Integrating 12 Spatial and Single Cell Technologies to Characterise Tumour Neighbourhoods and Cellular Interactions in three Skin Cancer Types.

Cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and melanoma, the three major types of skin cancer, account for over 70% of all cancer cases. Despite their prevalence, the skin cancer microenvironment remains poorly characterized, both in the outer skin layer where the cancer originates and at the deeper junctional and dermal layers into which it progresses. To address this, we integrated 12 complementary spatial single-cell technologies to construct orthogonally-validated cell signatures, spatial maps, and interactomes for cSCC, BCC, and melanoma.

Efficient spectral data reduction for accurate iodine quantification in multi-energy CT.

This study proposes a spectral data reduction method for multi-channel computed tomography (CT) that optimizes material decomposition accuracy while minimizing data complexity. Spectral CT enables quantitative assessments by utilizing multiple spectral channels, yet the associated noise and computational demands can limit its clinical application. We introduce a weighting scheme that reduces acquired four spectral channels-derived from a dual-layer, rapid kVp-switching (kVp-S) CT setup-into two optimized input channels for material decomposition.

A Thiopurine-like Mutagenic Process Defines TGCT Subtypes.

Testicular germ cell tumors (TGCTs) are the most common malignancy in young men, exhibit a unique developmental origin and exceptional chemosensitivity. However, the molecular distinctions between TGCT subtypes remain poorly understood. Here we present a comprehensive genomic analysis of 252 treatment-naive primary TGCTs, integrating deep whole-genome sequencing with matched transcriptomic and epigenomic data.

Mapping chromatin interactions at melanoma susceptibility loci uncovers distant cis-regulatory gene targets.

Genome-wide association studies (GWASs) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping chromatin interactions.

Hybrid Spectral CT: Combining rapid kVp-switching and dual-layer detectors for high sensitivity iodine imaging.

Over the past two decades, spectral computed tomography (CT) has undergone significant advancements, particularly in the realm of diagnostic accuracy, prompting a surge in clinical studies. This research examines the development of a new hybrid spectral CT system that combines a clinical-grade rapid kVp-switching X-ray tube with a dual-layer detector, aiming to boost quantitative spectral imaging performance in different clinical applications. The performance of the system was evaluated using varying tube voltages, duty cycles, and rotation times to enhance spectral outcomes.

Quantitative metal artifact reduction algorithm for spectral CT thermometry.

Spectral CT thermometry can non-invasively monitor internal temperatures to reduce local tumor recurrences caused by insufficient heating/treatment of the tumor and its surrounding safety margin. For its clinical translation, the applied metal artifact reduction algorithm requires quantitative accuracy to ensure the accuracy of generated temperature maps. The newly developed Spectrally Obtained Needle Artifact Reduction (SONAR) algorithm leverages the known shape of the applicator and spectral CT's material decomposition capabilities to isolate the applicator in projections.

Recurrent oncogenic ZC3H18 mutations stabilize endogenous retroviral RNA.

Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. We found that ZC3H18 (Z18), a component of multiple nuclear RNA surveillance complexes, has recurrent truncating mutations in cancer. We show that Z18 mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of ERV RNA.

Mapping chromatin interactions at melanoma susceptibility loci and cell-type specific dataset integration uncovers distant gene targets of -regulation.

Genome-wide association studies (GWAS) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped risk variants to candidate target genes by comprehensively mapping cell-type specific chromatin interactions.

Orthologs of ICM1 are dispensable for Ca mobilization in .

Apicomplexan parasites mobilize ionic calcium (Ca) from intracellular stores to promote microneme secretion and facilitate motile processes including gliding motility, invasion, and egress. Recently, a multipass transmembrane protein, ICM1, was found to be mportant for alcium obilization in and . Comparative genomics and phylogenetics have revealed putative ICM orthologs in and other apicomplexans.

Proteomic approaches for protein kinase substrate identification in Apicomplexa.

Apicomplexa is a phylum of protist parasites, notable for causing life-threatening diseases including malaria, toxoplasmosis, cryptosporidiosis, and babesiosis. Apicomplexan pathogenesis is generally a function of lytic replication, dissemination, persistence, host cell modification, and immune subversion. Decades of research have revealed essential roles for apicomplexan protein kinases in establishing infections and promoting pathogenesis.

Hybrid spectral CT system with clinical rapid kVp-switching x-ray tube and dual-layer detector for improved iodine quantification.

Spectral computed tomography (CT) is a powerful diagnostic tool offering quantitative material decomposition results that enhance clinical imaging by providing physiologic and functional insights. Iodine, a widely used contrast agent, improves visualization in various clinical contexts. However, accurately detecting low-concentration iodine presents challenges in spectral CT systems, particularly crucial for conditions like pancreatic cancer assessment.

Multi-ancestry genome-wide association study of kidney cancer identifies 63 susceptibility regions.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.

The monocarboxylate transporters are involved in the metabolism within the apicoplast and are linked to parasite survival.

The apicoplast is a four-membrane plastid found in the apicomplexans, which harbors biosynthesis and organelle housekeeping activities in the matrix. However, the mechanism driving the flux of metabolites, in and out, remains unknown. Here, we used TurboID and genome engineering to identify apicoplast transporters in .

Apicomplexan phosphodiesterases in cyclic nucleotide turnover: conservation, function, and therapeutic potential.

Apicomplexa encompasses a large number of intracellular parasites infecting a wide range of animals. Cyclic nucleotide signaling is crucial for a variety of apicomplexan life stages and cellular processes. The cyclases and kinases that synthesize and respond to cyclic nucleotides (i.

Single-cell profiling of MC1R-inhibited melanocytes.

The human red hair color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While MC1R variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility.

Loss of MC1R signaling implicates TBX3 in pheomelanogenesis and melanoma predisposition.

The human Red Hair Color (RHC) trait is caused by increased pheomelanin (red-yellow) and reduced eumelanin (black-brown) pigment in skin and hair due to diminished melanocortin 1 receptor (MC1R) function. In addition, individuals harboring the RHC trait are predisposed to melanoma development. While variants have been established as causative of RHC and are a well-defined risk factor for melanoma, it remains unclear mechanistically why decreased MC1R signaling alters pigmentation and increases melanoma susceptibility.

Oncogenic mutations impede nuclear RNA surveillance.

RNA surveillance pathways detect and degrade defective transcripts to ensure RNA fidelity. We found that disrupted nuclear RNA surveillance is oncogenic. Cyclin-dependent kinase 13 () is mutated in melanoma, and patient-mutated accelerates zebrafish melanoma.

Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity.

The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR < 1%).

Rare germline deleterious variants increase susceptibility for lung cancer.

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls.

Investigating the genetic architecture of eye colour in a Canadian cohort.

Eye color is highly variable in populations with European ancestry, ranging from low to high quantities of melanin in the iris. Polymorphisms in the locus have the largest effect on eye color in these populations, although other genomic regions also influence eye color. We performed genome-wide association studies of eye color in a Canadian cohort of European ancestry (N = 5,641) and investigated candidate causal variants.

ezQTL: A Web Platform for Interactive Visualization and Colocalization of QTLs and GWAS Loci.

Genome-wide association studies (GWAS) have identified thousands of genomic loci associated with complex diseases and traits, including cancer. The vast majority of common trait-associated variants identified via GWAS fall in non-coding regions of the genome, posing a challenge in elucidating the causal variants, genes, and mechanisms involved. Expression quantitative trait locus (eQTL) and other molecular QTL studies have been valuable resources in identifying candidate causal genes from GWAS loci through statistical colocalization methods.

Defining novel causal SNPs and linked phenotypes at melanoma-associated loci.

A number of genomic regions have been associated with melanoma risk through genome-wide association studies; however, the causal variants underlying the majority of these associations remain unknown. Here, we sequenced either the full locus or the functional regions including exons of 19 melanoma-associated loci in 1959 British melanoma cases and 737 controls. Variant filtering followed by Fisher's exact test analyses identified 66 variants associated with melanoma risk.