Distinct Phenotypes Research Articles

Visuo-Cognitive Phenotypes in Early Multiple Sclerosis: A Multisystem Model of Visual Processing

Background: Cognitive impairment can emerge in the earliest stages of multiple sclerosis (MS), with heterogeneity in cognitive deficits often hindering symptom identification and management. Sensory–motor dysfunction, such as visual processing impairment, is also common in early disease and can impact neuropsychological task performance in MS. However, cognitive phenotype research in MS does not currently consider the relationship between early cognitive changes and visual processing impairment. Objectives: This study explored the relationship between cognition and visual processing in early MS by adopting a three-system model of afferent sensory, central cognitive and efferent ocular motor visual processing to identify distinct visuo-cognitive phenotypes. Methods: Patients with clinically isolated syndrome and relapsing–remitting MS underwent neuro-ophthalmic, ocular motor and neuropsychological evaluation to assess each visual processing system. The factor structure of ocular motor variables was examined using exploratory factor analysis, and phenotypes were identified using latent profile analysis. Results: Analyses revealed three ocular-motor constructs (cognitive control, cognitive processing speed and basic visual processing) and four visuo-cognitive phenotypes (early visual changes, efferent-cognitive, cognitive control and afferent-processing speed). While the efferent-cognitive phenotype was present in significantly older patients than was the early visual changes phenotype, there were no other demographic differences between phenotypes. The efferent-cognitive and cognitive control phenotypes had poorer performance on the Symbol Digit Modalities Test compared to that of other phenotypes; however, no other differences in performance were detected. Conclusion: Our findings suggest that distinct visual processing deficits in early MS may differentially impact cognition, which is not captured using standard neuropsychological evaluation. Further research may facilitate improved symptom identification and intervention in early disease.

Identification of four latent classes of acute respiratory distress syndrome using PaO2/FIO2 ratio: an observational cohort study

Biological phenotypes in patients with the acute respiratory distress syndrome (ARDS) have previously been described. We hypothesized that the trajectory of PaO2/FIO2 ratio could be used to identify phenotypes of ARDS. We used a retrospective cohort analysis of an ARDS database to identify latent classes in the trajectory of PaO2/FIO2 ratio over time. We included all adult patients admitted to an intensive care unit who met the Berlin criteria for ARDS over a 4-year period in tertiary adult intensive care units in Manitoba, Canada. Baseline demographics were collected along with the daily PaO2/FIO2 ratio collected on admission and on days 1–7, 14 and 28. We used joint growth mixture modeling to test whether ARDS patients exhibit distinct phenotypes with respect to both longitudinal PaO2/FIO2 ratio and survival. The resulting latent classes were compared on several demographic variables. In our study group of 209 patients, we found that four latent trajectory classes of PaO2/FIO2 ratio was optimal. These four classes differed in their baseline PaO2/FIO2 ratio and their trajectory of improvement during the 28 days of the study. Despite similar baseline characteristics the hazard for death for the classes differed over time. This difference was largely driven by withdrawal of life sustaining therapy in one of the classes. Latent classes were identified in the trajectory of the PaO2/FIO2 ratio over time, suggesting the presence of different ARDS phenotypes. Future studies should confirm the existence of this finding and determine the cause of mortality differences between classes.

Fitness effects of a demography-dispersal trade-off in expandingSaccharomyces cerevisiaemats.

Fungi expand in space and time to form complex multicellular communities. The mechanisms by which they do so can vary dramatically and determine the life-history and dispersal traits of expanding populations. These traits influence deterministic and stochastic components of evolution, resulting in complex eco-evolutionary dynamics during colony expansion. We perform experiments on budding yeast strains genetically engineered to display rough-surface and smooth-surface phenotypes in colony-like structures called 'mats'. Previously, it was shown that the rough-surface strain has a competitive advantage over the smooth-surface strain when grown on semi-solid media. We experimentally observe the emergence and expansion of segments with a distinct smooth-surface phenotype during rough-surface mat development. We propose a trade-off between dispersal and local carrying capacity to explain the relative fitness of these two phenotypes. Using a modified stepping-stone model, we demonstrate that this trade-off gives the high-dispersing, rough-surface phenotype a competitive advantage from standing variation, but that it inhibits this phenotype's ability to invade a resident smooth-surface population via mutation. However, the trade-off improves the ability of the smooth-surface phenotype to invade in rough-surface mats, replicating the frequent emergence of smooth-surface segments in experiments. Together, these computational and experimental findings advance our understanding of the complex eco-evolutionary dynamics of fungal mat expansion.

Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer

Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (“hot nodule”), while the second displayed significantly fewer infiltrating lymphocytes (“cold nodule”). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.

Left main coronary artery morphological phenotypes and its hemodynamic properties.

Atherosclerosis may be linked to morphological defects that lead to variances in coronary artery hemodynamics. Few objective strategies exit at present for generalizing morphological phenotypes of coronary arteries in terms of hemodynamics. We used unsupervised clustering (UC) to classify the morphology of the left main coronary artery (LM) and looked at how hemodynamic distribution differed between phenotypes. In this study, 76 LMs were obtained from 76 patients. After LMs were reconstructed with coronary computed tomography angiography, centerlines were used to extract the geometric characteristics. Unsupervised clustering was carried out using these characteristics to identify distinct morphological phenotypes of LMs. The time-averaged wall shear stress (TAWSS) for each phenotype was investigated by means of computational fluid dynamics (CFD) analysis of the left coronary artery. We identified four clusters (i.e., four phenotypes): Cluster 1 had a shorter stem and thinner branches (n = 26); Cluster 2 had a larger bifurcation angle (n = 10); Cluster 3 had an ostium at an angulation to the coronary sinus and a more curved stem, and thick branches (n = 10); and Cluster 4 had an ostium at an angulation to the coronary sinus and a flatter stem (n = 14). TAWSS features varied widely across phenotypes. Nodes with low TAWSS (L-TAWSS) were typically found around the branching points of the left anterior descending artery (LAD), particularly in Cluster 2. Our findings demonstrated that UC is a powerful technique for morphologically classifying LMs. Different LM phenotypes exhibited distinct hemodynamic characteristics in certain regions. This morphological clustering method could aid in identifying people at high risk for developing coronary atherosclerosis, hence facilitating early intervention.

Chronic and acute exposure to rotenone reveals distinct Parkinson's disease-related phenotypes in human iPSC-derived peripheral neurons

Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). The majority of PD cases are sporadic and lack identified PD-associated genes involved. Epidemiological and animal model studies suggest an association with pesticides and other environmental toxins. However, the cellular mechanisms underlying toxin induced P-ANS dysfunctions remain unclear. Here, we mapped the global transcriptome changes in human induced pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons during inhibition of the mitochondrial respiratory chain by the PD-related pesticide, rotenone. We revealed distinct transcriptome profiles between acute and chronic exposure to rotenone. In the acute stage, there was a down regulation of specific cation channel genes, known to mediate electrophysiological activity, while in the chronic stage, the human P-ANS neurons exhibited dysregulation of anti-apoptotic and Golgi apparatus-related pathways. Moreover, we identified the sodium voltage-gated channel subunit SCN3A/Nav1.3 as a potential biomarker in human P-ANS neurons associated with PD. Our analysis of the rotenone-altered coding and non-coding transcriptome of human P-ANS neurons may thus provide insight into the pathological signaling events in the sympathetic neurons during PD progression.

Metabolic-Related Gene Prognostic Index for Predicting Prognosis, Immunotherapy Response, and Candidate Drugs in Ovarian Cancer.

Ovarian cancer (OC) is a highly heterogeneous disease, with patients at different tumor staging having different survival times. Metabolic reprogramming is one of the key hallmarks of cancer; however, the significance of metabolism-related genes in the prognosis and therapy outcomes of OC is unclear. In this study, we used weighted gene coexpression network analysis and differential expression analysis to screen for metabolism-related genes associated with tumor staging. We constructed the metabolism-related gene prognostic index (MRGPI), which demonstrated a stable prognostic value across multiple clinical trial end points and multiple validation cohorts. The MRGPI population had its distinct molecular features, mutational characteristics, and immune phenotypes. In addition, we investigated the response to immunotherapy in MRGPI subgroups and found that patients with low MRGPI were prone to benefit from anti-PD-1 checkpoint blockade therapy and exhibited a delayed treatment effect. Meanwhile, we identified four candidate therapeutic drugs (ABT-737, crizotinib, panobinostat, and regorafenib) for patients with high MRGPI, and we evaluated the pharmacokinetics and safety of the candidate drugs. In summary, the MRGPI was a robust clinical feature that could predict patient prognosis, immunotherapy response, and candidate drugs, facilitating clinical decision making and therapeutic strategy of OC.

Domestication and the evolution of crops: variable syndromes, complex genetic architectures, and ecological entanglements.

Domestication can be considered a specialized mutualism in which a domesticator exerts control over the reproduction or propagation (fitness) of a domesticated species to gain resources or services. The evolution of crops by human-associated selection provides a powerful set of models to study recent evolutionary adaptations and their genetic bases. Moreover, the domestication and dispersal of crops such as rice, maize, and wheat during the Holocene transformed human social and political organization by serving as the key mechanism by which human societies fed themselves. Here we review major themes and identify emerging questions in three fundamental areas of crop domestication research: domestication phenotypes and syndromes, genetic architecture underlying crop evolution, and the ecology of domestication. Current insights on the domestication syndrome in crops largely come from research on cereal crops such as rice and maize, and recent work indicates distinct domestication phenotypes can arise from different domestication histories. While early studies on the genetics of domestication often identified single large-effect loci underlying major domestication traits, emerging evidence supports polygenic bases for many canonical traits such as shattering and plant architecture. Adaptation in human-constructed environments also influenced ecological traits in domesticates such as resource acquisition rates and interactions with other organisms such as root mycorrhizal fungi and pollinators. Understanding the ecological context of domestication will be key to developing resource-efficient crops and implementing more sustainable land management and cultivation practices.

Phenotypic subtypes of fibrotic hypersensitivity pneumonitis identified by machine learning consensus clustering analysis

BackgroundPatients with fibrotic hypersensitivity pneumonitis (f-HP) have varied clinical and radiologic presentations whose associated phenotypic outcomes have not been previously described. We conducted a study to evaluate mortality and lung transplant (LT) outcomes among clinical clusters of f-HP as characterized by an unsupervised machine learning approach.MethodsConsensus cluster analysis was performed on a retrospective cohort of f-HP patients diagnosed according to recent international guideline. Demographics, antigen exposure, radiologic, histopathologic, and pulmonary function findings along with comorbidities were included in the cluster analysis. Cox proportional-hazards regression was used to assess mortality or LT risk as a combined outcome for each cluster.ResultsThree distinct clusters were identified among 336 f-HP patients. Cluster 1 (n = 158, 47%) was characterized by mild restriction on pulmonary function testing (PFT). Cluster 2 (n = 46, 14%) was characterized by younger age, lower BMI, and a higher proportion of identifiable causative antigens with baseline obstructive physiology. Cluster 3 (n = 132, 39%) was characterized by moderate to severe restriction. When compared to cluster 1, mortality or LT risk was lower in cluster 2 (hazard ratio (HR) of 0.42; 95% CI, 0.21–0.82; P = 0.01) and higher in cluster 3 (HR of 1.76; 95% CI, 1.24–2.48; P = 0.001).ConclusionsThree distinct phenotypes of f-HP with unique mortality or transplant outcomes were found using unsupervised cluster analysis, highlighting improved mortality in fibrotic patients with obstructive physiology and identifiable antigens.

Exploring the Interactions between Obesity and Diabetes: Implications for Understanding Metabolic Dysregulation in a Saudi Arabian Adult Population.

The rising prevalence of obesity in Saudi Arabia is a major contributor to the nation's high levels of cardiometabolic diseases such as type 2 diabetes. To assess the impact of obesity on the diabetic metabolic phenotype presented in young Saudi Arabian adults, participants (n = 289, aged 18-40 years) were recruited and stratified into four groups: healthy weight (BMI 18.5-24.99 kg/m2) with (n = 57) and without diabetes (n = 58) or overweight/obese (BMI > 24.99 kg/m2) with (n = 102) and without diabetes (n = 72). Distinct plasma metabolic phenotypes associated with high BMI and diabetes were identified using nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography mass spectrometry. Increased plasma glucose and dysregulated lipoproteins were characteristics of obesity in individuals with and without diabetes, but the obesity-associated lipoprotein phenotype was partially masked in individuals with diabetes. Although there was little difference between diabetics and nondiabetics in the global plasma LDL cholesterol and phospholipid concentration, the distribution of lipoprotein particles was altered in diabetics with a shift toward denser and more atherogenic LDL5 and LDL6 particles, which was amplified in the presence of obesity. Further investigation is warranted in larger Middle Eastern populations to explore the dysregulation of metabolism driven by interactions between obesity and diabetes in young adults.

Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks

Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. β-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized ligands for inducing innate immune training. However, many Dectin-1 ligands exist, and it is not known whether these all produce the same phenotype. Using a well-established in vitro model of innate immune training, we compared two commercially available Dectin-1 agonists, zymosan and depleted zymosan, with the gold standard β-glucan in the literature. We found that depleted zymosan, a β-glucan purified from Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical effects as C. albicans β-glucan. However, untreated zymosan produced a distinct training effect from β-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of cytokines such as TNF and IL-6. Zymosan activated NFκB and AP-1 transcription factors more strongly than β-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of β-glucans to a phenotype resembling zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1 ligands.

Abstract A065: Lineage tracing oncogenic isoforms of HER2 in a mouse model of pancreatic cancer

Abstract Among the numerous clinical challenges of pancreatic ductal adenocarcinoma (PDAC) is the eventual development of therapeutic resistance. Although previous studies report that only about 3% of PDAC cases are HER2 gene amplified, as many as 82% of PDAC tumors may have HER2 overexpressed. Anti-HER2 therapy with trastuzumab has yielded tremendous therapeutic success in breast cancer and multiple gastrointestinal malignancies, however minimal benefit is found in PDAC. Experimental mouse models have demonstrated initiation and acceleration of pancreatic tumorigenesis through overexpression of activated mutant HER2, yet the role of HER2 alone as a driver of PDAC and treatment resistance is still unknown. Multiple HER2 isoforms exist that are generated either via alternative splicing and loss of exon 16 (d16 HER2) or through N-terminal truncations (p95 HER2). These isoforms are implicated in differential responses to anti-HER2 therapy in the breast. Previously we described a HER2+ cancer rainbow mouse model in which human wild-type HER2 (WT HER2), d16 HER2, and p95 HER2 were expressed in the same mouse and lineage traced through co-expression of fluorescent protein reporters. Studies in the mammary gland revealed that each isoform drives distinct tumor phenotypes. Herein, we hypothesize that these isoforms drive HER2 positive PDAC. HER2 Crainbow mice were crossed with mice expressing PDX1-Cre recombinase to initiate recombination and expression of each fluorescently labelled HER2 isoform during pancreas development. PDX1-Cre/HER2 Crainbow (PHBOW) mice were followed for up to one year and sacrificed to lineage trace each isoform and register HER2 lineages with histopathology. Within our pilot cohort, early-stage pre-malignant pancreatic intraepithelial neoplasia (PanIN-1) was observed in 75% of PDAC HER2bow mice as early as five weeks. By one year, 50% demonstrated high grade PanIN (i.e. PanIN-3) and features of early invasion. Although WT HER2 was expressed abundantly throughout the pancreas, lineage tracing revealed WT HER2 was not found in pre-malignant lesions. Conversely, the pre-malignant PanIN lesions and early invasive histopathologic features traced to d16 HER2 expressing cells, while p95 HER2 traced with areas of acinar-to-ductal metaplasia, lesions known to be early initiators of pancreatic dysplasia. Our data show how the oncogenic HER2 isoforms, and not WT HER2, are able to drive PanIN lesions and, at lower frequency, invasive PDAC after one year. Future work seeks to complete HER2 Crainbow lineage tracing in PHBOW mice, test HER2 targeted therapy in PHBOW mice, and quantify HER2 isoforms in HER2+ human PDAC cases. Citation Format: Elishama N. Kanu, Joelle Sills, Rebecca Shelley, Joshua D. Ginzel, Joseph Fernandes, Ashley A. Fletcher, Peter J. Allen, Daniel P. Nussbaum, Joshua C. Snyder. Lineage tracing oncogenic isoforms of HER2 in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A065.

The phenotypic diversity of anteromedial osteoarthritis before and after treatment with medial unicompartmental knee arthroplasty: A radiographic analysis of 1000 knees.

This study aimed to assess phenotypic variation in the coronal plane of knees with anteromedial osteoarthritis using the functional knee phenotype classification, before and after treatment with medial unicompartmental knee arthroplasty (UKA). The study comprised 1000 knees of 835 patients (45% females, 55% males, 90% Caucasian) who underwent medial UKA for anteromedial osteoarthritis. Pre and postoperative alignment was evaluated through the hip-knee-ankle angle (HKA), femoral mechanical angle (FMA), and tibial mechanical angle (TMA). Knees were classified according to the functional knee phenotype system which combines limb phenotype (HKA), and femoral and tibial knee phenotypes (FMA and TMA, respectively). Restoration of prearthritic coronal alignment following medial UKA was evaluated by phenotype. Preoperatively, 76 distinct and 25 relevant (prevalence ≥1%) functional knee phenotypes were identified, of which VARHKA 6°VARFMA 3°NEUTMA 0° was the most common (9.4% of knees). The most prevalent limb phenotype, VARHKA 6°, comprised 15 distinct knee phenotypes (FMA and TMA combinations). Postoperatively, 58 distinct and 17 relevant functional knee phenotypes were observed, of which VARHKA 3°NEUFMA 0°NEUTMA 0° had the highest prevalence at 18.3%. Knees with combined tibial and femoral deformities were associated with a lower probability of restoration of prearthritic coronal alignment following medial UKA, compared to knees without extra-articular deformity, or knees with an isolated tibial or femoral deformity. Phenotype analysis using the functional knee phenotype system demonstrated a wide diversity of coronal alignment phenotypes among knees with anteromedial osteoarthritis in a predominantly Caucasian population. Following medial UKA, a reduction from 25 preoperative to 17 postoperative relevant phenotypes was observed. Consideration of phenotypic variation can be of importance when aiming to restore prearthritic coronal alignment during medial UKA. Level III, retrospective cohort study.

Elevated Eosinophil Counts in Acute Exacerbations of Bronchiectasis: Unveiling a Distinct Clinical Phenotype.

Non-cystic fibrosis bronchiectasis is a chronic respiratory disease characterized by bronchial dilation. However, the significance of elevated eosinophil counts in acute exacerbations of bronchiectasis remains unclear. This retrospective case-control study included 169 hospitalized patients with acute exacerbations of non-cystic fibrosis bronchiectasis. Based on blood eosinophil levels, patients were categorized into eosinophilic and non-eosinophilic bronchiectasis groups. Various clinical variables, including lung function, comorbidities and clinical features were collected for analysis. The study aimed to examine the differences between these groups and their clinical phenotypes. Eosinophilic bronchiectasis (EB) was present in approximately 22% of all hospitalized patients with bronchiectasis, and it was more prevalent among male smokers (P < 0.01). EB exhibited greater severity of bronchiectasis, including worse airway obstruction, higher scores in the E-FACED (FACED combined with exacerbations) and bronchiectasis severity index (BSI), a high glucocorticoids medication possession ratio, and increased hospitalization cost (P < 0.05 or P < 0.01). Furthermore, we observed a significant positive correlation between blood eosinophil count and both sputum eosinophils (r = 0.49, P < 0.01) and serum total immunoglobulin E levels (r = 0.21, P < 0.05). Additional analysis revealed that patients with EB had a higher frequency of shortness of breath (P < 0.05), were more likely to have comorbid sinusitis (P < 0.01), and exhibited a greater number of lung segments affected by bronchiectasis (P < 0.01). These findings suggest that EB presents a distinct pattern of bronchiectasis features, confirming the notion that it is a specific phenotype.

Discrete prefrontal neuronal circuits determine repeated stress-induced behavioral phenotypes in male mice

Chronic stress is a major risk factor for psychiatric disorders, including depression. Although depression is a highly heterogeneous syndrome, it remains unclear how chronic stress drives individual differences in behavioral responses. In this study, we developed a subtyping-based approach wherein stressed male mice were divided into four subtypes based on their behavioral patterns of social interaction deficits and anhedonia, the core symptoms of psychiatric disorders. We identified three prefrontal cortical neuronal projections that regulate repeated stress-induced behavioral phenotypes. Among them, the medial prefrontal cortex (mPFC)→anterior paraventricular thalamus (aPVT) pathway determines the specific behavioral subtype that exhibits both social deficits and anhedonia. Additionally, we identified the circuit-level molecular mechanism underlying this subtype: KDM5C-mediated epigenetic repression of Shisa2 transcription in aPVT projectors in the mPFC led to social deficits and anhedonia. Thus, we provide a set of biological aspects at the cellular, molecular, and epigenetic levels that determine distinctive stress-induced behavioral phenotypes.

Comprehensive review and expanding the genetic landscape of Cornelia-de-Lange spectrum: insights from novel mutations and skin biopsy in exome-negative cases

BackgroundCornelia de Lange Syndrome (CdLS) is a rare genetic disorder characterized by a range of physical, cognitive, and behavioral abnormalities. This study aimed to perform a comprehensive review of the literature on CdLS and investigate two cases of CdLS with distinct phenotypes that underwent WES to aid in their diagnosis.MethodsWe conducted a comprehensive review of the literature on CdLS along with performing whole-exome sequencing on two CdLS patients with distinct phenotypes, followed by Sanger sequencing validation and in-silico analysis.ResultsThe first case exhibited a classic CdLS phenotype, but the initial WES analysis of blood-derived DNA failed to identify any mutations in CdLS-related genes. However, a subsequent WES analysis of skin-derived DNA revealed a novel heterozygous mutation in the NIPBL gene (NM_133433.4:c.6534_6535del, p.Met2178Ilefs*8). The second case was presented with a non-classic CdLS phenotype, and WES analysis of blood-derived DNA identified a heterozygous missense variant in the SMC1A gene (NM_006306.4:c.2320G>A, p.Asp774Asn).ConclusionsThe study shows the importance of considering mosaicism in classic CdLS cases and the value of WES for identifying genetic defects. These findings contribute to our understanding of CdLS genetics and underscore the need for comprehensive genetic testing to enhance the diagnosis and management of CdLS patients.

P-32 A Seckel syndrome patient exhibited with metabolic problems

Abstract Introduction Seckel syndrome is a disease with nine distinct phenotypes that is inherited autosomally recessively and is caused by DNA damage on chromosomes 3, 13, and 18. It is also known as 'bird-headed dwarfism' due to the disease's characteristic phenotypic features, microcephaly and dwarfism. In addition to mental retardation, other possible complications include bilateral optic atrophy, strabismus, hearing difficulties, micrognathia, microdontia, hypodontia, malocclusion of the mandible, scoliosis, bone anomalies, hematological, endocrinological, genitourinary, neurological anomalies (epilepsy, etc.), and cancers. Presented here is a patient with metabolic dysfunction who has been diagnosed with Seckel's syndrome. Clinical Case A male patient, age 22, was admitted to the endocrinology outpatient clinic for regulation of hyperglycemia. The patient's medical history included diabetes of type 2 since 2021, hypothyroidism, mental retardation, and hepatosteatosis. His parents were related as first cousins. One of the patient's two brothers has been diagnosed with Seckel syndrome. On his physical examination, his temperature was 36.1°C, his blood pressure was 92/61 mmHg, his heart rate was 76 beats per minute, his height was 125 cm, his weight was 19 kg, and his BMI was 12 kg/m2. Microcephaly, hypodontia, and micrognotia were observed. The patient was using insulin glargin 32 units, insulin aspart 2×18 units, metformin 500mg once day, and levothyroxine sodium 50mcg. In blood glucose follow-ups, the highest was 304 mg/dl and the lowest was 127 mg/dl, whereas Hba1c was 7.5% and c-peptide was 2.44 ng/ml. Anti-GAD, anti-islet cell, anti-TPO, and antithyroglobulin antibodies were negative. Insulin glargine was changed to 34 units, and insulin aspart was changed to 2×20 units. Due to mental retardation and hypodontia, it was discovered that the patient could not pay attention to his diet, could hardly eat solid foods, and was provided primarily liquids, particularly sugar-sweetened, flavored, and carbonated soft drinks. The patient was referred to the dental polyclinic and dietitian, while the family was monitored at the genetics polyclinic. Conclusion Follow-up care for patients with Seckel syndrome should include routine metabolic screening. Due to the patient's mental cooperation and dietary habits resulting from dental anomalies, metabolic control may be challenging. To ensure metabolic homeostasis in these patients, a multidisciplinary approach is necessary, involving the patient, his or her family, in multidisciplinary setting.

Uncovering immune checkpoint heterogeneity in oral squamous cell carcinoma using single cell RNA-sequencing data highlights three subgroups of patients with distinct immune phenotypes

ObjectivesIn head and neck squamous cell carcinoma (HNSCC), PD-1/PD-L1 inhibitors remain inefficient in most patients, which points to the need for better characterization of immune checkpoint (ICP) molecule expression. Material and methodsWe evaluated the expression of 22 ICP ligands (ICPL) in 2,176 malignant cells from 10 patients in a public single-cell RNA-sequencing dataset and in two cohorts of HNSCC patients for which gene expression data are available. ResultsBased on ICPL expression, malignant cells formed three distinct clusters characterized either by a strong expression of ICPL together with an immune phenotype linked to IFN-γ response (cluster 1) or by a weak ICPL expression and little response to IFN-γ (clusters 2 and 3). Malignant cells from cluster 3 showed a high PD-L1 expression associated with NRF2 signature. The relevance of 3 groups of patients, i.e “high ICPL/high IFN-γ”, “low ICPL/low IFN-γ” or “low ICPL/low IFN-γ/high PD-L1” was confirmed in a cohort of 259 OSCC whole tumor samples from TCGA and in the CLB-IHN cohort including patients treated with PD1/PD-L1 inhibitors. The heterogeneous expression of ICPL among patients’ malignant cells was associated with immunologically distinct microenvironments, evaluated with the “hot/cold” and the Tumor microenvironment (TME) classification. Finally, the “low ICPL/low IFN-γ/high PD-L1” group 3 displayed a poor prognosis in the TCGA cohort. ConclusionHence, the global picture of ICPL gene expression in malignant cells from HNSCC patients may contribute to the broader issue of improving immunotherapy strategies though a better stratification of patients and the design of new treatment combinations.

Abnormal circulating steroids refine risk of progression to heart failure in ischemic heart disease.

Patients with ischemic heart disease (IHD) experience a high incidence of progression to heart failure (HF) despite current therapies. We speculated that steroid hormone metabolic disorders distinct adverse phenotypes and contribute to HF. We measured 18 steroids using liquid chromatography with tandem mass spectrometry in 2023 patients from the Registry Study of Biomarkers in Ischemic Heart Disease (BIOMS-IHD), including 1091 patients with IHD in a retrospective discovery set and 932 patients with IHD in a multicentre validation set. Our outcomes included incident HF after a median follow-up of 4 years. We demonstrated steroid-based signatures of inflammation, coronary microvascular dysfunction and left ventricular hypertrophy that were associated with subsequent HF events in patients with IHD. In both cohorts, patients with a high steroid-heart failure score (SHFS) (>1) exhibited a greater risk of incident HF than patients with a low SHFS (≤1). The SHFS further improved the prognostic accuracy beyond clinical variables (net reclassification improvement of 0.628 in the discovery set and 0.299 in the validation set) and demonstrated the maximal effect of steroid signatures in patients with IHD who had lower B-type natriuretic peptide levels (pinteraction = 0.038). A steroid-based strategy can simply and effectively identify individuals at higher HF risk who may derive benefit from more intensive follow-ups.

Genetic evidence on the causality between gut microbiota and various asthma phenotypes: a two-sample Mendelian randomization study.

Asthma is a multifarious disease that manifests in various phenotypes. Among the various factors that contribute to the development of asthma, the gut microbiota has recently emerged as a compelling area of investigation. This study aims to investigate the causal relationships between gut microbiota and distinct asthma phenotypes. The genome-wide association study (GWAS) summary statistics for 211 gut microbial taxa were used as study exposure. Five traits pertaining to various asthma phenotypes (asthma, allergic asthma, childhood asthma, suggestive for eosinophilic asthma and obesity-related asthma) were included as study outcome. We conducted Mendelian randomization (MR) analysis and sensitivity analysis for each bacterial taxa and asthma phenotypes. We discovered a total of 58 associations that exhibited evidence of causality. Out of these, 4 associations remained significant even after applying multiple correction. An increased risk of asthma was causally associated with higher abundance of genus Holdemanella (OR = 1.11; CI: 1.05-1.17; p = 0.027), genus Oxalobacter (OR = 1.09; CI: 1.04-1.15; p = 0.025) and genus Butyricimonas (OR = 1.14; CI: 1.06-1.22; p = 0.027). Order NB1n was causally linked with an increased risk of obesity-related asthma (OR = 1.17; CI: 1.07-1.29; p = 0.015). There was limited overlap among the taxa that exhibited potential causal relationships with distinct asthma phenotypes. Our research has provided genetic evidence that establishes multiple causal relationships between the gut microbiota and distinct asthma phenotypes, supporting the role of the gut microbiota in various asthma phenotypes. It is possible that different taxa play a role in the development of distinct asthma phenotypes. The causal relationships identified in this study require further investigation.