Molecular Profiling Research Articles

CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer

BackgroundCyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates.MethodsThe activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches.ResultsCDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo.ConclusionOur work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

Rapid phenotypic and genotypic change in a laboratory schistosome population.

Genomic analysis has revealed extensive contamination among laboratory-maintained microbes including malaria parasites, Mycobacterium tuberculosis and Salmonella spp. Here, we provide direct evidence for recent contamination of a laboratory schistosome parasite population, and we investigate its genomic consequences. The Brazilian Schistosoma mansoni population SmBRE has several distinctive phenotypes, showing poor infectivity, reduced sporocysts number, low levels of cercarial shedding and low virulence in the intermediate snail host, and low worm burden and low fecundity in the vertebrate rodent host. In 2021 we observed a rapid change in SmBRE parasite phenotypes, with a ~10x increase in cercarial production and ~4x increase in worm burden. To determine the underlying genomic cause of these changes, we sequenced pools of SmBRE adults collected during parasite maintenance between 2015 and 2023. We also sequenced another parasite population (SmLE) maintained alongside SmBRE without phenotypic changes. While SmLE allele frequencies remained stable over the eight-year period, we observed sudden changes in allele frequency across the genome in SmBRE between July 2021 and February 2023, consistent with expectations of laboratory contamination. (i) SmLE-specific alleles rose in the SmBRE population from 0 to 41-46% across the genome between September and October 2021, documenting the timing and magnitude of the contamination event. (ii) After contamination, strong selection (s = ~0.23) drove replacement of low fitness SmBRE with high fitness SmLE alleles. (iii) Allele frequency changed rapidly across the whole genome, except for a region on chromosome 4 where SmBRE alleles remained at high frequency. We were able to detect contamination in this case because SmBRE shows distinctive phenotypes. However, this would likely have been missed with phenotypically similar parasites. These results provide a cautionary tale about the importance of tracking the identity of parasite populations, but also showcase a simple approach to monitor changes within populations using molecular profiling of pooled population samples to characterize fixed single nucleotide polymorphisms. We also show that genetic drift results in continuous change even in the absence of contamination, causing parasites maintained in different labs (or sampled from the same lab at different times) to diverge.

Cell-free DNA from ascites identifies clinically relevant variants and tumour evolution in patients with advanced ovarian cancer.

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour-enriched tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this challenge. In this study, next-generation sequencing was performed on ascites-derived cfDNA samples (26 samples from 15 human participants with ovarian cancer), with matched DNA from ascites-derived tumour cells (n = 5) and archived formalin-fixed paraffin-embedded (FFPE) tissue (n = 5). Similar tumour purity and variant detection were achieved with cfDNA compared to FFPE and ascites cell DNA. Analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified six cases of high genomic instability (including four with pathogenic BRCA1 and BRCA2 mutations). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Ascites cfDNA identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. This advocates for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

Closing the gap: prognostic and predictive biomarker validation for personalized care in a Latin American hormone-dependent breast cancer cohort.

Several guidelines recommend the use of different classifiers to determine the risk of recurrence (ROR) and treatment decisions in patients with HR+HER2- breast cancer. However, data are still lacking for their usefulness in Latin American (LA) patients. Our aim was to evaluate the comparative prognostic and predictive performance of different ROR classifiers in a real-world LA cohort. The Molecular Profile of Breast Cancer Study (MPBCS) is an LA case-cohort study with 5-year follow-up. Stages I and II, clinically node-negative HR+HER2- patients (n = 340) who received adjuvant hormone therapy and/or chemotherapy, were analyzed. Time-dependent receiver-operator characteristic-area under the curve, univariate and multivariate Cox proportional hazards regression (CPHR) models were used to compare the prognostic performance of several risk biomarkers. Multivariate CPHR with interaction models tested the predictive ability of selected risk classifiers. Within this cohort, transcriptomic-based classifiers such as the recurrence score (RS), EndoPredict (EP risk and EPClin), and PAM50-risk of recurrence scores (ROR-S and ROR-PC) presented better prognostic performances for node-negative patients (univariate C-index 0.61-0.68, adjusted C-index 0.77-0.80, adjusted hazard ratios [HR] between high and low risk: 4.06-9.97) than the traditional classifiers Ki67 and Nottingham Prognostic Index (univariate C-index 0.53-0.59, adjusted C-index 0.72-0.75, and adjusted HR 1.85-2.54). RS (and to some extent, EndoPredict) also showed predictive capacity for chemotherapy benefit in node-negative patients (interaction P = .0200 and .0510, respectively). In summary, we could prove the clinical validity of most transcriptomic-based risk classifiers and their superiority over clinical and immunohistochemical-based methods in the heterogenous, real-world node-negative HR+HER2- MPBCS cohort.

ALK rearranged Spitz melanocytoma: a clinicopathological and molecular genetic analysis of two cases

Objective: To investigate the clinicopathological, immunohistochemical and molecular characteristics of cutaneous ALK-rearranged Spitz melanocytoma. Methods: Two cases of cutaneous ALK-rearranged Spitz melanocytoma from outside hospital consultations in Department of Pathology, Affiliated Cancer Hospital of Fudan University in August 2020 and in Shanghai Ackermann Medical Laboratory in June 2022 were collected. The clinicopathological features, immunophenotypes and molecular profiles of two patients with cutaneous Spitzoid melanocytic tumor harboring ALK-rearrangement were analyzed. The literatures were reviewed. Results: The study included an 8-year-old boy and an 11-year-old girl, who presented with a polypoid lesion in the skin of right thigh and left auricle measuring 1.0 cm and 1.2 cm, respectively. Histologically, they were composed of medium to large-sized epithelioid to plump spindle cells, arranged in nested, plexiform or fascicular patterns in the superficial dermis. The neoplastic cells had abundant eosinophilic cytoplasm with round to ovoid vesicular nuclei containing prominent eosinophilic nucleoli. One case showed mild to moderate nuclear pleomorphism and mitotic activity (average, 2/mm2). Immunohistochemically, the epithelioid and plump spindle cells showed diffuse and strong staining of S-100 protein, SOX10, and ALK (D5F3 and 1A4), but did not express HMB45, PNL2 and MiTF. ALK-rearrangement was detected by fuorescence in situ hybridization in both cases. Subsequent next generation sequence (NGS) analysis identified KANK1::ALK and TPM3:ALK fusions. At 34 and 14 months after surgical resection, both patients remained well with no signs of recurrence or metastasis. Conclusions: ALK-rearranged Spitz melanocytoma represents a morphologically and genetically distinct subset of Spitz melanocytoma, characterized clinically by predilection in children and adolescents, with Spitzoid morphology in plexiform pattern, positive immunohistochemical stains, and rearrangement of ALK. As some cases show atypical features and high mitotic activity, a distinction from Spitz melanoma is warranted.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s Disease

ObjectiveEpigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn’s disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as...

First Detection of Hepatitis B Virus Subgenotype A5, and Characterization of Occult Infection and Hepatocellular Carcinoma-Related Mutations in Latin American and African Immigrants in Brazil.

This study aims to characterize the molecular profile of the hepatitis B virus (HBV) among socially vulnerable immigrants residing in Brazil to investigate the introduction of uncommon HBV strains into the country. Serum samples from 102 immigrants with positive serology for the HBV core antibody (anti-HBc) were tested for the presence of HBV DNA by PCR assays. Among these, 24 were also positive for the HBV surface antigen (HBsAg). The full or partial genome was sequenced to determine genotype by phylogenetic analysis. Participants were from Haiti (79.4%), Guinea-Bissau (11.8%), Venezuela (7.8%), and Colombia (1%). Of the 21 HBV DNA-positive samples, subgenotypes A1 (52.4%), A5 (28.6%), E (9.5%), F2 (4.8%), and F3 (4.8%) were identified. Among the 78 HBsAg-negative participants, four were positive for HBV DNA, resulting in an occult HBV infection rate of 5.1%. Phylogenetic analysis suggested that most strains were likely introduced to Brazil by migration. Importantly, 80% of A5 sequences had the A1762T/G1764A double mutation, linked to an increased risk of hepatocellular carcinoma development. In conclusion, this study is the first report of HBV subgenotype A5 in Brazil, shedding new light on the diversity of HBV strains circulating in the country. Understanding the genetic diversity of HBV in immigrant communities can lead to better prevention and control strategies, benefiting both immigrants and wider society.

Microbiological and molecular profile of furcation defects in a population with untreated periodontitis.

To describe the microbiological composition of subgingival dental plaque and molecular profile of gingival crevicular fluid (GCF) of periodontal furcation-involved defects. Fifty-seven participants with periodontitis contributed with a degree II-III furcation involvement (FI), a non-furcation (NF) periodontal defect and a periodontally healthy site (HS). Subgingival plaque was analysed by sequencing the V3-V4 region of the 16S rRNA gene, and a multiplex bead immunoassay was carried out to estimate the GCF levels of 18 GCF biomarkers. Aiming to explore inherent patterns and the intrinsic structure of data, an AI-clustering method was also applied. In total, 171 subgingival plaque and 84 GCF samples were analysed. Four microbiome clusters were identified and associated with FI, NF and HS. A reduced aerobic microbiota (p = .01) was detected in FI compared with NF; IL-6, MMP-3, MMP-8, BMP-2, SOST, EGF and TIMP-1 levels were increased in the GCF of FI compared with NF. This is the first study to profile periodontal furcation defects from a microbiological and inflammatory standpoint using conventional and AI-based analyses. A reduced aerobic microbial biofilm and an increase of several inflammatory, connective tissue degradation and repair markers were detected compared with other periodontal defects.

BRCA1/2 Mutations and Breast/Ovarian Cancer Risk: A New Insights Review.

Breast and ovarian cancers are significant global health concerns, and understanding their genetic underpinnings is essential for effective prevention and cure. This narrative review provides a comprehensive analysis of studies conducted between 1994 and June 2024, focusing on the link between specific mutations in the breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) and the associated risks of both breast and ovarian cancers. It encompasses the findings of various works, including observational studies and molecular profiling analyses. Conducted on large international cohorts, these studies present compelling evidence of the relationship between different BRCA1 and BRCA2 mutations and the varying risks of breast and ovarian cancer. Furthermore, this review highlights the significance of nonsense-mediated decay mutations and their impact on cancer risk, particularly concerning the age of breast cancer onset. The implications of these findings are far-reaching, offering valuable information for risk assessment and decision-making in managing individuals who carry BRCA1 or BRCA2 mutations. The molecular subtyping profile BluePrint is discussed as a potential tool for enhancing clinical care by aiding the selection of appropriate treatment options, such as endocrine therapy or chemotherapy, based on the tumor's molecular characteristics. In conclusion, we establish a robust link between specific BRCA1 and BRCA2 gene mutations and increased susceptibility to breast and ovarian cancers. These mutations impact cancer onset age and severity, underscoring the need for targeted testing and screening. The current study enhances cancer detection, prevention, and cure strategies.

Durable benefit and slowdown in tumor growth dynamics with erdafitinib in a FGFR3-TACC3 fusion-positive IDH-wild type glioblastoma.

FGFR3-TACC3 fusion-positive IDH-wild-type (IDH-WT) glioblastoma (GB) is a rare GB subtype occurring in approximately 3% of cases. It is clinical behavior and molecular profile is different from those of fusion-negative IDH-WT GBs. Evidence on the role of FGFR inhibitors in FGFR-altered gliomas is limited. We present the case of a patient with a FGFR3-TACC3 fusion-positive IDH-WT GB that at its second recurrence was treated with the FGFR inhibitor erdafitinib through a compassionate use program. Although no objective response was achieved, an overt deceleration in tumor growth was evidenced and the patient remained on treatment for 5.5 months.

Biomarker Landscape in RASopathies.

RASopathies are a group of related genetic disorders caused by mutations in genes within the RAS/MAPK signaling pathway. This pathway is crucial for cell division, growth, and differentiation, and its disruption can lead to a variety of developmental and health issues. RASopathies present diverse clinical features and pose significant diagnostic and therapeutic challenges. Studying the landscape of biomarkers in RASopathies has the potential to improve both clinical practices and the understanding of these disorders. This review provides an overview of recent discoveries in RASopathy molecular profiling, which extend beyond traditional gene mutation analysis. mRNAs, non-coding RNAs, protein expression patterns, and post-translational modifications characteristic of RASopathy patients within pivotal signaling pathways such as the RAS/MAPK, PI3K/AKT/mTOR, and Rho/ROCK/LIMK2/cofilin pathways are summarized. Additionally, the field of metabolomics holds potential for uncovering metabolic signatures associated with specific RASopathies, which are crucial for developing precision medicine. Beyond molecular markers, we also examine the role of histological characteristics and non-invasive physiological assessments in identifying potential biomarkers, as they provide evidence of the disease's effects on various systems. Here, we synthesize key findings and illuminate promising avenues for future research in RASopathy biomarker discovery, underscoring rigorous validation and clinical translation.

Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer

BackgroundBiomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).MethodsWe analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.FindingsAnalyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).InterpretationGenomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Recent Insights into the Neurobiology of Alzheimer's Disease and Advanced Treatment Strategies.

In recent years, significant advancements have been made in understanding Alzheimer's disease from both neurobiological and clinical perspectives. Exploring the complex systems underlying AD has unveiled insights that could potentially revolutionize therapeutic approaches. Recent investigations have highlighted intricate interactions among genetic, molecular, and environmental factors in AD. Optimism arises from neurobiological advancements and diverse treatment options, potentially slowing or halting disease progression. Amyloid-beta plaques and tau protein tangles crucially influence AD onset and progression. Emerging treatments involve diverse strategies, such as approaches targeting multiple pathways involved in AD pathogenesis, such as inflammation, oxidative stress, and synaptic dysfunction pathways. Clinical trials using humanized monoclonal antibodies, focusing on immunotherapies eliminating amyloid-beta, have shown promise. Nonpharmacological interventions such as light therapy, electrical stimulation, cognitive training, physical activity, and dietary changes have drawn attention for their potential to slow cognitive aging and enhance brain health. Precision medicine, which involves tailoring therapies to individual genetic and molecular profiles, has gained traction. Ongoing research and interdisciplinary collaboration are expected to yield more effective treatments.

9 Delving into molecular underpinnings of sarcomatoid/rhabdoid dedifferentioation in renal cancers using spatial profiling

Abstract Background Renal cell carcinomas (RCC) are characterized by their largely diverse clinical outcomes. Leveraging genomic diversity among individual tumors, our research during the past decade has concentrated on developing personalized medicine approaches for the most common and the most aggressive type of RCC, clear cell renal carcinoma (ccRCC). We generated the largest dataset of ccRCC including somatic genomic and clinical annotations for over 940 ccRCC patients, and developed a genomic classifier, based on mutational status of 12 RCC-relevant genes, which is able to stratify patients according to their risk of relapse after nephrectomy and/or death due to RCC. Furthermore, we noticed the presence of mesenchymal-like cellular phenotypes in tumors of high-risk patients, representsing a de-differentiation process, known as sarcomatoic or rhabdoid (S/R) de-differentation. Methods The current knowledge about molecular mechanisms that may drive S/R de-differentiation is primarily generated from molecular profiling of bulk tumors, collecting data from a mixture of cells that co-exist in the tumor milieu. Therefore, high-resolution studies that precisely define molecular characteristics of different cellular phenotypes associated with S/R features are missing. We have used spatial transcriptomic profiling to investigate molecular mechanisms that underline S/R de-differentationin RCC. While preserving tissue context, we applied spatial whole human transcriptome profiling to areas exhibiting S/R or clear cell phenotypes within the same tumor specimens to generate phenotype-specific transcriptome profiles. In addition, we applied whole-exome sequencing (WES) to independent areas that exhibit different differentiation phenotype withing same tumors. Results Pathway and network analysis of genesets with upregulation in each area have revealed meaningful differences in cellular pathways which are active in each phenotype. Specifically, we observed that dysregulation of extracellular matrix (ECM) is a hallmark of S/R areas within RCC tumors. Furthermore, WES of phenotypically-distinct areas within each tumor has shed new light son the genome evoltuion of S/R phenotypes. Conclusions S/R dedifferentiation in RCC tumors is characterized by specific genomic evolutionary patterns and substantial dysregulation of ECM components. DOD CDMRP Funding: yes

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

JOSA: Joint surface-based registration and atlas construction of brain geometry and function

Surface-based cortical registration is an important topic in medical image analysis and facilitates many downstream applications. Current approaches for cortical registration are mainly driven by geometric features, such as sulcal depth and curvature, and often assume that registration of folding patterns leads to alignment of brain function. However, functional variability of anatomically corresponding areas across subjects has been widely reported, particularly in higher-order cognitive areas. In this work, we present JOSA, a novel cortical registration framework that jointly models the mismatch between geometry and function while simultaneously learning an unbiased population-specific atlas. Using a semi-supervised training strategy, JOSA achieves superior registration performance in both geometry and function to the state-of-the-art methods but without requiring functional data at inference. This learning framework can be extended to any auxiliary data to guide spherical registration that is available during training but is difficult or impossible to obtain during inference, such as parcellations, architectonic identity, transcriptomic information, and molecular profiles. By recognizing the mismatch between geometry and function, JOSA provides new insights into the future development of registration methods using joint analysis of brain structure and function.

Clinical Presentation and Treatment Strategies for Laryngeal Neuroendocrine Carcinoma: Insights from a Rare Case

Intriduction -Neuroendocrine neoplasms (NEN) of the larynx are very rare, accounting for <1% of all laryngeal carcinomas. Based on the 2022 IARCH/WHO classification, NENs are characterised as well-differentiated neuroendocrine tumours (NET), which can further be divided into grades 1-3 based on Ki-67 levels and mitotic count, or poorly differentiated neuroendocrine carcinomas (NEC) consisting of small cell carcinoma and large cell carcinoma. In this case report, we describe a rare presentation of NEC of the larynx encountered in a 54-year-old man and how diagnostic and therapeutic dilemmas unfolded. Case description: A 6-month history of breathing and swallowing difficulties led to a tracheostomy due to stridor, in the emergency department. Imaging revealed a soft tissue mass involving the supraglottic larynx but no significant associated cervical lymphadenopathy. The biopsy from the growth was suggestive of poorly differentiated NEC as an AJCC stage cT3N0M0. However, there was local progression post-initial treatment with vincristine, doxorubicin and cyclophosphamide (VAC). The chemotherapy regimen was switched to carboplatin and etoposide. The patient received definitive radiation therapy and completed the planned dose of radiation.After 10 months of disease-free interval, there was local recurrence with lung nodules that prompted rechallenge with platinum and etoposide. The patient is doing well and remains clinically and radiologically stable to maintenance therapy with carboplatin & etoposide. Conclusion: NENs of the larynx and especially NECs, are difficult to diagnose as they are rare and have varied molecular profiles. Its management frequently calls for multimodal approaches with chemotherapy and radiation therapy. Due to the developments in diagnostic and therapeutic modalities, our knowledge of NENs has been enhanced which contributed to better practice standards. Nevertheless, standardized treatment strategies remain to be determined by large cohort studies and comprehensive molecular profiling that can determine improved clinical outcomes.

Tissue characterization at an enhanced resolution across spatial omics platforms with deep generative model

Recent advances in spatial omics have expanded the spectrum of profiled molecular categories beyond transcriptomics. However, many of these technologies are constrained by limited spatial resolution, hindering our ability to deeply characterize intricate tissue architectures. Existing computational methods primarily focus on the resolution enhancement of transcriptomics data, lacking the adaptability to address the emerging spatial omics technologies that profile various omics types. Here, we introduce soScope, a unified generative framework designed to enhance data quality and spatial resolution for molecular profiles obtained from diverse spatial technologies. soScope aggregates multimodal tissue information from omics, spatial relations and images, and jointly infers omics profiles at enhanced resolutions with omics-specific modeling through distribution priors. With comprehensive evaluations on diverse spatial omics platforms, including Visium, Xenium, spatial-CUT&Tag, and slide-DNA/RNA-seq, soScope improves performances in identifying biologically meaningful intestine and kidney architectures, revealing embryonic heart structure that cannot be resolved at the original resolution and correcting sample and technical biases arising from sequencing and sample processing. Furthermore, soScope extends to spatial multiomics technology spatial-CITE-seq and spatial ATAC-RNA-seq, leveraging cross-omics reference for simultaneous multiomics enhancement. soScope provides a versatile tool to improve the utilization of continually expanding spatial omics technologies and resources.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information. Integration of single-cell and spatial transcriptomics uncover region-specific markers and zonation patterns of expression. Network inference shows heterogeneous gene regulatory networks across the CCS. Notably, region-specific gene regulation is recapitulated in vitro using neonatal mouse atrial and ventricular myocytes overexpressing CCS-specific transcription factors, Tbx3 and/or Irx3. This finding is supported by ATAC-seq of different CCS regions, Tbx3 ChIP-seq, and Irx motifs. Overall, this study provides comprehensive molecular profiles of the postnatal CCS and elucidates gene regulatory mechanisms contributing to its heterogeneity.