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• Investigation of respiratory chain integrity in skeletal muscle in Parkinson's disease

  The aim of this study is to investigate mitochondrial dysfunction in skeletal muscle as a potential biomarker for identifying a distinct subtype of Parkinson’s disease (PD) characterized by mitochondrial complex I (CI) deficiency (CI-PD). Based on previous post-mortem findings, the study hypothesizes that widespread CI deficiency is present in a subset of PD patients and could be detectable in clinically accessible muscle samples. By analyzing mitochondrial function in muscle biopsies from individuals with PD and healthy controls, the study seeks to explore the extent of mitochondrial dysfunction in PD and identify a stratification marker for future diagnostic and therapeutic interventions. This study is part of the STRAT-PARK initiative, a longitudinal cohort study that aims to stratify neurodegenerative parkinsonisms into biological subtypes using a biomarker-based approach (https://doi.org/10.1016/j.pneurobio.2024.102603).

  Study EGAS50000000671

• Single-cell and spatial transcriptomic profiling of hormone-naïve localised prostate cancer

  Localised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naïve localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease.

  Study EGAS00001008332

• Mutational signatures in normal tissues of patients treated with clinical stage G-quadruplex binder CX5461

  Drug induced photoreactions following exposure to UVA have been documented for several therapeutic compound classes, including psoralens and fluoroquinolones. CX5461, a quinolone-derived small molecule currently in phase 1 studies for cancer treatment, has been shown to be a clinically significant UV photosensitizer. Here we examined the mutagenic spectrum of CX5461 in normal tissues of patients undergoing treatment, by comparing deep whole genome sequencing (WGS) from skin biopsies taken from non-sun exposed areas pre and post drug exposure of patients in the Canadian Cancer Clinical Trials Group (CCTG) IND.231 trial (NCT02719977). We show that a low burden of SNVs (<100) and indels (<40) mutations was detected in post CX5461 skin biopsies, with a pattern resembling background or sequencing artefact signatures. To further characterize the mutational pattern of CX5461 photoreactivity, we compared mutational profiles of human retinal pigment epithelial cells exposed to UVA, CX5461, or a combination of both UV and CX5461. Treatment with CX5461 or UVA alone, resulted in a low SNV burden. In contrast, human cells exposed to UVA and CX5461 had a two to four orders higher mutational burden, with a distinct mutational pattern characterized by T>A, T>C mutations, dissimilar to that of UV alone or CX5461 alone. Our results suggest that human exposure to CX5461 alone is not associated with high levels of single base mutagenesis. However, CX5461 is a very potent UV photosensitizer, underscoring the need for adequate UV screening and controls when studying the effects of photosensitizing small molecules on single base DNA variation.

  Study EGAS50000001145

• Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids

  Lissencephaly is a developmental cortical malformation characterized by reduced to absent gyri and a disorganized cortex, often leading to severe impairments in affected individuals and a reduced life expectancy. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule motor dynein, cause lissencephaly with different clinical severities. While the clinical disease spectrum correlates with the degree of lissencephaly, location and type of mutation may not. We leveraged forebrain-type organoids from LIS1-lissencephaly patients, diagnosed with mild, moderate or severe lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, how the severity degree in patients might relate to specific mutations in the LIS1 gene. We questioned which processes during cortical development might be differentially affected by severity grade, and whether they could be pharmacologically targeted. We found alterations in neurodevelopment often with a severity-dependent gradient. Specifically, we identified alterations of the cytoarchitecture, progenitor cell homeostasis and neurogenesis. Particularly important disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient, or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids, and an in silico approach with therapeutic potential. Thus, we show that different LIS1-severity grades can be recapitulated in vitro, that there is a direct link between the phenotype and genotype, that organoid-based disease modeling can identify molecular underpinnings of malformations of cortical development and that organoids provide a valid platform to develop and test therapeutic strategies.

  Study EGAS00001008227

• Nicotine Addiction Genetics and Correlates

  Ascertainment: Families were ascertained through panels of adult Australian twins, and a sample of spouses of Australian twins. Families with at least one offspring who was identified as a current or former smoker in an earlier survey. Screening telephone interviews were conducted with index cases to provide confirmation of a history of heavy cigarette smoking, to obtain confirmation of a history of heavy cigarette smoking, and to obtain additional information on the history of cigarette use and the survival status of other family members, and their full siblings and parents. Index cases were the affected spouse of a twin, or the affected twin from pairs discordant for a history of heavy smoking, or a randomly chosen twin from pairs where both have a history of regular smoking (i.e., has smoked at least 100 cigarettes lifetime), and at least one live biological parent to identify sibships with at least one affected sib pair (ASP) concordant for heavy smoking, and at least one living parent. If permission was granted by the index case, eligible family members were contacted and invited to provide a blood sample and to complete a telephone diagnostic interview. In families with just one available biological parent, and additional unaffected sibling who had never smoked on a regular basis (i.e., has smoked fewer than 100 cigarette lifetime, but has experimented with cigarettes once or twice) was included (when available) to help compensate for the loss of information due to missing parental phenotypes. (Target N=400 Australian families with approximately 600 ASPs; and 600 TDT trios comprised of a nicotine dependent index case and both biological parents). Diagnostic Assessment: The telephone diagnostic interview assessed DSM-IV and modified DSM-IIIR diagnoses (i.e., without time clustering) for nicotine dependence, alcohol and other drug dependence and abuse, major depression, and childhood conduct disorder. Most diagnostic assessments were based on the SSAGA/SSAGA-II, developed for the multi-site gene-mapping alcoholism study (the Collaborative Study on the Genetics of Alcohol. An exception was the tobacco section, which was developed directly from the CIDI and DIS (as the original SSAGA did not include a diagnostic section on nicotine dependence). In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001299

• A Comprehensive Platform for Analyzing Longitudinal Multi-Omics Data

  PALMO (Platform for Analyzing Longitudinal Multi-omics data) is a platform for analyzing longitudinal data from bulk as well as single cell. It allows to identify inter-, intra-donor variations in genes over longitudinal time points. The analysis can be done on bulk expression dataset without known cell type information or single cell with cell type or user defined groups. It allows to infer stable and variable features in a given donor and each cell type or a user defined group. The outlier analysis can be performed to identify technical/biological perturbed samples in a donor or a participant. Further, differential analysis can be performed to decipher time-wise changes in gene expression in a cell type. The data that is available in the dbGaP is the demo longitudinal samples used in the study, which includes hashed raw fastq files for single-cell RNA-sequencing (scRNA-seq) and non-hashed fastq files for single-cell ATAC-sequencing (scATAC) experiment.

  Study phs003203

• Genomic analysis of a hypermutated gliosarcoma

  Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology. Metastasis is not uncommon but involvement of the spinal cord is rare, and comprehensive genetic characterization of spinal gliosarcoma is lacking. We describe a patient initially diagnosed with a low-grade brain glioma via biopsy, followed by adjuvant radiation and temozolomide treatment. Nearly two years after diagnosis, she developed neurological deficits from an intradural, extramedullary tumor anterior to the spinal cord at T4, which was resected and diagnosed as gliosarcoma. Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C&gt;T transitions within the identified somatic SNVs, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis. This is the first report of a hypermutator phenotype in gliosarcoma, which may represent a novel genomic mechanism of progression from lower-grade glioma.

  Study EGAS00001004864

• A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

  Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

  Study EGAS00001007611

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: Clear2Go - A Digital Identity Wallet for Health Status

  Clear2Go is a solution/app that provides digital, non-refutable cryptographic proof of testing or vaccination that can be used to evaluate risk of allowing individuals to return to normal work, travel, and public life activities. It is a mobile service that maps a person's vetted identity and biometrics to the phone and then cryptographically binds it with their COVID-19 test and vaccination records. The person can then prove their status by utilizing the credentials with a QRCode or NFC tap.DOI: https://rapids.ll.mit.edu/10.57895/b2d6-8060

  Study phs002628

• Comprehensive genetic landscape, immune checkpoint profiling, and establishment of patient-derived xenograft (PDX) of metachronous brain tumors from constitutive mismatch repair deficiency with a biallelic variant on MSH6

  Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare genetic disorder caused by biallelic pathogenic variants in mismatch repair genes (PMS2, MSH6, MLH1, or MSH2) resulting in the development of a variety of different tumors, including brain neoplasms. This study molecularly characterized a Brazilian child with CMMRD, harboring two metachronous brain tumors (medulloblastoma and high-grade glioma), and established a patient-derived xenograft (PDX) of the CMMRD-associated brain tumor. Keywords: Brazil, Constitutional mismatch repair deficiency syndrome, exome, MSH6, medulloblastoma, high-grade glioma.

  Study EGAS50000000351