Common Signature Research Articles

Clinical and mutational signatures of CRB1-associated retinopathies: a multicentre study

BackgroundTo delineate the clinical and mutational signatures of patients with CRB1-associated retinopathies.MethodsThis multicentre retrospective cohort study involved 40 patients with CRB1 mutations and 40 age-matched and gender-matched inherited retinal diseases...

Metabolic Effects of the SGLT2 Inhibitor Dapagliflozin in Heart Failure Across the Spectrum of Ejection Fraction.

Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis-defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis-derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo (P=0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF (Pinteraction>0.10), whereas the ketogenic effect diminished at higher LVEF (Pinteraction=0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT03030235 and NCT02653482.

Syntax drives default language selection in bilingual connected speech production.

The present study investigated the role of syntactic processing in driving bilingual language selection. In two experiments, 120 English-dominant Spanish-English bilinguals read aloud 18 paragraphs with language switches. In Experiment 1a, each paragraph included eight switch words on function targets (four that repeated in every paragraph), and Experiment 1b was a replication with eight additional switches on content words in each paragraph. Both experiments had three conditions: (a) normal, (b) noun-swapped (in which nouns within consecutive sentences were swapped), and (c) random (in which words in each sentence were reordered randomly). In both experiments bilinguals produced intrusion errors, automatically translating language switch words by mistake, especially on function words (e.g., saying the day and stay awake instead of the day y stay awake). Intrusion rates did not vary across experiments even though switch rate was doubled in Experiment 1b relative to Experiment 1a. Bilinguals produced the most intrusions in normal paragraphs, slightly but significantly fewer intrusions in noun-swapped paragraphs, and a dramatic drop in intrusion rates in the random condition, even though the random condition elicited the most within-language errors. Bilinguals also demonstrated a common signature of inhibitory control in the form of reversed language dominance effects, which did not vary significantly across paragraph types. Finally, intrusions increased with switch word predictability (surprisal), but significant differences between conditions remained when controlling for predictability. These results demonstrate that bilingual language selection is driven by syntactic processing, which operates independently from other language control mechanisms, such as inhibition.the day and stay (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Autophagy and inflammasome activation are associated with poor response to FLT3 inhibitors in patients with FLT3-ITD acute myeloid leukemia

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.

Unraveling the pathogenic interplay between SARS-CoV-2 and polycystic ovary syndrome using bioinformatics and experimental validation

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among polycystic ovary syndrome (PCOS) is significantly higher than in the general population. However, the mechanisms underlying this remain obscure. This study aimed to explore the mechanisms by identifying the genetic signature of SARS-CoV-2 infection in PCOS. In the present study, a total of 27 common differentially expressed genes (DEGs) were selected for subsequent analyses. Functional analyses showed that immunity and hormone-related pathways collectively participated in the development and progression of PCOS and SARS-CoV-2 infection. Under these, 7 significant hub genes were identified, including S100A9, MMP9, TLR2, THBD, ITGB2, ICAM1, and CD86 by using the algorithm in Cytoscape. Furthermore, hub gene expression was confirmed in the validation set, PCOS clinical samples, and mouse model. Immune microenvironment analysis with the CIBERSORTx database demonstrated that the hub genes were significantly correlated with T cells, dendritic cells, mast cells, B cells, NK cells, and eosinophils and positively correlated with immune scores. Among the hub genes, S100A9, MMP9, THBD, ITGB2, CD86, and ICAM1 demonstrated potential as possible diagnostic markers for COVID-19 and PCOS. In addition, we established the interaction networks of ovary-specific genes, transcription factors, miRNAs, drugs, and chemical compounds with hub genes with NetworkAnalyst. This work uncovered the common pathogenesis and genetic signature of PCOS and SARS-CoV-2 infection, which might provide a theoretical basis and innovative ideas for further mechanistic research and drug discovery of the comorbidity of the two diseases.

Interpretable deep cross networks unveiled common signatures of dysregulated epitranscriptomes across 12 cancer types

Cancer is a complex and multifaceted group of diseases characterized by uncontrolled cell growth that leads to the formation of malignant tumors. Recent studies suggest that N6-methyladenosine (m6A) RNA methylation plays pivotal roles in cancer pathology by influencing various cellular processes. However, the degree to which these mechanisms are shared across different cancer types remains unclear. In this study, we analyzed an expansive array of 167 m6A epitranscriptome profiles covering 12 distinct cancer types and their originating normal tissues. We trained 12 distinct, cancer type-specific interpretable deep cross network models, which successfully distinguish between specific pairs of normal and cancer m6A contexts using integrated information from both the sequences and curated genomic knowledge. Interestingly, cross-cancer type testing indicated the existence of shared genomic patterns across various cancers at the epitranscriptome level. A pan-cancer model was subsequently developed to identify these shared patterns that could not be observed in a single cancer type. Our analysis uncovered, for the first time, a common epitranscriptome signature shared across multiple cancer types, particularly associated with RNA hybridization process and aberrant splicing. This highlights the importance of a comprehensive understanding of the pan-cancer epitranscriptome and holding potential implications in the development of RNA methylation-based therapeutics for various cancers.

Pre-challenge gut microbial signature predicts RhCMV/SIV vaccine efficacy in rhesus macaques.

Rhesus cytomegalovirus expressing simian immunodeficiency virus (RhCMV/SIV) vaccines protect ~59% of vaccinated rhesus macaques against repeated limiting-dose intra-rectal exposure with highly pathogenic SIVmac239M, but the exact mechanism responsible for the vaccine efficacy is unknown. It is becoming evident that complex interactions exist between gut microbiota and the host immune system. Here, we aimed to investigate if the rhesus gut microbiome impacts RhCMV/SIV vaccine-induced protection. Three groups of 15 rhesus macaques naturally pre-exposed to RhCMV were vaccinated with RhCMV/SIV vaccines. Rectal swabs were collected longitudinally both before SIV challenge (after vaccination) and post-challenge and were profiled using 16S rRNA based microbiome analysis. We identified ~2,400 16S rRNA amplicon sequence variants (ASVs), representing potential bacterial species/strains. Global gut microbial profiles were strongly associated with each of the three vaccination groups, and all animals tended to maintain consistent profiles throughout the pre-challenge phase. Despite vaccination group differences, by using newly developed compositional data analysis techniques, we identified a common gut microbial signature predictive of vaccine protection outcome across the three vaccination groups. Part of this microbial signature persisted even after SIV challenge. We also observed a strong correlation between this microbial signature and an early signature derived from whole blood transcriptomes in the same animals. Our findings indicate that changes in gut microbiomes are associated with RhCMV/SIV vaccine-induced protection and early host response to vaccination in rhesus macaques.IMPORTANCEThe human immunodeficiency virus (HIV) has infected millions of people worldwide. Unfortunately, still there is no vaccine that can prevent or treat HIV infection. A promising pre-clinical HIV vaccine based on rhesus cytomegalovirus (RhCMV) expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) provides sustained, durable protection against SIV challenge in ~59% of vaccinated rhesus macaques. There is an urgent need to understand the cause of this protection vs non-protection outcome. In this study, we profiled the gut microbiomes of 45 RhCMV/SIV vaccinated rhesus macaques and identified gut microbial signatures that were predictive of RhCMV/SIV vaccination groups and vaccine protection outcomes. These vaccine protection-associated microbial features were significantly correlated with early vaccine-induced host immune signatures in whole blood from the same animals. These findings show that the gut microbiome may be involved in RhCMV/SIV vaccine-induced protection, warranting further research into the impact of the gut microbiome in human vaccine trials.

Identification of common MicroRNAs expression signatures in antiphospholipid syndrome and thromboembolic disease: A scoping review.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by distinct pathophysiological mechanisms leading to heterogeneous manifestations, including venous and arterial thrombosis. Despite the lack of specific markers of thrombosis risk in APS, some of the mechanisms responsible for thrombosis in APS may overlap with those of other thromboembolic diseases. Understanding these similarities is important for improving the assessment of thrombosis risk in APS. MicroRNAs (MiRNAs) are RNA molecules that regulate gene expression and may influence the autoimmune response and coagulation. In this scoping review we aimed to investigate shared miRNAs profiles associated with APS and other thromboembolic diseases as a means of identifying markers indicative of a pro-thrombotic profile among patients with APS. Through a comprehensive search of scientific databases, 45 relevant studies were identified out of 1020 references. miRs-124-3p, 125b-5p, 125a-5p, and 17-5p, were associated with APS and arterial thrombosis, while miRs-106a-5p, 146b-5p, 15a-5p, 222-3p, and 451a were associated with APS and venous thrombosis. Additionally, miR-126a-3p was associated with APS and both arterial and venous thrombosis. We observed that APS shares a common miRNAs signature with non-APS related thrombosis, suggesting that miRNA expression profiles may serve as markers of thrombotic risk in APS. Further validation of a pro-thrombotic miRNA signature in APS is warranted to improve risk assessment, diagnosis, and management of APS.

Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.

Mitochondria are implicated in regulation of the innate immune response. We hypothesized that abnormalities in interferon signaling may contribute to pathophysiology in patients with primary mitochondrial disease (PMD). Expression of interferon stimulated genes (ISGs) was measured by real-time polymerase chain reaction (PCR) in whole blood samples from a cohort of patients with PMD. Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently IFI27 upregulation, seen in 50% of the samples. Some patients had extremely high IFI27 levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated IFI27 gene expression and PMD, but not between IFI27 and secondary mitochondrial dysfunction, suggesting that ISG upregulation is a biomarker of PMD. In some patients with PMD, ISG abnormalities persisted on repeat measurement over several years, indicative of ongoing chronic inflammation. Subgroup analyses suggested common ISG signatures in patients with similar mitochondrial disease mechanisms and positive correlations with disease severity among patients with identical genetic diagnoses. Dysregulated interferon signaling is frequently seen in patients with PMD suggesting that interferon dysregulation is a contributor to pathophysiology. This may indicate a role for repurposing of immunomodulatory therapies for the treatment of PMDs by targeting interferon signaling. ANN NEUROL 2024.

Identification of common signature genes and pathways underlying the pathogenesis association between nonalcoholic fatty liver disease and heart failure.

Non-alcoholic fatty liver disease (NAFLD) and heart failure (HF) are related conditions with an increasing incidence. However, the mechanism underlying their association remains unclear. This study aimed to explore the shared pathogenic mechanisms and common biomarkers of NAFLD and HF through bioinformatics analyses and experimental validation. NAFLD and HF-related transcriptome data were extracted from the Gene Expression Omnibus (GEO) database (GSE126848 and GSE26887). Differential analysis was performed to identify common differentially expressed genes (co-DEGs) between NAFLD and HF. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted to explore the functions and regulatory pathways of co-DEGs. Protein-protein interaction (PPI) network and support vector machine-recursive feature elimination (SVM-RFE) methods were used to screen common key DEGs. The diagnostic value of common key DEGs was assessed by receiver operating characteristic (ROC) curve and validated with external datasets (GSE89632 and GSE57345). Finally, the expression of biomarkers was validated in mouse models. A total of 161 co-DEGs were screened out in NAFLD and HF patients. GO, KEGG, and GSEA analyses indicated that these co-DEGs were mainly enriched in immune-related pathways. PPI network revealed 14 key DEGs, and SVM-RFE model eventually identified two genes (CD163 and CCR1) as common key DEGs for NAFLD and HF. Expression analysis revealed that the expression levels of CD163 and CCR1 were significantly down-regulated in HF and NAFLD patients. ROC curve analysis showed that CD163 and CCR1 had good diagnostic values for HF and NAFLD. Single-gene GSEA suggested that CD163 and CCR1 were mainly engaged in immune responses and inflammation. Experimental validation indicated unbalanced macrophage polarization in HF and NAFLD mouse models, and the expression of CD163 and CCR1 were significantly down-regulated. This study identified M2 polarization impairment characterized by decreased expression of CD163 and CCR1 as a common pathogenic pathway in NAFLD and HF. The downregulation of CD163 and CCR1 may reflect key pathological changes in the development and progression of NAFLD and HF, suggesting their potential as diagnostic and therapeutic targets.

Multicohort Epigenome-Wide Association Study of All-Cause Cardiovascular Disease and Cancer Incidence: A Cardio-Oncology Approach

BackgroundEmerging evidence reveals a complex relationship between cardiovascular disease (CVD) and cancer, which share common risk factors and biological pathways. ObjectivesThe aim of this study was to evaluate common epigenetic signatures for CVD and cancer incidence in 3 ethnically diverse cohorts: Native Americans from the SHS (Strong Heart Study), European Americans from the FHS (Framingham Heart Study), and European Americans and African Americans from the ARIC (Atherosclerosis Risk In Communities) study. MethodsA 2-stage strategy was used that included first conducting untargeted epigenome-wide association studies for each cohort and then running targeted models in the union set of identified differentially methylated positions (DMPs). We also explored potential molecular pathways by conducting a bioinformatics analysis. ResultsCommon DMPs were identified across all populations. In a subsequent meta-analysis, 3 and 1 of those DMPs were statistically significant for CVD only and both cancer and CVD, respectively. No meta-analyzed DMPs were statistically significant for cancer only. The enrichment analysis pointed to interconnected biological pathways involved in cancer and CVD. In the DrugBank database, elements related to 1-carbon metabolism and cancer and CVD medications were identified as potential drugs for target gene products. In an additional analysis restricted to the 950 SHS participants who developed incident CVD, the C index for incident cancer increased from 0.618 (95% CI: 0.570-0.672) to 0.971 (95% CI: 0.963-0.978) when adjusting the models for the combined cancer and CVD DMPs identified in the other cohorts. ConclusionsThese results point to molecular pathways and potential treatments for precision prevention of CVD and cancer. Screening based on common epigenetic signatures of incident CVD and cancer may help identify patients with newly diagnosed CVD at increased cancer risk.

Photospheric signatures of CME onset

ABSTRACT Coronal mass ejections (CMEs) are solar eruptions that involve large-scale changes to the magnetic topology of an active region. There exists a range of models for CME onset which are based on twisted or sheared magnetic field above a polarity inversion line (PIL). We present observational evidence that topological changes at PILs, in the photosphere, form a key part of CME onset, as implied by many models. In particular, we study the onset of 30 CMEs and investigate topological changes in the photosphere by calculating the magnetic winding flux, using the artop code. By matching the times and locations of winding signatures with CME observations produced by the almanac code, we confirm that these signatures are indeed associated with CMEs. Therefore, as well as presenting evidence that changes in magnetic topology at the photosphere are a common signature of CME onset, our approach also allows for the finding of the source location of a CME within an active region.

Whole-Exome Sequencing Reveals Novel Candidate Driver Mutations and Potential Druggable Mutations in Patients with High-Risk Neuroblastoma.

Neuroblastoma is the most prevalent solid tumor in early childhood, with a 5-year overall survival rate of 40-60% in high-risk cases. Therefore, the identification of novel biomarkers for the diagnosis, prognosis, and therapy of neuroblastoma is crucial for improving the clinical outcomes of these patients. In this study, we conducted the whole-exome sequencing of 48 freshly frozen tumor samples obtained from the Biobank. Somatic variants were identified and selected using a bioinformatics analysis pipeline. The mutational signatures were determined using the Mutalisk online tool. Cancer driver genes and druggable mutations were predicted using the Cancer Genome Interpreter. The most common mutational signature was single base substitution 5. MUC4, MUC16, and FLG were identified as the most frequently mutated genes. Using the Cancer Genome Interpreter, we identified five recurrent cancer driver mutations spanning MUC16, MUC4, ALK, and CTNND1, with the latter being novel and containing a missense mutation, R439C. We also identified 11 putative actionable mutations including NF1 Q1798*, Q2616*, and S636X, ALK F1174L and R1275Q, SETD2 P10L and Q1829E, BRCA1 R612S, NOTCH1 D1670V, ATR S1372L, and FGFR1 N577K. Our findings provide a comprehensive overview of the novel information relevant to the underlying molecular pathogenesis and therapeutic targets of neuroblastoma.

A common druggable signature of oncogenic c-Myc, mutant KRAS and mutant p53 reveals functional redundancy and competition among oncogenes in cancer

The major driver oncogenes MYC, mutant KRAS, and mutant TP53 often coexist and cooperate to promote human neoplasia, which results in anticancer therapeutic opportunities within their downstream molecular programs. However, little research has been conducted on whether redundancy and competition among oncogenes affect their programs and ability to drive neoplasia. By CRISPR‒Cas9-mediated downregulation we evaluated the downstream proteomics and transcriptomics programs of MYC, mutant KRAS, and mutant TP53 in a panel of cell lines with either one or three of these oncogenes activated, in cancers of the lung, colon and pancreas. Using RNAi screening of the commonly activated molecular programs, we found a signature of three proteins - RUVBL1, HSPA9, and XPO1, which could be efficiently targeted by novel drug combinations in the studied cancer types. Interestingly, the signature was controlled by the oncoproteins in a redundant or competitive manner rather than by cooperation. Each oncoprotein individually upregulated the target genes, while upon oncogene co-expression each target was controlled preferably by a dominant oncoprotein which reduced the influence of the others. This interplay was mediated by redundant routes of target gene activation - as in the case of mutant KRAS signaling to c-Jun/GLI2 transcription factors bypassing c-Myc activation, and by competition - as in the case of mutant p53 and c-Myc competing for binding to target promoters. The global transcriptomics data from the cell lines and patient samples indicate that the redundancy and competition of oncogenic programs are broad phenomena, that may constitute even a majority of the genes dependent on oncoproteins, as shown for mutant p53 in colon and lung cancer cell lines. Nevertheless, we demonstrated that redundant oncogene programs harbor targets for efficient anticancer drug combinations, bypassing the limitations for direct oncoprotein inhibition.

Common molecular and pathophysiological underpinnings of delirium and Alzheimer’s disease: molecular signatures and therapeutic indications

BackgroundDelirium and Alzheimer's disease (AD) are common causes of cognitive dysfunction among older adults. These neurodegenerative diseases share a common and complex relationship, and can occur individually or concurrently, increasing the chance of permanent mental dysfunction. However, the common molecular pathophysiology, key proteomic biomarkers, and functional pathways are largely unknown, whereby delirium is superimposed on AD and dementia.MethodsWe employed an integrated bioinformatics and system biology analysis approach to decipher such common key proteomic signatures, pathophysiological links between delirium and AD by analyzing the gene expression data of AD-affected human brain samples and comparing them with delirium-associated proteins. The present study identified the common drug target hub-proteins examining the protein–protein interaction (PPI) and gene regulatory network analysis. The functional enrichment and pathway analysis was conducted to reveal the common pathophysiological relationship. Finally, the molecular docking and dynamic simulation was used to computationally identify and validate the potential drug target and repurposable drugs for delirium and AD.ResultsWe detected 99 shared differentially expressed genes (sDEGs) associated with AD and delirium. The sDEGs-set enrichment analysis detected the transmission across chemical synapses, neurodegeneration pathways, neuroinflammation and glutamatergic signaling pathway, oxidative stress, and BDNF signaling pathway as the most significant signaling pathways shared by delirium and AD. The disease-sDEGs interaction analysis highlighted the other disease risk factors with delirium and AD development and progression. Among the sDEGs of delirium and AD, the top 10 hub-proteins including ALB, APP, BDNF, CREB1, DLG4, GAD1, GAD2, GFAP, GRIN2B and GRIN2A were found by the PPI network analysis. Based on the maximum molecular docking binding affinities and molecular dynamic simulation (100 ns) results, the ALB and GAD2 were found as prominent drug target proteins when tacrine and donepezil were identified as potential drug candidates for delirium and AD.ConclusionThe study outlined the common key biomolecules and biological pathways shared by delirium and AD. The computationally reported potential drug molecules need a deeper investigation including clinical trials to validate their effectiveness. The outcomes from this study will help to understand the typical pathophysiological relationship between delirium and AD and flag future therapeutic development research for delirium.

Genomic landscape of early-stage prostate adenocarcinoma in Mexican patients: an exploratory study

BackgroundHealth disparities have been highlighted among patient with prostate adenocarcinoma (PRAD) due to ethnicity. Mexican men present a more aggressive disease than other patients resulting in less favorable treatment outcome. We aimed to identify the mutational landscape which could help to reduce the health disparities among minority groups and generate the first genomics exploratory study of PRAD in Mexican patients.MethodsParaffin-embedded formalin-fixed tumoral tissue from 20 Mexican patients with early-stage PRAD treated at The Instituto Nacional de Cancerología, Mexico City from 2017 to 2019 were analyzed. Tumoral DNA was prepared for whole exome sequencing, the resulting files were mapped against h19 using BWA-MEM. Strelka2 and Lancet packages were used to identify single nucleotide variants (SNV) and insertions or deletions. FACETS was used to determine somatic copy number alterations (SCNA). Cancer Genome Interpreter web interface was used to determine the clinical relevance of variants.ResultsPatients were in an early clinical stage and had a mean age of 59.55 years (standard deviation [SD]: 7.1 years) with 90% of them having a Gleason Score of 7. Follow-up time was 48.50 months (SD: 32.77) with recurrences and progression in 30% and 15% of the patients, respectively. NUP98 (20%), CSMD3 (15%) and FAT1 (15%) were the genes most frequently affected by SNV; ARAF (75%) and ZNF419 (70%) were the most frequently affected by losses and gains SNCA’s. One quarter of the patients had mutations useful as biomarkers for the use of PARP inhibitors, they comprise mutations in BRCA, RAD54L and ATM. SBS05, DBS03 and ID08 were the most common mutational signatures present in this cohort. No associations with recurrence or progression were identified.ConclusionsThis pilot study reveals the mutational landscape of early-stage prostate adenocarcinoma in Mexican men, providing a first approach to understand the mutational patterns and actionable mutations in early prostate cancer can inform personalized treatment approaches and reduce the underrepresentation in genomic cancer studies.

Archaeological investigation of burials preluded by ground penetrating radar and geospatial technologies

Ground penetrating radar (GPR) is a non-invasive and efficient scientific tool in burial analysis that can 'see the unseen,' answering both simple questions such as the existence and boundaries of burials, as well as more difficult questions like whether burials are intact or decayed. This paper reviews common reflection signatures associated with burials and applies the three fundamental GPR principles (dielectric contrast, scattering and polarity of reflections) to two distinct caseworks involving historical graves and civilian burials, which serve as benchmarks with known ground truth. It encompasses a third test case involving family tree research in a civilian cemetery, drawing upon the benchmarked results obtained from the first two caseworks. In adherence to geophysical signal reflection principles, our study discerns distinct hyperbolic traits associated with three burial types including intact shroud-wrapped, coffin burials, and decayed or mass-grave burials. A GPR-geospatial integration workflow incorporating GPR, aerial photogrammetry and global navigation satellite system - real time kinetics (GNSS-RTK), is derived to enhance the identification and investigation of burials using GPR. Our workflow encompasses a range of indicators for survey methods and burial classification, presenting a general framework for the systematic contextualization of tailored workflows to individual contexts. This work exemplifies the efficacy of GPR in the detection of burials that have been undisturbed for over a century in the soils of Hong Kong and how geophysics and geospatial science can address the limitations inherent in conventional desktop-based archaeological investigation. Its implications extend to professionals in diverse fields including historians, archaeologists, cemetery management officials, and even family members searching for their lost loved ones.

Combined generalized and focal epilepsy with reflex features in Adaptor protein complex 4-associated hereditary spastic paraplegias: A cohort observational study

BackgroundPatients with genetic deficiency of the adaptor protein complex 4 (AP-4) exhibit earlyonset developmental delay, spastic diplegia, intellectual disability, speech impairment. The phenotype overlaps with other hereditary spastic paraplegias and cerebral palsies. Febrile seizures are common at onset. Epilepsy has been described in more than half of cases, arising in early infancy often with status epilepticus, but no typical seizure semiology or electroencephalographic features have been identified thus far. PurposeWe aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency. MethodsObservational cohort study on patients with bi-allelic pathogenic variants in AP-4 subunits and epilepsy. We focused on the seizure semiology, electroencephalographic characteristics and response to antiseizure medications. ResultsPatients harboured pathogenic variants in AP4S1 (n = 5) or AP4M1 (n = 1). The phenotype included spastic paraparesis, intellectual disability, speech/language impairment, microcephaly, and MRI evidence of hypoplasia of the corpus callosum. In 66 % of the patients, febrile seizures preceded the onset of epilepsy, which spanned from infancy to adolescence (range=14 months-13 years). Absences (66 %) and focal motor seizures (50 %) were common. No patient met the criteria for drug-resistance. Peculiar electroencephalographic features arose after the epilepsy onset and persisted at long-term follow-up: bilateral and asynchronous focal discharges combined with independent diffuse spike-wave-discharges (100 %) and reflex abnormalities (66 %). ConclusionIn AP-4 complex disease, epilepsy could arise beyond early infancy, until adolescence, with variable combination of generalized and focal seizures. The prognosis was favourable. We observed a common electroencephalographic signature - combined focal/generalized and reflex abnormalities - which may constitute a biomarker of AP-4 deficiency with epilepsy, applicable to inform genetic testing and disentangle the differential diagnosis.

Single-cell transcriptomics identifies aberrant glomerular angiogenic signalling in the early stages of WT1 kidney disease.

WT1 encodes a podocyte transcription factor whose variants can cause an untreatable glomerular disease in early childhood. Although WT1 regulates many podocyte genes, it is poorly understood which of them are initiators in disease and how they subsequently influence other cell-types in the glomerulus. We hypothesised that this could be resolved using single-cell RNA sequencing (scRNA-seq) and ligand-receptor analysis to profile glomerular cell-cell communication during the early stages of disease in mice harbouring an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell-type in the early stages of Wt1R394W/+ disease, with disrupted angiogenic signalling between podocytes and the endothelium, including the significant downregulation of transcripts for the vascular factors Vegfa and Nrp1. These signalling changes preceded glomerular endothelial cell loss in advancing disease, a feature also observed in biopsy samples from human WT1 glomerulopathies. Addition of conditioned medium from murine Wt1R394W/+ primary podocytes to wild-type glomerular endothelial cells resulted in impaired endothelial looping and reduced vascular complexity. Despite the loss of key angiogenic molecules in Wt1R394W/+ podocytes, the pro-vascular molecule adrenomedullin was upregulated in Wt1R394W/+ podocytes and plasma and its further administration was able to rescue the impaired looping observed when glomerular endothelium was exposed to Wt1R394W/+ podocyte medium. In comparative analyses, adrenomedullin upregulation was part of a common injury signature across multiple murine and human glomerular disease datasets, whilst other gene changes were unique to WT1 disease. Collectively, our study describes a novel role for altered angiogenic signalling in the initiation of WT1 glomerulopathy. We also identify adrenomedullin as a proangiogenic factor, which despite being upregulated in early injury, offers an insufficient protective response due to the wider milieu of dampened vascular signalling that results in endothelial cell loss in later disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dysfunctional mechanotransduction regulates the progression of PIK3CA-driven vascular malformations.

Somatic activating mutations in PIK3CA are common drivers of vascular and lymphatic malformations. Despite common biophysical signatures of tissues susceptible to lesion formation, including compliant extracellular matrix and low rates of perfusion, lesions vary in clinical presentation from localized cystic dilatation to diffuse and infiltrative vascular dysplasia. The mechanisms driving the differences in disease severity and variability in clinical presentation and the role of the biophysical microenvironment in potentiating progression are poorly understood. Here, we investigate the role of hemodynamic forces and the biophysical microenvironment in the pathophysiology of vascular malformations, and we identify hemodynamic shear stress and defective endothelial cell mechanotransduction as key regulators of lesion progression. We found that constitutive PI3K activation impaired flow-mediated endothelial cell alignment and barrier function. We show that defective shear stress sensing in PIK3CA E542K endothelial cells is associated with reduced myosin light chain phosphorylation, junctional instability, and defective recruitment of vinculin to cell-cell junctions. Using 3D microfluidic models of the vasculature, we demonstrate that PIK3CA E542K microvessels apply reduced traction forces and are unaffected by flow interruption. We further found that draining transmural flow resulted in increased sprouting and invasion responses in PIK3CA E542K microvessels. Mechanistically, constitutive PI3K activation decreased cellular and nuclear elasticity resulting in defective cellular tensional homeostasis in endothelial cells which may underlie vascular dilation, tissue hyperplasia, and hypersprouting in PIK3CA-driven venous and lymphatic malformations. Together, these results suggest that defective nuclear mechanics, impaired cellular mechanotransduction, and maladaptive hemodynamic responses contribute to the development and progression of PIK3CA-driven vascular malformations.