Characterization Of Landscape Research Articles

Abstract 4138348: Mechanical stress-mediated nuclear envelope damage promotes Aortic Valve Calcification through the ZBP1-RIPK3-NF-κB signaling axis

Methods and Results: We describe a comprehensive characterization of the AVICs nucleus landscape as determined by transmission electron microscopy (TEM) of samples obtained from CAVD patients. Turbulence led to nuclear envelope integrity lose in AVICs cultured in shear stress experiments, with three different fluid conditions [static (ST), laminar stress (LS), and oscillatory stress (OS)], indicated by Western blot and immunofluorescence (IF). Silencing lamin A/C (LMNA) through small interfering RNA (siRNA), accelerated nuclear envelope damage , as indicated by Western blot, qPCR, and immunofluorescence (IF). The formation of Z-DNA and its co-localization with Z-DNA binding protein (ZBP1) was observed due to the nuclear envelope damage by IF. Western blot, qPCR, IHC and IF confirmed Z-DNA-induced inflammation in AVICs through the ZBP1-RIPK3-NF-κB signaling pathway. ZBP1 and RIPK3 knockdown with siRNA markedly reduced the protein level of osteogenic markers alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein 2 (BMP2) in VICs. In vivo, aortic valve disease was constructed by direct wire injury (DWI), and we showed that overexpression of LMNA by adeno-associated virus significantly decelerated the progression of aortic valve lesion induced by DWI in mice. Conclusion: Excessive mechanical stress can induce damage to the nuclear envelope of AVICs by causing cytoskeletal remodeling, initiating the formation of Z-DNA, and hastening the calcification process in AVICs and CAVD.

Alternatively activated macrophages are associated with faster growth rate in vestibular schwannoma

Abstract The variability in vestibular schwannoma growth rates greatly complicates clinical treatment. Management options are limited to radiological observation, surgery, radiotherapy and, in specific cases, bevacizumab therapy. As such, there is a pressing requirement for growth restricting drugs for vestibular schwannoma. This study explored potential predictors of vestibular schwannoma growth in depth, highlighting differences between static and growing vestibular schwannoma to identify potential therapeutic targets. High dimensional imaging was used to characterise the tumour microenvironment of four static and five growing vestibular schwannoma (indicated by volumetric change < 20% or ≥ 20% per year, respectively). Single cell spatial information and protein expression data from a panel of 35 tumour immune-targeted antibodies identified specific cell populations, their expression profiles, and their spatial localisation within the tumour microenvironment. Growing vestibular schwannoma contained significantly more proliferative and non-proliferative alternatively activated tumour-associated macrophages per mm2 compared to static vestibular schwannoma. Furthermore, two additional proliferative cell types were identified in growing and static vestibular schwannoma: transitioning monocytes and Programmed Cell Death Ligand 1 (PD-L1+) Schwann cells. In agreement, growing vestibular schwannoma were characterised by a tumour microenvironment composed of immune-enriched, proliferative neighbourhoods, whereas static vestibular schwannoma were composed of tumour-enriched, non-proliferative neighbourhoods. Finally, classically activated macrophages significantly co-localised with alternatively activated macrophages in static vestibular schwannoma, but this sequestration was reduced in growing vestibular schwannoma. This study provides a novel, spatial characterisation of the immune landscape in growing vestibular schwannoma, whilst highlighting the need for new therapeutic targets that modulate the tumour immune microenvironment.

Characterization of genetic landscape and novel inflammatory biomarkers in patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD cohort to investigate the underlying pathology and identify novel targets for potential treatment. We investigated AOSD cases (n=60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n=106), alongside measurements of NLRP3 inflammasome activation using a custom assay, and Type I Interferon (IFN) score using a novel method. We observed higher-than-expected frequencies of rare germline variants associated with monogenic autoinflammatory disorders in AOSD cases (AOSD 38.4% vs healthy controls 20.4%), and earlier onset of putative somatic variants associated with clonal haematopoiesis of indeterminate potential. Transcriptome profiling revealed positive correlation between Still's activity score (SAS) and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and Type I IFN scores were significantly elevated in AOSD cases compared to healthy controls (p=0.0001 and 0.0015 respectively), in addition to several cytokines: IL-6 (p<0.0001), IL-10 (p<0.0075), IL-12p70 (p=0.0005), IL-18 (p<0.0001), IL-23 (p<0.0001), IFN-α2 (p=0.0009), and IFNγ (p=0.0002). Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not, by themselves, be sufficient to cause disease but may contribute to a polygenic model for AOSD.

Characterization of the single cell landscape in normal and osteoarthritic equine joints.

Osteoarthritis (OA) is a major source of pain and disability worldwide. Understanding of disease progression is evolving, but OA is increasingly thought to be a multifactorial disease in which the innate immune system plays a role in regulating and perpetuating low-grade inflammation. The aim of this study was to enhance our understanding of OA immunopathogenesis through characterization of the transcriptomic responses in OA joints, with the goal to facilitate the development of targeted therapies. Single-cell RNA sequencing (scRNA-seq) was completed on cells isolated from the synovial fluid of three normal and three OA equine joints. In addition to synovial fluid, scRNA-seq was also performed on synovium from one normal joint and one OA joint. Characterization of 28,639 cells isolated from normal and OA-affected equine synovial fluid revealed the composition to be entirely immune cells (CD45+) with 8 major populations and 26 subpopulations identified. In synovial fluid, we found myeloid cells (macrophage and dendritic cells) to be overrepresented and T cells (CD4 and CD8) to be underrepresented in OA relative to normal joints. Through subcluster and differential abundance analysis of T cells we further identified a relative overrepresentation of IL23R+ gamma-delta (γδ) T cells in OA-affected joints (a cell type we report to be enriched in gene signatures associated with T helper 17 mediated immunity). Analysis of an additional 17,690 cells (11 distinct cell type clusters) obtained from synovium of one horse led to the identification of an OA-associated reduction in the relative abundance of synovial macrophages, which contrasts with the increased relative abundance of macrophages in synovial fluid. Completion of cell-cell interaction analysis implicated myeloid cells in disease progression, suggesting that the myeloid-myeloid interactions were increased in OA-affected joints. Overall, this work provides key insights into the composition of equine synovial fluid and synovium in health and OA. The data generated in this study provides equine-specific cell type gene signatures which can be applied to future investigations. Furthermore, our analysis highlights the potential role of macrophages and IL23R+ γδ T cells in OA immunopathogenesis.

Andean Landscape Legacies: Comprehensive Remote Sensing Mapping and GIS Analysis of Long-Term Settlement and Land Use for Sustainable Futures (NW Argentina)

The Andes region has an exceptional record of high-altitude settlements integrated within widespread regional chains of mobility and exchange. The Sierra de Aconquija (NW Argentina, south-central Andes) is an effective climatic barrier that has afforded an enduring indigenous approach to land use, mobility, and exchange over millennia. Despite this rich history, the Sierra has been largely considered marginal in pre-Columbian regional cultural developments. Today, the expansion of extractive industries threatens the region’s heritage and the sustainable futures of local communities. Innovative, integrative methodologies are needed for landscape characterisation, heritage assessment, and sustainable policy development. Building on earlier work, we undertook the first comprehensive mapping of archaeological features over 3800 sq. km of the Sierra using interpreter-led assessment of commercial and open-access satellite imagery and DSM data, to verify earlier assumptions and to identify previously unnoticed trends in the aggregation, distribution, and connectivity of archaeological features. The mapping identified 6794 features distributed unevenly but with clear tendencies towards maximising topographic, ecologic, and connectivity advantages expressed consistently across the study area. The outcomes confirm the important role the Sierra had in pre-Hispanic times, highlighting the significance of ancient indigenous practices for the sustainability of vulnerable upland landscapes both in the Andes and worldwide.

Characterization of stem cell landscape and assessing the stemness degree to aid clinical therapeutics in hematologic malignancies

Hematological malignancies are a group of cancers that affect the blood, bone marrow, and lymphatic system. Cancer stem cells (CSCs) are believed to be responsible for the initiation, progression, and relapse of hematological malignancies. However, identifying and targeting CSCs presents many challenges. We aimed to develop a stemness index (HSCsi) to identify and guide the therapy targeting CSCs in hematological malignancies. We developed a novel one-class logistic regression (OCLR) algorithm to identify transcriptomic feature sets related to stemness in hematologic malignancies. We used the HSCsi to measure the stemness degree of leukemia stem cells (LSCs) and correlate it with clinical outcomes.We analyze the correlation of HSCsi with genes and pathways involved in drug resistance and immune microenvironment of acute myeloid leukemia (AML). HSCsi revealed stemness-related biological mechanisms in hematologic malignancies and effectively identify LSCs. The index also predicted survival and relapse rates of various hematologic malignancies. We also identified potential drugs and interventions targeting cancer stem cells (CSCs) of hematologic malignancies by the index. Moreover, we found a correlation between stemness and bone marrow immune microenvironment in AML. Our study provides a novel method and tool to assess the stemness degree of hematologic malignancies and its implications for clinical outcomes and therapeutic strategies. Our HSC stemness index can facilitate the precise stratification of hematologic malignancies, suggest possible targeted and immunotherapy options, and guide the selection of patients.

CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma.

Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4+ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4+ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy. HIGHLIGHTS: We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC). CircAATF is positively associated with CD4+ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model. CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.

EP.06G.19 Characterization of Metabolomic Landscape in Underrepresented Patients with Lung Cancer

EP.06G.19 Characterization of Metabolomic Landscape in Underrepresented Patients with Lung Cancer

Single-cell transcriptome atlas revealed bronchoalveolar immune features related to disease severity in pediatric Mycoplasma pneumoniae pneumonia.

The mechanisms underlying protective immunity in mild Mycoplasma pneumoniae pneumonia (MPP) and the pathogenesis of severe MPP, characterized by dysregulated immune responses, remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) to profile bronchoalveolar lavage fluid (BALF) samples from 13 healthy donors and 24 hospitalized pediatric patients with MPP, covering both mild and severe cases. Severe MPP patients exhibited high levels of exhausted T cells and M1-like macrophages, with the exhaustion of T cells attributed to persistent type I interferon signaling and inadequate assistance from CD4+ T cells. Significant cell-cell interactions between exhausted T cells and programmed death-ligand 1+ (PD-L1+) macrophages were detected in severe patients, potentially mediated through inhibitor molecules (e.g., PD1) and their receptors (e.g., PD-L1), as well as human leukocyte antigen class I molecules and their receptors (e.g., KLRC1/D2), resulting in the dysfunction of anti-MP immune responses. Mild MPP patients were featured by an increased abundance of neutrophils, coupled with enhanced activation, contributing to protective immunity. Together, our study provides a detailed characterization of the BALF immune landscape in MPP patients, revealing distinct immune characteristics between mild and severe cases, which offers a valuable resource for understanding MPP immunopathogenesis and formulating effective therapeutic strategies.

Spatial Transcriptomic Profiling of Human Saphenous Vein Exposed to Ex Vivo Arterial Haemodynamics-Implications for Coronary Artery Bypass Graft Patency and Vein Graft Disease.

Vein graft disease is the process by which saphenous vein grafts, utilised for revascularisation during coronary artery bypass graft surgery, undergo an inflammation-driven intimal hyperplasia and accelerated atherosclerosis process in subsequent years after implantation. The role of the arterial circulation, particularly the haemodynamic properties' impact on graft patency, have been investigated but have not to date been explored in depth at the transcriptomic level. We have undertaken the first-in-man spatial transcriptomic analysis of the long saphenous vein in response to ex vivo acute arterial haemodynamic stimulation, utilising a combination of a custom 3D-printed perfusion bioreactor and the 10X Genomics Visium Spatial Gene Expression technology. We identify a total of 413 significant genes (372 upregulated and 41 downregulated) differentially expressed in response to arterial haemodynamic conditions. These genes were associated with pathways including NFkB, TNF, MAPK, and PI3K/Akt, among others. These are established pathways involved in the initiation of an early pro-inflammatory response, leukocyte activation and adhesion signalling, tissue remodelling, and cellular differentiation. Utilising unsupervised clustering analysis, we have been able to classify subsets of the expression based on cell type and with spatial resolution. These findings allow for further characterisation of the early saphenous vein graft transcriptional landscape during the earliest stage of implantation that contributes to vein graft disease, in particular validation of pathways and druggable targets that could contribute towards the therapeutic inhibition of processes underpinning vein graft disease.

Bacteriocin distribution patterns in Enterococcus faecium and Enterococcus lactis: bioinformatic analysis using a tailored genomics framework.

This work significantly expands the knowledge on the understudied bacteriocin diversity in opportunistic enterococci, revealing their contribution in the adaptation to different environments. It underscores the importance of placing increased emphasis on genetic platforms carrying bacteriocins as well as on cryptic plasmids that often exclusively harbor bacteriocins since bacteriocin production can significantly contribute to plasmid maintenance, potentially facilitating their stable transmission across generations. Further characterization of strain-level bacteriocin landscapes could inform strategies to combat high-risk clones. Overall, these insights provide a framework for unraveling the therapeutic and biotechnological potential of bacteriocins.

Current Landscape of NTRK Inhibition for Pediatric CNS Tumors.

Over the last decade, as molecular platforms have permitted the characterization of the genomic landscape of pediatric central nervous system (CNS) tumors, pediatric neuro-oncology has dramatically transformed. NTRK fusions are oncogenic driver alterations that have been found in a multitude of tumor types, including pediatric CNS tumors. In recent years, NTRK inhibitors have emerged as a promising class of targeted therapies for pediatric CNS tumors with NTRK gene fusions. The use of larotrectinib and entrectinib in the relapsed setting for pediatric CNS tumors has resulted in rapid and robust responses in an important fraction of patients. These agents are well tolerated, although close to 20% of patients have spontaneous bone fractures. Given the existing data for patients with relapsed disease, clinical trials using NTRK inhibitors in the upfront setting is the next natural progression of efficacy testing and many are currently underway. There are still several challenges that need to be addressed to optimize the use of NTRK inhibitors and identify the patients with NTRK fusion-positive CNS tumors who are most likely to benefit from them. As these agents are more broadly used, resistance will become a more pervasive issue and strategies will need to be determined for this scenario. This article summarizes the current status of NTRK inhibitors for pediatric CNS tumors and discusses the opportunities and challenges of their expanding use in the future.

The utility of MOF-based materials in direct air capture (DAC) application to ppm-level CO2

Metal-organic frameworks (MOFs) are well-suited materials for CO2 removal and have robust capture capacity and selectivity. Although the adsorption of CO2 in MOFs has been studied, the implementation of ppm-level CO2 uptake in MOFs and the effects of the pore size and charge have not been fully explored. We performed grand canonical Monte Carlo (GCMC) simulations combined with the Density Functional Theory plus U (DFT + U) charge method to investigate MOF screening for ppm-level CO2 uptake and its application in a direct air capture (DAC) system. Three types of MOFs containing eight members were studied: i.e., ZIF-68, 69, 70; UiO-66, 67, 68; CAU-10; and MIL-125. The pore landscape characterization, electrostatic field-induced enhancement, and preferential binding sites of these MOFs were examined for CO2 capture. MOFs with pore limited diameters (PLD) 1.5 times the size of CO2 molecules and with large cavity diameters (LCD) smaller than 10 Å exhibit robust confinement capacity. Polar functional groups and metal ions dominate the electrostatic contributions and subsequently enhance the surface adhesion of CO2 molecules. For a given framework, favorable CO2 binding occurs in the following order: small pores/cages > polar functional group/metal ions > larger pores/cages. ZIF-69 which comprises smaller pores (7.5 Å) and robust polar functional groups (–Cl) collectively enhances CO2 capture; thus, ZIF-69 outperforms other MOFs; the performance of ZIF-69 is followed by that of CAU-10 which has an optimal pore size of 6 Å. These findings are of fundamental and practical importance for the application of MOFs in DAC technologies for CO2 removal.

Unraveling the key role of chromatin structure in cancer development through epigenetic landscape characterization of oral cancer

Epigenetic alterations, such as those in chromatin structure and DNA methylation, have been extensively studied in a number of tumor types. But oral cancer, particularly oral adenocarcinoma, has received far less attention. Here, we combined laser-capture microdissection and muti-omics mini-bulk sequencing to systematically characterize the epigenetic landscape of oral cancer, including chromatin architecture, DNA methylation, H3K27me3 modification, and gene expression. In carcinogenesis, tumor cells exhibit reorganized chromatin spatial structures, including compromised compartment structures and altered gene-gene interaction networks. Notably, some structural alterations are observed in phenotypically non-malignant paracancerous but not in normal cells. We developed transformer models to identify the cancer propensity of individual genome loci, thereby determining the carcinogenic status of each sample. Insights into cancer epigenetic landscapes provide evidence that chromatin reorganization is an important hallmark of oral cancer progression, which is also linked with genomic alterations and DNA methylation reprogramming. In particular, regions of frequent copy number alternations in cancer cells are associated with strong spatial insulation in both cancer and normal samples. Aberrant methylation reprogramming in oral squamous cell carcinomas is closely related to chromatin structure and H3K27me3 signals, which are further influenced by intrinsic sequence properties. Our findings indicate that structural changes are both significant and conserved in two distinct types of oral cancer, closely linked to transcriptomic alterations and cancer development. Notably, the structural changes remain markedly evident in oral adenocarcinoma despite the considerably lower incidence of genomic copy number alterations and lesser extent of methylation alterations compared to squamous cell carcinoma. We expect that the comprehensive analysis of epigenetic reprogramming of different types and subtypes of primary oral tumors can provide additional guidance to the design of novel detection and therapy for oral cancer.

A novel molecular classification based on efferocytosis-related genes for predicting clinical outcome and treatment response in acute myeloid leukemia.

Previous studies have shown that macrophage-mediated efferocytosis is involved in immunosuppression in acute myeloid leukemia (AML). However, the regulatory role of efferocytosis in AML remains unclear and needs further elucidation. We first identified the key efferocytosis-related genes (ERGs) based on the expression matrix. Efferocytosis-related molecular subtypes were obtained by consensus clustering algorithm. Differences in immune landscape and biological processes among molecular subtypes were further evaluated. The efferocytosis score model was constructed to quantify molecular subtypes and evaluate its value in prognosis prediction and treatment decision-making in AML. Three distinct efferocytosis-related molecular subtypes were identified and divided into immune activation, immune desert, and immunosuppression subtypes based on the characteristics of the immune landscape. We evaluated the differences in clinical and biological features among different molecular subtypes, and the construction of an efferocytosis score model can effectively quantify the subtypes. A low efferocytosis score is associated with immune activation and reduced mutation frequency, and patients have a better prognosis. A high efferocytosis score reflects immune exhaustion, increased activity of tumor marker pathways, and poor prognosis. The prognostic predictive value of the efferocytosis score model was confirmed in six AML cohorts. Patients exhibiting high efferocytosis scores may derive therapeutic benefits from anti-PD-1 immunotherapy, whereas those with low efferocytosis scores tend to exhibit greater sensitivity towards chemotherapy. Analysis of treatment data in ex vivo AML cells revealed a group of drugs with significant differences in sensitivity between different efferocytosis score groups. Finally, we validated model gene expression in a clinical cohort. This study reveals that efferocytosis plays a non-negligible role in shaping the diversity and complexity of the AML immune microenvironment. Assessing the individual efferocytosis-related molecular subtype in individuals will help to enhance our understanding of the characterization of the AML immune landscape and guide the establishment of more effective clinical treatment strategies.

53128 Characterization of Mutational Landscape and Tumor Mutational Burden in Adult Patients with Metastatic Melanoma arising in Congenital Nevi

53128 Characterization of Mutational Landscape and Tumor Mutational Burden in Adult Patients with Metastatic Melanoma arising in Congenital Nevi

The transcriptional landscape and clinico-biological characterization of human endogenous retroviruses in esophageal squamous cell carcinoma.

Human endogenous retroviruses (HERVs) are emerging as critical elements in host genomic regulation. Aberrant HERV transcription has been implicated in developmental and tissue-specific aging and pathological processes. In this study, we presenteda comprehensive locus-specific characterization of the HERV expression landscape in esophageal squamous cell carcinoma (ESCC). We demonstrated the transcriptional diversity among patients and identified 12 clinically relevant HERVs in the SCH cohort, which were experimentally validated by Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) in the CAMS cohort. ESCC patients were stratified into three HERV-based subtypes (HERVhigh, HERVmedian and HERVlow) with distinct clinical and biological characteristics. The HERVhigh subtype was associated with worse survival, increased CD4+ T cellsinfiltration and decreased metabolic activity, whereas the HERVlow subtype was characterized by abundant CD8+ T cells, increased metabolic activity, and better survival. The HERV-based tumor subtyping was further robustly validated by RNA sequencing and RT-qPCR in two additional external cohorts. Our findings demonstrate the clinical significance of HERVs for tumor subtyping and prognosis, provide insights into the functional role of HERVs and a valuable resource for developing novel biomarkers and therapeutic targets in ESCC.

Uncovering structural variants in Creole cattle from Guadeloupe and their impact on environmental adaptation through whole genome sequencing.

Structural variants play an important role in evolutionary processes. Besides, they constitute a large source of inter individual genetic variation that might represent a major factor in the aetiology of complex, multifactorial traits. Their importance in adaptation is becoming increasingly evident in literature. Yet, the characterization of the genomic landscape of structural variants in local breeds remains scarce to date. Herein, we investigate patterns and gene annotation of structural variants in the Creole cattle from Guadeloupe breed using whole genome sequences from 23 bulls representative of the population. In total, we detected 32821 ascertained SV defining 15258 regions, representing ~ 17% of the Creole cattle genome. Among these, 6639 regions have not been previously reported in the Database of Genomic Variants archive. Average number of structural variants detected per individual in the studied population is in the same order of magnitude of that observed in indicine populations and higher than that reported in taurine breeds. We observe an important within-individual variability where approximately half of the detected structural variants have low frequency (MAF < 0.25). Most of the detected structural variants (55%) occurred in intergenic regions. Genic structural variants overlapped with 7793 genes and the predicted effect of most of them is ranked as "modifier". Among the structural variants that were predicted to have a high functional impact on the protein, a 5.5 Kb in length, highly frequent deletion on chromosome 2, affects ALPI, a gene associated with the interaction between gut microbiota and host immune system. The 6639 newly identified structural variants regions include three deletions and three duplications shared by more than 80% of individuals that are significantly enriched for genes related to tRNA threonylcarbamoyladenosine metabolic process, important for temperature adaptation in thermophilic organisms, therefore suggesting a potential role in the thermotolerance of Creole cattle from Guadeloupe cattle to tropical climate. Overall, highly frequent structural variants that are specific to the Creole cattle population encompass olfactory receptor and immunity genes as well as genes involved in muscle tone, muscle development and contraction. Beyond mapping and characterizing structural variants in the Creole cattle from Guadeloupe breed, this study provides valuable information for a better understanding of the potential role of chromosomal rearrangements in adaptive traits in cattle.

Characterization of the stem cell landscape and identification of a stemness-associated prognostic signature in bladder cancer

It is accepted that cancer stem cells (CSCs) are key to the occurrence, progression, drug resistance, and recurrence of bladder cancer (BLCA). Here, we aimed to characterize the landscapes of CSCs and investigate the biological and clinical signatures based on a prognostic model constructed by genes associated with CSCs. The malignant epithelial cells were discovered and sorted into six clusters through single cell analysis. C2 was identified as the CSCs. The signaling involved in the interactions between C2, cancer-associated fibroblasts (CAFs), and immune cells mainly consisted of MK, THBS, ANGPTL, VISFATIN, JAM, and ncWNT pathways. The CSC-like prognostic index (CSCLPI) constructed by the random survival forest was a reliable risk factor for BLCA and had a stable and powerful effect on predicting the overall survival of patients with BLCA. The level of CAFs was higher among patients with higher CSCLPI scores, suggesting that CAFs play a significant role in regulating biological characteristics. The CSCLPI-developed survival prediction nomogram has the potential to be applied clinically to predict the 1-, 2-, 3-, and 5-year overall survival of patients with BLCA. The CSCLPI can be used for prognostic prediction and drug treatment evaluation in the clinic.

Characterization of the genomic landscape of HIV-associated lymphoma reveals heterogeneity across histological subtypes.

Individuals with human immunodeficiency virus (HIV) experience an increased risk of lymphoma, making this an important cause of death among people with HIV. Nevertheless, little is known regarding the underlying genetic aberrations, which we therefore set out to characterize. We conducted next-generation panel sequencing to explore the mutational status of diagnostic lymphoma biopsies from 18 patients diagnosed with lymphoma secondary to HIV infection. Ion Torrent next-generation sequencing was performed with an AmpliSeq panel on diagnostic lymphoma biopsies from HIV-associated B-cell lymphomas (n = 18), comprising diffuse large B-cell lymphoma (n = 9), classic Hodgkin lymphoma (n = 6), Burkitt lymphoma (n = 2), follicular lymphoma (n = 1), and marginal zone lymphoma (n = 1). The panel comprised 69 lymphoid- and/or myeloid-relevant genes, in which either the entire coding sequence or a hotspot region was sequenced. Among the 18 lymphomas, we detected 213 variants. The number of detected mutations ranged from 4 to 41 per tumor distributed among 42 genes, including both exonic and intronic regions. The most frequently mutated genes included KMT2D (67%), TNFAIP3 (50%), and TP53 (61%). Notably, no gene was found to harbor variants across all the HIV-associated lymphomas, nor did we find subtype-specific variants. While some variants were shared among patients, most were unique to the individual patient and were often not reported as malignant genetic variants in databases. Our findings demonstrate genetic heterogeneity across histological subtypes of HIV-associated lymphomas and thus help elucidate the genetics and pathophysiological mechanisms underlying the disease.