture the dynamics of tumor lineage plasticity throughout the progression of PCa, accurately estimating the status of lineage plasticity. Based on LPSig, we identified a previously undefined minority population of lineage plasticity-related PCa cells (LPCs) from the human PCa scRNA-seq meta-atlas assembled by this study. Furthermore, in-depth dissection revealed pivotal roles of LPCs in trans-differentiation, tumor recurrence, and poor patient survival during PCa progression. Furthermore, we identified HMMR as a representative cell surface marker for LPCs, which was validated using additional scRNA-seq datasets and multiplexed immunohistochemistry. Moreover, HMMR was transcriptionally inhibited by androgen receptor (AR), and was required for the aggressive adenocarcinoma features and NE phenotype.

Interpretation: Our study uncovers a novel population of lineage plasticity-related cells with low AR activity, stemness-like traits, and elevated HMMR expression, that may facilitate poor prognosis in PCa.

Funding: This work was supported by National Key R&D Program of China (2022YFA0807000), National Natural Science Foundation of China (82160584), Advanced Prostate Cancer Diagnosis and Treatment Technology Innovation Team of Kunming Medical University (CXTD202216), and Reserve Talents of Young and Middle-aged Academic Leaders in Yunnan Province (202105AC160013).

Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.

Background: Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms.

Methods: We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m².

Findings: Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV.

Interpretation: Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories.

Funding: The 2000HIV study is funded by ViiV Healthcare.