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Nature Oct 2023The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we...
The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics.
Topics: Humans; ABO Blood-Group System; Biological Specimen Banks; Blood Proteins; COVID-19; Databases, Factual; Drug Discovery; Epistasis, Genetic; Fucosyltransferases; Genetic Predisposition to Disease; Genomics; Health; Plasma; Proprotein Convertase 9; Proteome; Proteomics; Public-Private Sector Partnerships; Quantitative Trait Loci; United Kingdom; Galactoside 2-alpha-L-fucosyltransferase
PubMed: 37794186
DOI: 10.1038/s41586-023-06592-6 -
JAMA Neurology Jun 2023Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not...
IMPORTANCE
Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown.
OBJECTIVE
To test the association between pathogenic somatic variants in the hippocampus and MTLE.
DESIGN, SETTING, AND PARTICIPANTS
This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022.
EXPOSURES
Drug-resistant MTLE.
MAIN OUTCOMES AND MEASURES
Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex.
RESULTS
Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism.
CONCLUSIONS AND RELEVANCE
Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.
Topics: Humans; Female; Adult; Middle Aged; Male; Epilepsy, Temporal Lobe; Mitogen-Activated Protein Kinases; Retrospective Studies; Hippocampus; Epilepsy; Drug Resistant Epilepsy; Neocortex
PubMed: 37126322
DOI: 10.1001/jamaneurol.2023.0473 -
BMC Medicine Jul 2023Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored...
BACKGROUND
Increasing evidence suggests an association between pro-inflammatory diets and cognitive function. However, only a few studies based on small sample sizes have explored the association between pro-inflammatory diets and dementia using the dietary inflammatory index (DII). Additionally, the relationship between DII and different subtypes of dementia, such as Alzheimer's dementia and vascular dementia, remains largely unexplored. Given the changes in brain structure already observed in patients with dementia, we also investigated the association between DII and magnetic resonance imaging (MRI) measures of brain structure to provide some hints to elucidate the potential mechanisms between pro-inflammatory diet and cognitive decline.
METHODS
A total of 166,377 UK Biobank participants without dementia at baseline were analyzed. DII calculations were based on the information collected by the 24-h recall questionnaire. Brain structural anatomy and tissue-specific volumes were measured using brain MRI. Cox proportional hazards models, competing risk models, and restricted cubic spline were applied to assess the longitudinal associations. The generalized linear model was used to assess the association between DII and MRI measurements.
RESULTS
During a median follow-up time of 9.46 years, a total of 1372 participants developed dementia. The incidence of all-cause dementia increased by 4.6% for each additional unit of DII [hazard ratio (HR): 1.046]. Besides, DII displayed a "J-shaped" non-linear association with Alzheimer's dementia (P = 0.003). When DII was above 1.30, an increase in DII was significantly associated with an increased risk of Alzheimer's dementia (HR: 1.391, 95%CI: 1.085-1.784, P = 0.009). For brain MRI, the total volume of white matter hyperintensities increased with an increase in DII, whereas the volume of gray matter in the hippocampus decreased.
CONCLUSIONS
In this cohort study, higher DII was associated with a higher risk of all-cause dementia and Alzheimer's dementia. However, our findings suggested that the association with DII and vascular and frontotemporal dementia was not significant.
Topics: Humans; Prospective Studies; Alzheimer Disease; Cohort Studies; Biological Specimen Banks; Diet; United Kingdom
PubMed: 37480061
DOI: 10.1186/s12916-023-02940-5 -
Nature Aging Sep 2023Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks....
Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
Topics: Humans; Mice; Animals; DNA Methylation; Epigenesis, Genetic; Aging; Longevity; Mammals
PubMed: 37563227
DOI: 10.1038/s43587-023-00462-6 -
Alzheimer's & Dementia : the Journal of... Mar 2024Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type...
Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type dementia by early midlife. Despite ongoing clinical trials to treat late-onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not available. Of the genetic causes of AD, people with DS represent the largest cohort. Currently, there is a knowledge gap regarding the underlying neurobiological mechanisms of DS-related AD (DS-AD), partly due to limited access to well-characterized brain tissue and biomaterials for research. To address this challenge, we created an international consortium of brain banks focused on collecting and disseminating brain tissue from persons with DS throughout their lifespan, named the Down Syndrome Biobank Consortium (DSBC) consisting of 11 biobanking sites located in Europe, India, and the USA. This perspective describes the DSBC harmonized protocols and tissue dissemination goals.
Topics: Humans; Down Syndrome; Biological Specimen Banks; Alzheimer Disease; Brain; Europe
PubMed: 38270275
DOI: 10.1002/alz.13692 -
Human Reproduction (Oxford, England) Dec 2023Endometriosis is defined by the presence of extrauterine endometrial-like tissue, which can cause pain and infertility in 10% of reproductive-age women. To date, the... (Review)
Review
Endometriosis is defined by the presence of extrauterine endometrial-like tissue, which can cause pain and infertility in 10% of reproductive-age women. To date, the pathogenesis is poorly understood resulting in significant diagnostic delays and poor therapeutic outcomes in many women. Small extracellular vesicles (sEVs) (<200 nm) are cell-derived vesicles containing molecules that can influence gene expression and behaviour in target cells. One such cargo are microRNAs (miRNAs), which are short, non-coding RNAs mostly 19-25 nucleotides in length that regulate post-transcriptional gene expression. This mini-review focuses on the role of sEV-miRNAs, which are conceivably better biomarkers for endometriosis than free miRNAs, which reflect the true pathophysiological state in the body, as sEV-encapsulated miRNAs are protected from degradation compared to free miRNA and provide direct cell-to-cell communication via sEV surface proteins. sEV-miRNAs have been implicated in the immunomodulation of macrophages, the proliferation, migration and invasion of endometrial cells, and angiogenesis, all hallmarks of endometriosis. The diagnostic potential of sEV-miRNA was investigated in one study that reported the sensitivity and specificity of two sEV-miRNAs (hsa-miR-22-3p and hsa-miR-320a-3p) in distinguishing endometriosis from non-endometriosis cases. Only three studies have explored the therapeutic potential of sEV-miRNAs in vivo in mice-two looked into the role of sEV-hsa-miR-214-3p in decreasing fibrosis, and one investigated sEV-hsa-miR-30c-5p in suppressing the invasive and migratory potential of endometriotic lesions. While early results are encouraging, studies need to further address the potential influence of factors such as the menstrual cycle as well as the location and extent of endometriotic lesions on miRNA expression in sEVs. Given these findings, and extrapolating from other conditions such as cancer, diabetes, and pre-eclampsia, sEV-miRNAs could present an attractive and urgently needed future diagnostic and therapeutic target for millions of women suffering from endometriosis. However, research in this area is hampered by lack of adherence to the International Society for Extracellular Vesicles 2018 guideline in separating and characterising sEVs, as well as the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project protocols.
Topics: Humans; Female; Animals; Mice; Endometriosis; Biological Specimen Banks; MicroRNAs; Extracellular Vesicles; Biomarkers
PubMed: 37877421
DOI: 10.1093/humrep/dead216 -
Indian Journal of Ophthalmology Sep 2023Corneal blindness (CB) is one of the leading causes of blindness in India and globally, affecting around 8 million population worldwide. Many of these corneal blind... (Review)
Review
Corneal blindness (CB) is one of the leading causes of blindness in India and globally, affecting around 8 million population worldwide. Many of these corneal blind patients may be visually rehabilitated by corneal transplantation (CT). Eye banking plays a crucial role in facilitating CT and ocular research. Many countries have adopted regulatory frameworks, quality assurance programs, and technological advancements to enhance the efficacy and safety of CT. Various infrastructural and organizational frameworks of eye banks (EBs) in India, according to the Eye Bank Association of India (EBAI), aid in establishing guidelines and standards for EB practices. Initiatives such as the National Programme for Control of Blindness (NPCB) have significantly contributed to eye donation rates and improved access to donor corneas. This review article discusses the established eye banking networks in countries such as India, the United States (USA), and Europe, where dedicated EB organizations work collaboratively to ensure efficient procurement, processing, and distribution of corneal tissue. It also highlights specific strategies employed in India and global countries to address EBs' challenges. These challenges include the shortage of donor corneas, improving donor screening and tissue processing techniques, ensuring timely distribution of corneal tissue, and maintaining high-quality standards. Interestingly, the comparative analysis between India and other developed countries highlights the similarities and differences in eye banking strategies. By understanding the strategies employed by different regions, EBs can learn from each other's experiences and work toward achieving optimal outcomes in CT and ocular research worldwide. It underscores the importance of knowledge sharing and collaborative efforts in addressing common challenges and implementing best practices in eye banking.
Topics: Humans; Blindness; Cornea; Corneal Transplantation; Eye Banks; Visually Impaired Persons; Tissue and Organ Procurement
PubMed: 37602600
DOI: 10.4103/IJO.IJO_1942_23 -
The Lancet. Oncology Nov 2023Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected... (Review)
Review
Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.
Topics: Humans; Brain Neoplasms; Prospective Studies; Biological Specimen Banks; Neoplasm Recurrence, Local; Glioma
PubMed: 37922934
DOI: 10.1016/S1470-2045(23)00453-9 -
Blood Transfusion = Trasfusione Del... Nov 2023Most public cord blood (CB) banks currently discard more than 80% of umbilical CB units not suitable for hemopoietic stem cell transplant due to low stem cell count....
BACKGROUND
Most public cord blood (CB) banks currently discard more than 80% of umbilical CB units not suitable for hemopoietic stem cell transplant due to low stem cell count. Although CB platelets, plasma, and red blood cells have been used for experimental allogeneic applications in wound healing, corneal ulcer treatment, and neonatal transfusion, no standard procedures for their preparation have been defined internationally.
MATERIALS AND METHODS
A network of 12 public CB banks in Spain, Italy, Greece, the UK, and Singapore developed a protocol to validate a procedure for the routine production of CB platelet concentrate (CB-PC), CB platelet-poor plasma (CB-PPP), and CB leukoreduced red blood cells (CB-LR-RBC) using locally available equipment and the commercial BioNest ABC and EF medical devices. CB units with >50 mL volume (excluding anticoagulant) and ≥150×10/L platelets were double centrifuged to obtain CB-PC, CB-PPP, and CB-RBC. The CB-RBC were diluted with saline-adenine-glucose-mannitol (SAGM), leukoreduced by filtration, stored at 2-6°C, and tested for hemolysis and potassium (K+) release over 15 days, with gamma irradiation performed on day 14. A set of acceptance criteria was pre-defined. This was for CB-PC: volume ≥5 mL and platelet count 800-1,200×10/L; for CB-PPP: platelet count <50×10/L; and for CB-LR-RBC: volume ≥20 mL, hematocrit 55-65%, residual leukocytes <0.2×10/unit, and hemolysis ≤0.8%.
RESULTS
Eight CB banks completed the validation exercise. Compliance with acceptance criteria was 99% for minimum volume and 86.1% for platelet count in CB-PC, and 90% for platelet count in CB-PPP. Compliance in CB-LR-RBC was 85.7% for minimum volume, 98.9% for residual leukocytes, and 90% for hematocrit. Compliance for hemolysis ≤0.8% decreased from 89.0 to 63.2% from day 0 to 15. K+ release increased from 3.0±1.8 to 25.0±7.0 mmol/L from day 0 to 15, respectively.
DISCUSSION
The MultiCord12 protocol was a useful tool to develop preliminary standardization of CB-PC, CB-PPP, and CB-LR-RBC.
Topics: Infant, Newborn; Humans; Hemolysis; Blood Banking; Erythrocytes; Blood Banks; Blood Platelets
PubMed: 37146297
DOI: 10.2450/BloodTransfus.492