Individual Subtypes Research Articles

Paradigms in periorbital scar management

Periocular scarring following surgery or trauma is of great aesthetic and functional concern and is difficult to predict. In today’s era, with increasing scientific knowledge and technological advances, both physicians and their patients are highly concerned with minimizing scar appearance as a rising number of patients feel disappointed with their scars and are frequently seeking help for functional and aesthetic improvement. Although various non-surgical and surgical treatment strategies are available it is still difficult to improve excessive scarring. Thus, the importance of thorough knowledge of eyelid anatomy and heal­ing mechanisms along with appreciation of wound closure techniques like placing the sutures at natural cosmetic subunit junctions and along relaxed skin tension lines (RSTLs) in order to achieve scar camouflage and to ensure decreased tension on the wound cannot be more emphasised. Periorbital area should be tackled by the oculoplasty surgeons in view of their distinct anatomy and close proximity to the eye.Scars are commonly treated with a combination of non-surgical techniques, including watchful waiting, scar massage, pressure therapy, silicone gel sheeting, topical or intralesional injections, cryotherapy, laser therapy or radiotherapy. Surgical approaches include pincushioning debulking, direct scar excision, broken line closure techniques, scar lengthening procedures (Z plasty, V-Y/Y-V advancement) and scar excision with lid reconstruction. Mastery of this content is essential for consistent operative success. For good cosmetic and functional outcomes, scar revision techniques should be thoughtfully tailored to the individual and scar subtype.

B7-H3 is widely expressed in soft tissue sarcomas

PurposeTargeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.Patients and methodsThis retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.ResultsSpecimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93–0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61–0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.ConclusionThese data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Cardiovascular Risks With SGLT2 Inhibitors in Clinical Practice Among Patients With Type 2 Diabetes

Cardiovascular disease (CVD) can be recurrent during type 2 diabetes (T2D) progression in this aging population. The effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy on total (ie, first and subsequent) CVD among patients with T2D in clinical practice remains uncertain. To analyze the comparative association of SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP4i) therapy with total CVD among patients with T2D in clinical practice. This retrospective cohort study used electronic medical records at the National Cheng Kung University Hospital, a leading medical center in Taiwan, from 2015 through 2021. Adult patients with T2D who initiated first use of the study drugs from 2016 through 2019, with up to 6 years of follow-up, were identified. The primary outcomes included total composite CVD events and individual CVD subtypes (ie, atrial fibrillation, coronary heart disease, heart failure, stroke, myocardial infarction, and transient ischemic attack). A shared frailty model analysis was used to assess the association of treatment with repeat CVD events. Data from patients at high risk for CVD recurrence were further analyzed. Data were analyzed from September 1, 2022, to December 31, 2023. Overall, 8384 patients with T2D were identified (mean [SD] age, 63.7 [12.4] years; 4645 [55.4%] male). A total of 1632 propensity score-matched pairs of SGLT2i (mean [SD] age, 57.8 [12.0] years; 673 [41.2%] female and 959 [58.8%] male) and DPP4i (mean [SD] age, 58.2 [12.9] years; 655 [40.1%] female and 977 [59.9%] male) users were included. SGLT2i was associated with reduced total CVD risk vs DPP4i therapy (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98]) but not the first CVD event (with the use of SGLT2i therapy were more prominent for patients at high risk of CVD (ie, HR, 0.70 [95% CI, 0.62-0.80] for individuals with estimated glomerular filtration rate lower than 60 mL/min/1.73 m2; HR, 0.70 [95% CI, 0.64-0.78]; for individuals having any diabetes-related complications; and HR, 0.72 [95% CI, 0.65-0.80] for individuals with a history of CVD) compared with the overall cohort. Among patients at high risk of CVD, greater reduced total CVD burden associated with SGLT2i therapy was observed for women vs men (eg, HR, 0.59 [95% CI, 0.49-0.72] in the subgroup with CVD history). In this cohort study of patients with T2D, the use of SGLT2is vs DPP4is was associated with reduced total cardiovascular burden, suggesting that long-term use of this therapy may optimize treatment benefit among patients with chronic CVD. The SGLT2i-associated benefit among patients with high risk of CVD encourages the prioritization of SGLT2i use for these vulnerable individuals.

Using Bifactor Twin Modeling to Assess the Genetic and Environmental Dimensionality of Adult ADHD Symptoms.

Attention Deficit Hyperactivity Disorder (ADHD) is a common and heritable neurodevelopmental condition that has been the subject of a wealth of genetics research. Because ADHD has an early age of onset, most of this work has focused on children, meaning that less is known about the genetics of ADHD in adults. Additionally, while much research has assessed the heritability of ADHD as a general dimension, less has assessed the heritability of individual subtypes (inattention, hyperactivity) or symptoms of ADHD. It therefore remains unclear whether the genetic factors underlying ADHD symptoms conform to a unidimensional or multidimensional structure. The aim of this study was to assess the genetic and environmental dimensionality of adult ADHD symptoms. We analyzed data from 10,454 twins of the Twins Early Development Study, who provided self-reports of ADHD symptoms using the Conners scale at age 21 years. The data conformed well to a psychometric bifactor model, providing support for a general dimension of ADHD in addition to secondary dimensions for inattention and hyperactivity. However, a bifactor independent pathway twin model provided support for a general dimension only at the level of non-shared environmental effects and not additive genetic or shared environmental effects. This suggests that symptoms of ADHD cluster together under a general dimension of non-shared environmental effects, although the two subtypes of ADHD (inattention and hyperactivity) are meaningfully genetically distinct. We found the overall heritability of ADHD to be 40%, comparable with previous estimates for adult ADHD symptoms. Our results provide useful insights into the genetic and environmental architecture of specific ADHD symptoms.

Around the clock: unveiling giraffe rest-activity rhythms and social dynamics

Understanding the daily activity patterns and social dynamics of giraffes (Giraffa camelopardalis) is crucial for their management and conservation. In this study, a comprehensive 24-hour observational analysis of three female reticulated giraffes kept for three weeks at the Opel-Zoo in Kronberg, Germany, was conducted. Using infrared-sensitive cameras, the study captured behavioral data across baseline and two intervention phases involving changes in group composition. Social network analysis was performed using the Mantel test to assess changes in social interactions between day and night and across different study periods, while the MRQAP was applied to evaluate the influence of individual subtypes on the social structure. During the day, the giraffes exhibited a high level of activity, primarily engaging in walking, standing, and feeding behaviors. Diurnal resting was minimal, with sporadic lying phases. Night-time behavior was markedly different, with the giraffes spending most of the night lying down, interspersed with periods of feeding. The presence of a male giraffe during one intervention phase significantly altered diurnal activity patterns, increasing standing behaviors and decreasing feeding time. Social interactions, including nearest neighbor preferences, varied across day and night periods and changed with alterations in group composition. The study highlights the complexity of giraffe social dynamics and their adaptation to different social contexts. These findings provide valuable insights into the natural behavioral rhythms and social behaviors of giraffes, which are essential for effective zoo management and conservation strategies.

First trimester maternal infections and offspring congenital heart defects: a systematic review and meta-analysis

Abstract Background Maternal infections early in pregnancy have been proposed as playing a role in the development of congenital heart defects. We aimed to summarise contemporary evidence regarding the association between first-trimester maternal infection and risk of offspring congenital heart defects. Methods For this systematic review and meta-analysis, we searched Medline and Embase for studies reporting associations of at least one measure of maternal infection during pregnancy and offspring congenital heart disease in humans and published in English between January 1, 1990 and February 13, 2024. Studies were eligible for inclusion if they reported rates of offspring congenital heart defects among both infected and non-infected mothers, and included a minimum of 50 offspring with congenital heart defects. We stratified associations by type of infection and type of heart defect when data from at least two studies were available. We used inverse variance weighted random-effect meta-analyses to pool the estimates. In main analyses, we pooled crude estimates from studies reporting maternal infections during the first trimester of pregnancy. We performed sensitivity analyses to include studies that i) investigated infections later in pregnancy or at unspecified time-points, and ii) adjusted for potential confounders such as maternal age, socioeconomic status, or ethnicity. Findings: We identified 11 studies (7 case control studies, 4 cohort studies) with data from 1,805,115 pregnancies. Nine of these studies assessed maternal infectious status through self-reported questionnaires or medical records, two used laboratory antibody testing and three reported on specific infectious pathogens. Studies reported on various types of bacterial and viral infections, including influenza, urinary tract infections, cytomegalovirus, herpes simplex virus, or chlamydia, with varying effect sizes. Ten studies reported a positive association between maternal infection variables and offspring congenital heart defects, with a pooled odds ratio (OR) and 95% confidence interval of 1.56 (1.27, 1.91) across all types of infections. Associations differed by individual subtype of congenital heart defects, with ORs ranging from 1.28 (0.89, 1.85) for pulmonary atresia to 1.75 (1.23, 2.49) for ventricular septal defects. Sensitivity analyses that included infections measured later in pregnancy, or adjusted rates for potential confounders, showed broadly similar trends but attenuated effect sizes. Interpretation: First trimester maternal infections are associated with increased risk of congenital heart defects. Associations appear to vary by type of infection and type of congenital heart defect, and to extend beyond infections commonly tested for during routine pregnancy screening. Larger-scale studies are warranted to confirm these findings using laboratory antibody testing and investigating how these associations vary by specific pathogens and subtypes of congenital heart defects.

Examining the measurement of severity of intimate partner violence and its association to mental health outcomes: a narrative synthesis.

The aims of this synthesis were to investigate the relationship between IPV severity and mental health outcomes and shed light to gaps and limitations in existing methodologies used to assess IPV severity and its association with mental health outcomes. We conducted a two-stage narrative synthesis of 76 studies. First, we identified IPV measures used in at least five studies, focusing on their variations and severity score calculation. Then, we analyzed findings of studies correlating IPV severity with mental health outcomes, identifying features of measures and statistical methods influencing result consistency. Measures of intimate partner violence were often modified from their original, potentially impact on the reliability and validity of these measures. The operationalization of violence severity varied across studies, leading to inconsistencies in scoring whereby compromising the consistency of severity levels across studies. We found lack of consistency in applying validated methods for scoring instruments to determine abuse severity. In this review, we consistently found that the severity of IPV and its various subtypes were linked to different mental health outcomes across multiple studies. We discovered evidence suggesting that experiencing more types of IPV was associated with worse mental health outcomes. Generally, higher levels of overall IPV severity and its specific subtypes were correlated with poorer mental health outcomes. However, our analyses did not reveal consistent patterns that would allow for a definitive determination of how individual IPV subtypes differently affect mental health outcomes. Nevertheless, we observed that increasing severity of physical IPV tended to have a notable impact on post-traumatic stress disorder (PTSD). Conversely, increasing severity of psychological IPV was consistently associated with depression. While sexual IPV severity was explored in fewer studies, the evidence regarding its impact on various mental health outcomes was less conclusive. To achieve a comprehensive understanding of the mechanism by which IPV severity is related to mental health it may be time to take an alternative approach to measuring IPV severity. No IPV measures assessed the acceptability of the content to people who have experienced IPV. This is an important omission with significant consequences for the validity of the evidence base.

Activation of ionotropic and group I metabotropic glutamate receptors stimulates kisspeptin neuron activity in mice.

Different populations of hypothalamic kisspeptin (KISS1) neurons located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC) are thought to generate the sex-specific patterns of gonadotropin secretion. These neuronal populations integrate gonadal sex steroid feedback with internal and external cues relayed via the actions of neurotransmitters and neuropeptides. The excitatory amino acid neurotransmitter glutamate, the main excitatory neurotransmitter in the brain, plays a role in regulating gonadotropin secretion, at least partially through engaging KISS1 signaling. The expression and function of individual glutamate receptor subtypes in KISS1 neurons, however, are not well characterized. Here, we used GCaMP-based calcium imaging and patch-clamp electrophysiology to assess the impact of activating individual ionotropic (iGluR) and group I metabotropic (mGluR) glutamate receptors on KISS1 neuron activity in the mouse RP3V and ARC. Our results indicate that activation of all iGluR subtypes and of group I mGluRs, likely mGluR1, consistently drives activity in the majority of KISS1 neurons within the RP3V and ARC of males and females. Our results also revealed, somewhat unexpectedly, sex- and region-specific differences. Indeed, activating (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type iGluRs evoked larger responses in female ARCKISS1 neurons than in their male counterparts whereas activating group I mGluRs induced larger responses in RP3VKISS1 neurons than in ARCKISS1 neurons in females. Together, our findings suggest that glutamatergic neurotransmission in KISS1 neurons, and its impact on the activity of these cells, might be sex- and region-dependent in mice.

Cancer-Associated Fibroblast Subtypes Reveal Distinct Gene Signatures in the Tumor Immune Microenvironment of Vestibular Schwannoma.

Cancer-associated fibroblast (CAF) composition within the same organ varies across different cancer subtypes. Distinct CAF subtypes exhibit unique features due to interactions with immune cells and the tumor microenvironment. However, data on CAF subtypes in individuals with vestibular schwannoma (VS) are lacking. Therefore, we aimed to distinguish CAF subtypes at the single-cell level, investigate how stem-like CAF characteristics influence the tumor immune microenvironment, and identify CAF subtype-specific metabolic reprogramming pathways that contribute to tumor development. Data were analyzed from three patients with VS, encompassing 33,081 single cells, one bulk transcriptome cohort, and The Cancer Genome Atlas Pan-Cancer database (RNA sequencing and clinical data). Our findings revealed that antigen-presenting CAFs are linked to substantially heightened immune activity, supported by metabolic reprogramming, which differs from tumorigenesis. High expression of the stem-like CAF gene signature correlated with poor prognosis in low-grade gliomas within the pan-cancer database. This is the first study to classify CAF subtypes in VS patients and identify a therapeutic vulnerability biomarker by developing a stem-like CAF gene signature. Personalized treatments tailored to individual patients show promise in advancing precision medicine.

Patients with achondroplasia have increased risk of 90-day adverse events following laminectomy: A matched comparison using a national database.

Performing laminectomies in patients with achondroplasia-a common skeletal dysplasia-can present unique challenges. There are a limited number of studies that have reported on the adverse effects of laminectomies in patients with achondroplasia. To compare the 90-day postoperative adverse events following laminectomy in patients with and without achondroplasia. Retrospective cohort study using the 2010-2020 PearlDiver Mariner 91 administrative database was used to identify patients who underwent thoracic, thoracolumbar, or lumbar laminectomy. Patients with achondroplasia were matched 1:4 to patients without achondroplasia based on age, sex, insurance, and ECI. Univariate and multivariate logistic regression analyses assessed and compared 90-day adverse events. Odds ratios (OR), 95% confidence intervals (CI), and p-values were reported with significance set at p < 0.05. A multivariate analysis revealed that when laminectomy was performed, patients with achondroplasia were 2.82 times more likely to have 90-day AE compared to those without achondroplasia (p < 0.001). When comparing individual subtypes of adverse events, patients with achondroplasia were found to have significantly greater odds of a transfusion (OR 6.40, p < 0.001), UTI (OR 3.79, p < 0.001), disruption of wound (OR 3.71, p < 0.001), and hematoma (OR 2.94, p = 0.032). Pneumonia, cardiac arrest, AKI, other perioperative events, durotomy, and VTE were not significantly different between the two cohorts. This study uses one of the largest cohorts to compare patients with and without achondroplasia undergoing laminectomy. Patients with achondroplasia were found to have a significantly greater risk of 90-day adverse events following laminectomy compared to their matched cohort of patients without achondroplasia.

Comprehensive transcriptomic analysis identifies three distinct subtypes of pituitary adenomas: insights into tumor behavior, prognosis, and stem cell characteristics

BackgroundPituitary adenomas (PAs) are the second most common intracranial tumor. While current diagnostic practices rely primarily on histological testing, they often fail to capture the molecular complexities of pituitary adenomas, underscoring the need for a molecular-based classification to refine therapeutic strategies and prognostic assessments. This study aims to provide a molecularly unbiased classification of pituitary adenomas and explore their unique gene expression patterns and clinical features.MethodsWe performed unsupervised hierarchical clustering of the gene expression profiles of 117 PA samples to identify three distinct molecular subtypes. Subsequently, we analyzed the compiled transcriptomic profiles of each individual subtype for pathway enrichment. We also validated the new classification with a validation set containing 158 PAs and 24 pituitary adenoma stem cells (PASCs).ResultsConsensus clustering of transcriptomic data from 117 pituitary adenoma (PA) samples identified three distinct molecular subtypes, each showing unique gene expression patterns and associated biological processes: Group I is enriched in signaling pathways, such as the cAMP signaling pathway and the calcium signaling pathway. Group II is primarily related to metabolic processes, including nitrogen metabolism and arginine biosynthesis in cancer. Group III predominantly shows enrichment in immune responses and potential malignant transformation of the disease, especially through cancer-related pathways such as the JAK–STAT signaling pathway and the PI3K–Akt signaling pathway. The immune profiling revealed distinct patterns for each subtype: Group I had higher dendritic cells and fewer CD8+ T cells, Group II had more monocytes and macrophages, and Group III had elevated levels of T cells. Additionally, there were differences in clinical characteristics and prognosis among the subtypes, with Group III having a worse prognosis, despite the smaller tumor size compared to other groups. Notably, differences in PASCs correlated with the molecular subtypes, with Group III stem cells being enriched in tumorigenesis pathways, PI3K–Akt signaling pathway and Ras signaling pathway.ConclusionOur study introduces a novel molecular classification for pituitary adenomas, independent of traditional histological methods. Each subtype features distinct genetic, molecular, and immunological profiles. We have isolated pituitary adenoma stem-like cells (PASCs), pairing them with tumor tissues for detailed transcriptomic analysis. These PASCs exhibit diverse molecular traits consistent with the new classification.

Effect of Personalized Prebiotic and Probiotic Supplements on the Symptoms of Irritable Bowel Syndrome: An Open-Label, Single-Arm, Multicenter Clinical Trial.

Prebiotics and probiotics have been reported to improve symptoms of irritable bowel syndrome (IBS). Nevertheless, the effects of prebiotics/probiotics can vary depending on the IBS subtypes. The purpose of this study was to investigate the effects of personalized prebiotic and probiotic supplements based on intestinal microbiota and IBS subtypes in patients. Patients with diarrhea-type IBS (IBS-D), constipation-type IBS (IBS-C), and mixed-type IBS (IBS-M) were enrolled (n = 40 per group; total: n = 120). Personalized prebiotic and probiotic supplements were determined according to the IBS subtypes and intestinal microbiota. The patients received supplements for 4 weeks. The primary outcome was the change in the IBS-severity scoring system from baseline to week 4. The IBS-severity scoring system significantly decreased in all patients (-38.0 [95% confidence interval (CI): -53.6, -22.4]; p < 0.001), in patients with IBS-D (-44.5 [95% CI: -70.6, -18.5]; p = 0.004) and IBS-C (-51.2 [95% CI: -79.4, -22.9]; p = 0.002), but not in those with IBS-M (-20.0 [95% CI: -48.0, 8.1]; p = 0.47). In this study, no serious adverse events were observed that had a causal relationship with the intervention. In conclusion, personalized prebiotic and probiotic supplements selected according to individual intestinal microbiota and IBS subtype may alleviate the severity of IBS symptoms, particularly in patients with IBS-C and IBS-D.

Neuronal lineage tracing from progenitors in human cortical organoids reveals mechanisms of neuronal production, diversity, and disease

The contribution of progenitor subtypes to generating the billions of neurons produced during human cortical neurogenesis is not well understood. We developed the cortical organoid lineage-tracing (COR-LT) system for human cortical organoids. Differential fluorescent reporter activation in distinct progenitor cells leads to permanent reporter expression, enabling the progenitor cell lineage of neurons to be determined. Surprisingly, nearly all excitatory neurons produced in cortical organoids were generated indirectly from intermediate progenitor cells. Additionally, neurons of different progenitor lineages were transcriptionally distinct. Isogenic lines made from an autistic individual with and without a likely pathogenic CTNNB1 variant demonstrated that the variant substantially altered the proportion of neurons derived from specific progenitor cell lineages, as well as the lineage-specific transcriptional profiles of these neurons, suggesting a pathogenic mechanism for this mutation. These results suggest individual progenitor subtypes play roles in generating the diverse neurons of the human cerebral cortex.

Hypertensive Disorders and Cardiovascular Severe Maternal Morbidity in the US, 2015-2019

The incidence of severe maternal morbidity (SMM)-and particularly cardiovascular SMM (cvSMM), the first cause of pregnancy-related mortality-has been rising in North America. Although hypertensive disorders of pregnancy (HDP) are common, their association with cvSMM specifically remains unclear. To assess the association between individual subtypes of HDP and cvSMM, in addition to overall SMM, in a large, nationally representative sample. A population-based cohort study using the United States National Inpatient Sample was conducted. Individuals with obstetric deliveries between 2015 and 2019 were included. Data analysis was performed from October 2023 to February 2024. HDP subtypes included gestational hypertension, chronic hypertension, preeclampsia without severe features, severe preeclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelet) syndrome. The primary outcome was a composite of cvSMM (including conditions such as pulmonary edema, stroke, and acute myocardial infarction) and the secondary outcome was a composite of overall SMM (including cvSMM and other conditions such as respiratory failure, severe postpartum hemorrhage, and sepsis). Adjusted risk ratios (aRRs) for the association between HDP subtypes and the outcomes were estimated using modified Poisson regression models adjusted for demographic and clinical characteristics. Among 15 714 940 obstetric deliveries, 2 045 089 (13.02%) had HDP, 23 445 (0.15%) were affected by cvSMM, and 282 160 (1.80%) were affected by SMM. The mean (SD) age of the cohort was of 29 (6) years. The incidence of cvSMM was higher in participants with HDP than those without HDP (0.48% [9770 of 2 045 089] vs 0.10% [13 680 of 13 669 851]; P < .001). Participants with HELLP syndrome had the highest risk for cvSMM (aRR, 17.55 [95% CI, 14.67-21.01]), followed by severe preeclampsia (aRR, 9.11 [95% CI, 8.26-10.04]), and chronic hypertension (aRR, 3.57 [95% CI, 3.15-4.05]). Although HDP subtypes were also associated with overall SMM, the association with HELLP syndrome (aRR, 9.94 [95% CI, 9.44-10.45]), severe preeclampsia (aRR, 3.66 [95% CI, 3.55-3.78]), and chronic hypertension (aRR, 1.96 [95% CI, 1.88-2.03]) was attenuated compared with cvSMM. In this cohort study, a graded relationship by severity characterized the association between HDP and cvSMM. Although all HDP subtypes were associated with an increased risk of overall SMM, the risk was more pronounced for cvSMM.

The prevalence and risk factors associated with hypertension subtypes among ethnic Dai adults in rural China

This study was conducted from June to September 2020 and conducted a population-based study of 2149 rural Dai residents aged 50 years or above in Xishuangbanna. The definition of hypertension was a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg, or a current treatment plan with an antihypertensive medication. High blood pressure (HBP) included the following subtypes: SDH, ISH and IDH. All participants were interviewed, had physical examinations performed, and had blood pressure measurements taken. Multivariable logistic regression analysis was applied to analyse the risk factors forhypertension. The prevalence of HBP was 43.2 %. The subtype-specific prevalence of hypertension was 16.5 % for SDH, 24.2 % for ISH and 2.5 % for IDH. Among hypertensive participants, 38.2 % were SDH, 56.0 % were ISH and 5.8 % were IDH. Older age is a risk factor for HBP and ISH. Obesity, smoking, drinking and history of hypertension are risk factors for HBP and its subtypes including SDH and ISH (OR >1). Among all the hypertensive participants, only 25.0 % of the participants were aware of their hypertension while 34.7 % of SDH participants, 20.0 % of ISH participants and 9.3 % of IDH participants knew the individual subtype of hypertension. Among Dai people, the prevalence of hypertension is high, while the awareness and the rate of adequate treatment of hypertension is low. ISH stood out as the most prevalent type ofHBP among the rural elderly. Rising ageing population in China, ISH remains an important public health problem and a challenging management issue in rural China.

Abstract A023: Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications

Abstract Patient-derived organoids (PDOs) have emerged as a powerful tool for modeling human cancers due to their ability to closely mirror in vivo architecture and preserve the genetic landscape of tumors. They offer a crucial platform for studying disease progression and treatment responses. In this study, we present a comprehensive characterization of a unique collection of PDO cultures derived from pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy often diagnosed in advanced stages with limited treatment options and poor prognosis. Our investigation explores morphological and genetic profiling of 10 PDAC PDOs, specifically identifying distinct drug-response patterns. The morphological characteristics of these PDO cultures were investigated by microscopy, while the mutational status was acquired by panel sequencing. Subsequently, PDOs were treated with a panel of 10 inhibitors, either individually or in combination. The response to these treatments was assessed through live-cell imaging (Incucyte®) to capture and quantify changes in organoid morphology and endpoint measurements of cellular viability using a CellTiter-Glo® assay. Our detailed in vitro drug sensitivity testing revealed a remarkable diversity in the responses of the PDAC PDOs to different chemotherapeutic agents, including those currently under clinical trials. Of notable significance is the depth of understanding we have achieved, allowing us to establish potential correlations between PDO morphology, genetic mutations, and drug reactions. This finding provides a key insight into the complex interplay of these factors and their impact on treatment outcomes, offering valuable insights into understanding individual tumor subtypes' sensitivity or resistance to treatments. The PDOs exhibited a spectrum of cancer-associated mutations, including KRAS, TP53, SMAD4, CDKN2A, and ARID1A, reflecting the heterogeneity observed in PDAC patients. Morphologically, the organoids displayed various growth patterns, ranging from cystic and regular structures to filled or unfilled, granular, dark, and light membrane structures. Drug treatments underscored the diverse and unique drug-response profiles within the PDOs, with some demonstrating sensitivity to multiple treatments. In contrast, others exhibited resistance, highlighting the intricate nature of drug responses within this model. Overall, our findings emphasize the ability of PDAC organoids to faithfully capture the complexity and heterogeneity of the disease, making them promising platforms for guiding personalized oncology approaches. The diverse drug response profiles observed in PDOs advocate leveraging this model to develop precision medicine strategies tailored to patients' characteristics, ultimately paving the way for more effective and personalized treatment regimens in the fight against PDAC. Citation Format: Constanza Tapia Contreras, Günter Schneider, Denise Müller, Kimia Mirzakhani, Karly Conrads, Silke Kaulfuß, Tim Beißbarth, Gabriela Salinas, Nils Beyer, Sophia Reinländer, Ulrix Sax, Elisabeth Heßmann, Volker Ellenrieder, Philipp Ströbel, Michael Ghadimi. Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A023.

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.

Correlation between Periostin Expression and Pro-Angiogenic Factors in Non-Small-Cell Lung Carcinoma.

The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC.

The neurobiological mechanisms underlying the effects of exercise interventions in autistic individuals.

Autism spectrum disorder is a pervasive and heterogeneous neurodevelopmental condition characterized by social communication difficulties and rigid, repetitive behaviors. Owing to the complex pathogenesis of autism, effective drugs for treating its core features are lacking. Nonpharmacological approaches, including education, social-communication, behavioral and psychological methods, and exercise interventions, play important roles in supporting the needs of autistic individuals. The advantages of exercise intervention, such as its low cost, easy implementation, and high acceptance, have garnered increasing attention. Exercise interventions can effectively improve thecore features and co-occurring conditions of autism, buttheunderlying neurobiological mechanisms are unclear. Abnormal changes in the gut microbiome, neuroinflammation, neurogenesis, and synaptic plasticity may individually or interactively be responsible for atypical brain structure and connectivity, leading to specific autistic experiences and characteristics. Interestingly, exercise can affect these biological processes and reshape brain network connections, which may explain how exercise alleviates core features and co-occurring conditions in autistic individuals. In this review, we describe the definition, diagnostic approach, epidemiology, and current support strategies for autism; highlight the benefits of exercise interventions; and call for individualized programs for different subtypes of autistic individuals. Finally, the possible neurobiological mechanisms by which exercise improves autistic features are comprehensively summarized to inform the development of optimal exercise interventions and specific targets to meet the needs of autistic individuals.

A clustering approach identifies an Autism Spectrum Disorder subtype more responsive to chronic oxytocin treatment

Over the last decade, a number of clinical trials have reported effects of chronic treatment with intranasal oxytocin on autistic symptoms but with inconsistent findings. Autism is a heterogeneous disorder and one factor which may influence treatment outcome is whether a subtype of individuals is more sensitive to oxytocin. In a recent cross-over trial on 41 young autistic children we reported that 44% showed a reliable improvement in clinical symptoms (Autism Diagnostic Observation Schedule, ADOS-2) after a placebo-controlled, 6-week intranasal oxytocin intervention where treatment was given every other day followed by a period of positive social interaction. In the current re-assessment of the data, we used an unsupervised data-driven cluster analysis approach to identify autism subtypes using 23 different demographic, social subtype, endocrine, eye-tracking and clinical symptom measures taken before treatment and this revealed an optimum of two different subtypes. We then assessed the proportion of identified responders to oxytocin and found that while 61.5% of one subtype included responders only 13.3% of the other did so. During the placebo phase there was no difference between the two subtypes for the small proportion of responders (19.2% vs 6.7%). This oxytocin-sensitive subtype also showed overall significant post-treatment clinical and eye-tracking measure changes. The oxytocin-sensitive subtype was primarily characterized at baseline by lower initial clinical severity (ADOS-2) and greater interest in the eye-region of emotional faces. These features alone were nearly as efficient in identifying the two subtypes as all 23 baseline measures and this easy-to-conduct approach may help rapidly and objectively screen for oxytocin responders. Future clinical trials using oxytocin interventions may therefore achieve greater success by focusing on children with this specific autism subtype and help develop individualized oxytocin intervention.