Profiling Studies Research Articles

Positive homologous recombination signature (HRDsig+) and the genomic landscape of intrahepatic cholangiocarcinoma (iCCA).

627 Background: Defective DNA repair has not been a major focus in iCCA clinical research. In this comprehensive genomic profiling (CGP) study, we queried whether the presence of a scar-based HRDsig biomarker could identify a subset of patients with unique genomic alterations (GA) and potential for responsiveness to PARP inhibitor-based treatment regimens. Methods: 6,271 cases of clinically advanced iCCA underwent hybrid capture based CGP to evaluate all classes of GA. Microsatellite instability (MSI) status, tumor mutation burden (TMB) levels, genomic ancestry and genomic trinucleotide signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS). Results were compared using the Fisher exact system with the Benjamini-Hochberg procedure. Results: 288 (4.6%) of the sequenced iCCA featured an HRDsig+ status. Gender distribution (46-49% male) and median age (67 years) were similar in both HRDsig+ and HRDsig- iCCA. More pathogenic GA per tumor were found in HRDsig+ vs HRDsig- iCCA (5 vs 4; P<0.0001). Genomic ancestry distribution was similar; European ancestry ranged from 73% to 76% in the two cohorts. The APOBEC signature was uncommon but slightly more frequent in the HRDSig+ cases (1.7% vs 0.4%; P=.034). MSI High status was slightly more frequent in the HRDsig- group (1.8% vs 0.0%; P=0.034). Median TMB was higher in the HRDsig+ cases (3.6 vs 1.2 mut/Mb; P<0.0001) as was the frequency of TMB > 10 mut/Mb (9.1% vs 3.5%; P<0.0001). PD-L1 expression was similar with low level (1-49% TPS) ranging from 19% to 23% in the 2 groups. As anticipated, GA in genes associated with HRD including BRCA1 (6.6% vs 0.8%; P<0.0001), BRCA2 (25.0% vs 1.3%; P<0.0001), PALB2 (8.7% vs 0.3%; P<0.0001), and ATM (6.3% vs 3.4%; P=0.033) were all more frequent in the HRDsig+ iCCA. In contrast, GA in genes associated with iCCA targeted therapies were less frequent in the HRDsig+ cases including FGFR2 (8.0% vs 12.5%; P=0.033), IDH1 (3.5% vs 14.0%; P<0.0001) and ERBB2 (3.5% vs 5.7%; NS). In the HRDsig- group, 83.3%/74.1% of BRCA1 / BRCA2 mutated iCCA were mono-allelic likely non-driver GA respectively. MTOR pathway activating GA were more frequent in the HRDsig+ cases including PTEN (7.3% vs 3.3%; P=0.003) and NF1 (8.0% vs 2.8%; P<0.0001). MTAP deletion, an emerging iCCA target, was more frequent in the HRDsig+ iCCA (23.3% vs 16.9%; P=0.024). Conclusions: Nearly 5% of advanced iCCA feature HRDsig positive status which is associated with both significant differences in the frequencies of therapy associated genomic targets and the potential for introducing PARP inhibitors for these patients. HRDsig- iCCAN = 5983 HRDsig+ iCCAN = 288 P-value ATM 3.4% 6.3% 0.033 BRCA1 0.8% (83.3% mono-allelic) 6.6% <.0001 BRCA2 1.3% (74.1% mono-allelic) 25.0% <.0001 PALB2 0.3% 8.7% <.0001

Analysis of total RNA as a potential biomarker of Parkinson's disease in silico.

Knowledge about total RNA molecules in Parkinson's disease is limited. This gene expression profiling study was conducted with a preclinical experimental design using a mouse model to examine the molecular-biological characteristics and the pathological implication of total RNA gene interaction in Parkinson's disease in silico. In silico analysis of total RNA molecules, the Gene Expression Omnibus database, published results, and preliminary findings of available patient samples apply. The potential signaling network and the effect of the interaction of molecules with total RNA was predicted and confirmed. The research consists of four parts. At first, we analyzed the control and MPTP groups. In the second part, we analyzed FVB-N control and MPTP. In the third part, we analyzed controls. In the fourth part, we analyzed MTPT separately. The constructed network contains total RNA, where the Kyoto Encyclopedia of Genes and Genomes database analysis showed that genes from the signaling pathway are involved in the development and complications of Parkinson's disease in male and female rats. Identified total RNA and genes are involved in altered signaling. There is direct interconnection and interdependence of interactions in the signaling network. Results identified the significant total-RNA molecules of the signaling pathway that connect other molecules. In silico analysis shows upregulated and downregulated genes in Parkinson's disease rats. Preliminary data shows that total RNA molecules interact with other genes, and they are applicable in Parkinson's disease course monitoring, shedding light on how factors impact the expression of genes and offering strategies for management.

Association between ctDNA levels, timing of blood collection, and overall survival in metastatic colorectal cancer.

245 Background: While circulating tumor DNA (ctDNA) detection is influenced by various factors, the impact of blood collection timing remains understudied. This study investigated the relationship between ctDNA detection, and blood collection timing and prognosis in patients with metastatic colorectal cancer (mCRC) from the GOZILA study. Methods: GOZILA is a nationwide plasma genomic profiling study using Guardant360 CDx for advanced solid tumors. This study evaluated the association of ctDNA levels with blood collection timing and prognosis in patients with mCRC. ctDNA levels were determined by the maximum variant allele frequency. Blood collection timing was categorized into five groups: naive (before initiation of 1st line treatment), after treatment initiation (days 1-14 of treatment), during treatment (between “after treatment initiation” and “before progression disease [PD]”), before PD (from 28 days before PD to PD), and after PD (after disease progression but before the next line of treatment). Overall survival (OS) was compared across treatment lines using ctDNA level cutoff of 10. Results: We analyzed 2,398 blood samples from 1,994 patients with mCRC enrolled in the GOZILA between February 2018 and July 2023. ctDNA levels were significantly lower during treatment compared to the naive (median, 13.2 vs. 5.7, p < 0.001). No significant differences were observed between naive and other blood collection timing. Compared to blood collection before 1st line treatment, ctDNA levels significantly decreased before 2nd line (median, 13.5 vs. 8.3, p = 0.02) and 3rd line treatments (median, 13.5 vs. 7.6, p = 0.01). Patients with ctDNA levels<10 demonstrated significantly better OS across all treatment lines, including 1st line (median, NA vs. 23.9 months, HR 0.49, 95% CI, 0.34-0.72), 2nd line (median, 22.1 vs. 10.3 months, HR 0.42, 95% CI, 0.33-0.55), and later line treatments (FTD/TPI: median, 12.7 vs. 5.7 months, HR 0.51, 95% CI, 0.26-0.99; FTD/TPI+Bev: median, 9.3 vs. 6.5 months, HR 0.55, 95% CI, 0.37-0.82; Regorafenib: median, 13.5 vs. 7.4 months, HR 0.45, 95% CI, 0.26-0.80). Conclusions: In mCRC, blood collection during treatment is suboptimal due to decreased ctDNA levels. Patients with ctDNA levels <10 showed significantly better OS across all treatment lines. Optimal timing of blood collection can enhance ctDNA levels, enabling more accurate gene mutation assessment and stratifying outcomes.

The NACCHO Profile Study Dashboard: Empowering Local Public Health With Data-Driven Insights.

The NACCHO Profile Study Dashboard: Empowering Local Public Health With Data-Driven Insights.

Highly Efficient Recovery of Bioactive Puerarin from Roots of Pueraria lobata Using Generally Recognized as Safe Solvents

Puerarin (daidzein-8-C-glucoside), one of the bioactive isoflavones, has attracted attention in various industries due to its excellent pharmacological effects such as antioxidant effect, estrogen-like activity, reduction of blood sugar, and neuroprotective effect. Puerarin is most abundantly found in the roots of Pueraria lobata (RPL) among various biomass sources. To improve the utilization feasibility of puerarin, a high-yield extraction process should be designed for RPL. This study aimed to optimize the extraction process to more efficiently recover puerarin from RPL while using generally recognized as safe solvents as extraction solvents, considering the potential industrial applications of puerarin. The extraction variables were optimized by the one-factor-at-a-time method, response surface methodology, and time profiling study. As a result, puerarin yield was achieved at 60.56 mg/g biomass under optimal conditions (ethanol concentration of 46.06%, extraction temperature of 65.02 °C, ratio of extraction solvent to biomass of 11.50 mL/g, and extraction time of 22 min). High puerarin yield achieved in this study contributed to improving the industrial applicability of puerarin.

Abstract B010: Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma

Abstract Background: Preclinical studies with transplanted GL261 glioma in mouse brain treated with radiosurgery and checkpoint blockade showed dramatic improvement of tumor cure and prolonged survival, associated with activated macrophage infiltration in the tumor site. We perform phase I study in patients with glioblastoma to assess safety and local tumor response by combined radiosurgery and checkpoint inhibitor given during window-of-opportunity prior to surgical resection, and progression-free survival and overall survival. Method and Procedure: Biopsy-proven WHO grade 4 glioblastoma patients were enrolled to the study (NCT05423210). Patients were treated with two doses of intravenous Atezolizumab at the beginning and at the end of the two-week period, concomitantly with fractionated radiosurgery (8 Gy x 4 to the grossly enhancing tumor) over 4 days during the course of 2 weeks. Maximal safe surgical resection was subsequently performed within 2 weeks from completion of radiosurgery. Adjuvant radiation 50 Gy over 5 weeks and Temozolomide were given as per standard treatment of GBM along with continuation of Atezolizumab until unacceptable toxicity or tumor progression. The initial biopsy specimen and surgical specimen were collected for laboratory examination of immune profiles. Results: The study plans to enroll total 12 histologically confirmed CNS WHO Grade 4 GBM patients also planned for surgical resection. Six patients were enrolled after consenting so far. There was no grade 3 or 4 toxicity from the window-of-opportunity combination treatment, all 6 patients successfully completing the treatment. Three patients reported fatigue and two patients had skin rash. There was one patient experiencing metallic taste. At present, five patients survive progression-free at 25, 18, 16 and 6 months since the treatment. An unanticipated finding is that there was significantly less intraoperative bleeding in the surgical field than usual brain tumor surgery. Conclusion: Preoperative fractionated radiosurgery and Atezolizumab was well tolerated so far, and appear to improve tumor control. We continue enroll the patients. Lab study of immune cell profile is underway. Citation Format: Samuel Ryu, Alexander Stessin, Charles Mikell, Agnieszka Kowalska, Roberta Seidman, Steven West, Kartik Mani. Interim report of Phase I study of window-of-opportunity fractionated stereotactic radiotherapy combined with checkpoint blockade prior to surgical resection for newly diagnosed glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B010.

Targeting Antibacterial Resistance: Computational Exploration of Bioactive Compounds in Dipsacus asper Integrating Docking, ADMET Analysis, and Molecular Dynamics Simulations

Natural compounds derived from plants offer a sustainable and promising solution to the global challenge of antimicrobial resistance. This study focuses on Dipsacus asper (D. asper), a plant traditionally used in Chinese medicine, and investigates its bioactive potential to identify novel antibacterial agents. Leveraging comprehensive in‐silico analyses, 44 compounds previously isolated from D. asper were evaluated for their binding affinities against four key bacterial proteins: DNA gyrase B, Tyrosyl‐tRNA‐synthetase, Penicillin Binding Protein 2X (PBP2X), and Penicillin Binding Protein 4 (PBP4). This integrated approach, combining molecular docking, ADMET profiling, DFT, and MESP studies, identified Dipsalignan, Cantleyoside, Triplostoside A, and Dipsanoside N as leading candidates. Dipsalignan demonstrated superior bioavailability and distinct electronic properties influencing its reactivity. Molecular dynamics (MD) simulations validated the stability of protein‐ligand interactions, with RMSD and RMSF analyses confirming equilibrium under physiological conditions. Binding free energy calculations revealed that van der Waals and hydrophobic interactions are critical in enhancing inhibitory potential. Biological significance was evident as the computationally identified compounds align with essential criteria for effective antibacterial agents, warranting further in vitro and in vivo studies. This research underscores the potential of D. asper‐derived compounds to address antimicrobial resistance and presents a robust framework for discovering plant‐based antibacterial agents.

Abstract B031: Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy

Abstract Background: The trajectory of metastatic castration-sensitive prostate cancer varies based on disease presentation and biology. While proteomic profiling studies of primary prostate tissue have linked protein expression with metastatic progression and prognosis, few studies have explored biological changes after treatment and their associations with response. Therefore, we conducted proteomic profiling of patients with oligometastatic castration-sensitive prostate cancer (omCSPC) treated with stereotactic ablative radiotherapy (SABR) or observation in the ORIOLE phase 2 randomized clinical trial (RCT). Methods Plasma from omCSPC patients in the ORIOLE trial was collected at baseline (day 1), day 90, and day 180. Protein abundance was quantified using the Olink Explore Assay. Differential expression from baseline to day 90 or 180 in each treatment arm was analyzed using a 2-sided t-test with Benjamini-Hochberg correction. Changes in protein expression at day 90 and 180 were compared with a Pearson correlation. Pathway enrichment was performed via gene set enrichment analysis (GSEA) using Reactome, KEGG, and Hallmark gene sets. Associations with progression-free survival (PFS) were analyzed using Kaplan-Meier and log-rank tests. Results In total, 1,472 proteins were assayed across 130 samples from 46 patients over 3 time points. Significant changes in expression post-SABR were noted at day 90 and 180 compared to baseline (using adjusted p-value cutoff of 0.05). At day 90, four proteins (FCRL1, CD22, TCL1A, FCER2) were downregulated; at day 180, only FCRL1, a Fc receptor-like gene family preferentially expressed in B cells, remained downregulated. No significant expression changes were found in the observation arm. Differential expression of proteins during follow-up were associated with PFS. In particular, LTO1, a maturation factor of ABCE1 important for ribosomal biogenesis and translation, was overexpressed at both day 90 and 180 post-SABR, and overexpression was associated with improved PFS at day 90 (median 24.5 mo vs 6 mo; p=0.017) and day 180 (median 33 mo vs 6 mo; p=0.043). These associations were absent in the observation arm. For proteins differentially expressed in the SABR arm at day 90, several signaling pathways were significantly enriched for patients with prolonged PFS, including positive enrichment of unfolded protein response (UPR) (p=0.008) and IL-4/IL-13 (p=0.009). At 180 days, several pathways were enriched for patients with prolonged PFS including negative enrichment of CTLA4 inhibitory signaling (p=0.005) and CD28 co-stimulation (p=0.008). Conclusion Proteomic analysis in omCSPC patients from the ORIOLE trial reveals significant expression changes at days 90 and 180 after SABR. B-cell signaling proteins were selectively downregulated in the SABR arm, and pathways associated with protein translation and immune response were enriched post-SABR for patients with prolonged PFS. Further research will explore connections to genomic and transcriptomic changes, with additional validation needed. Citation Format: Jarey H. Wang, Amol Shetty, Yang Song, Noura Radwan, Soha Bazyar, Xiaolei Shi, Theodore L. DeWeese, Daniel Y. Song, Ryan M. Phillips, Matthew P. Deek, Philip Sutera, Ana P. Kiess, Phuoc T. Tran. Proteomic profiling of oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B031.

Exploration of Personality Characteristics of Individuals with Panic Attacks: A Personality Profile Study

ABSTRACT The study of panic attacks is especially relevant today because of the world’s rapid changes, which have always caused people to experience excessive stress and anxiety. The purpose was to thoroughly investigate and analyze the specific features of panic attacks to reveal their etiological context and identify the factors contributing to their occurrence. It was found that the main symptoms of a panic attack are panic, sudden outbursts of extreme anxiety or discomfort, and a variety of physical symptoms such as palpitations, shortness of breath, numbness, and dizziness. From an empirical study on panic attacks, personal and psychological traits of university students prone to panic attacks were identified, leading to the creation of a profile for individuals experiencing such episodes. The study is crucial as all theoretical findings and recommendations can aid psychiatrists, psychotherapists, and other specialists in raising awareness of panic attacks, improving diagnostic methods, and developing effective treatments.

Current pathogenicity factors of viral and bacterial pathogens of young cattle

Infectious pathologies of animals remain the main problem on the path of high productivity, preservation and, as a result, productive longevity of animals and ultimately determines the profitability of agricultural industrial production of animal products. The possibility of developing pathologies is caused by specific substances of predominantly organic origin (proteins, enzymes, toxins, glycopeptides, etc.), which cause a set of highly specific pathogenic properties of microorganisms. In this connection, there is a growing interest and need to study the pathogenic properties of viruses and bacteria, which cause a number of mechanisms that ensure the neutralization of protective immune mechanisms of animals (adhesive, anti-complementary, anti-lactoferin, antihemoglobin, anti-lysozyme activity, biofilm formation, antibiotic resistance, etc.). The study and development of effective methods to counteract these pathogenicity factors is possible only taking into account the study and search for the practical application of specific substances in the form of vaccines and drugs. Numerous studies of infectious agents causing pathology of the gastrointestinal tract with diarrhea syndrome in calves, according to statistics, distinguish the most common bovine rotavirus, bovine coronavirus, bovine viral diarrhea virus, bovine calicivirus and bovine torovirus, as well as bacteria Salmonella spp., E. coli, C. perfringens and C. parvum. The data from the review of the pathogenicity factors of bacteria and viruses show their diversity, which causes various forms of the course and manifestations of infectious pathologies. Monitoring and further study of the antigenic profile of infectious pathogens allows timely development of relevant diagnostic methods for their identification. The study of protein antigenic proteins makes it possible to develop means for the treatment and prevention of infectious animal diseases.

Clinicopathological study and molecular subtyping of muscle-invasive bladder cancer (MIBC) using dual immunohistochemical (IHC) markers

BackgroundMuscle-invasive bladder carcinomas (MIBCs) exhibit significant heterogeneity, with diverse histopathological features associated with varied prognosis and therapeutic response. Although genomic profiling studies have identified several molecular subtypes of MIBC, two basic molecular subtypes are identified - luminal and basal, differing in biological behaviour and response to treatment. As molecular subtyping is complex, surrogate immunohistochemical (IHC) markers have been used to determine the molecular subtypes with good correlation to genomic profiling.MethodsWe analysed the clinicopathological features of 66 cases of MIBCs received over a 5-year study period. IHC expression was determined using GATA3 and CK5/6 to classify MIBC into luminal, basal and double-negative subtypes. The association between clinicopathologic variables and molecular subtypes were analysed using Chi-square test.ResultsThe mean age at diagnosis of MIBC was 65.91 years with a male predominance. Based on IHC expression of GATA3 and CK5/6, MIBCs were classified into luminal, basal and double negative subtypes in 62.1%, 30.3% and 7.6% respectively. The luminal subtype occurred at an older age and showed predominantly conventional urothelial carcinoma with papillary morphology. Basal subtype occurred at earlier age, showed greater association with smoking and was more commonly associated with urothelial carcinoma with non -papillary morphology and exhibiting divergent differentiation as well as pure squamous cell carcinoma on histopathological examination. The double-negative subtype was found exclusively in males and exhibited a non-papillary morphology. Notably, all diagnosed neuroendocrine carcinomas were classified as double-negative type. While there was no statistically significant difference in tumour stage in cystectomy specimens between the molecular subtypes, lympho-vascular invasion and lymph node metastasis was more commonly associated with the basal type (p < 0.05) There was no significant difference in recurrence rates, metastasis and death between luminal and basal subtypes.ConclusionA simple two-antibody panel using GATA3 and CK5/6 could help in classifying MIBC into basic molecular subtypes of MIBC with distinctive histopathological features that can provide insights into the corresponding molecular subtype. Greater association of lymphovascular invasion and lymph nodal involvement in cystectomy specimens in basal type and distant metastasis in the double-negative subtype suggests a more aggressive clinical behaviour of these, necessitating more intensive treatment.

Integrative deep immune profiling of the elderly reveals systems-level signatures of aging, sex, smoking, and clinical traits.

Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability. We conducted an immune profiling study of 550 elderly participants (≥60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral flow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches. We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout. This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our findings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280.

Pervasive formation of double-stranded RNAs by overlapping sense/antisense transcripts in budding yeast mitosis and meiosis.

Previous RNA profiling studies revealed co-expression of overlapping sense/antisense (s/a) transcripts in pro- and eukaryotic organisms. Functional analyses in yeast have shown that certain s/a mRNA/mRNA and mRNA/lncRNA pairs form stable double-stranded RNAs (dsRNAs) that affect transcript stability. Little is known, however, about the genome-wide prevalence of dsRNA formation and its potential functional implications during growth and development in diploid budding yeast. To address this question, we monitored dsRNAs in a Saccharomyces cerevisiae strain expressing the ribonuclease DCR1 and the RNA binding protein AGO1 from Naumovozyma castellii. We identify dsRNAs at 347 s/a loci that express partially or completely overlapping transcripts during mitosis, meiosis or both stages of the diploid life cycle. We associate dsRNAs with s/a loci previously thought to be exclusively regulated by antisense interference, and others that encode antisense RNAs, which downregulate sense mRNA-encoded protein levels. To facilitate hypothesis building we developed the Sense/Antisense double-stranded RNA (SensR) expression viewer. Users are able to retrieve different graphical displays of dsRNA and RNA expression data using genome coordinates and systematic or standard names for mRNAs and different types of stable or cryptic long non-coding RNAs (lncRNAs). Our data are a useful resource for improving yeast genome annotation and for work on RNA-based regulatory mechanisms controlling transcript and protein levels. The data are also interesting from an evolutionary perspective, since natural antisense transcripts that form stable dsRNAs have been detected in many species from bacteria to humans. The SensR viewer is freely accessible at https://sensr.genouest.org.

Larval instar‐dependent hemocytes in specialist herbivore Cydalima perspectalis fed on Buxus hyrcana and Buxus microphylla

AbstractThe boxwood moth, Cydalima perspectalis Walker (Lepidoptera: Crambidae), as invasive specialist species in Iran has caused considerable damage in endemic forest stands of Buxus hyrcana Pojark since 2016. Host plant species can alter herbivore–plant interactions through the quantitative and qualitative changes of hemocytes even within a specialist herbivore. To determine the hemocyte variations on different host plants across larval development, the third and sixth instar larvae of C. perspectalis fed on B. hyrcana (native boxwood) and B. microphylla Sieb. and Zucc. (introduced nonnative boxwood) were compared. Total (THC) and differential (DHC) hemocyte count were determined using light, phase‐contrast, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Based on results, six types of hemocytes were recognized in hemolymph including prohemocytes (PRs), plasmatocytes (PLs), granulocytes (GRs), oenocytoides (OEs) and spherulocytes (SPs) as well as unknown elongated quadrangular cells (elongocytes [ELs], the term has been first employed here) with obvious and distinguishable nuclei which were observed by the SEM and TEM microscopy. The ELs were rectangular or trapezoidal in shape, and the largest cells in hemolymph—their length varied from 14.00 to 15.73 μm. Our results showed that the total number of hemocytes (THC) significantly increased across larval development. Moreover, host plant species significantly affected total hemocyte count where the THC of sixth instar larvae on B. microphylla (2561.00 ± 10.60 cell/mm3) was significantly higher than on B. hyrcana (2440.00 ± 51.50 cell/mm3). The differential hemocyte count (DHC) profile study showed that GRs along with PLs were the most abundant cells in the hemolymph irrespective of larval instar and host plant species. Furthermore, the GRs% and ELs% increased throughout the larval development on both host plants, while a significant reduction of PLs% was recorded from third instar to sixth instar during the larval stage on two Buxus species. Apart from larval instar, host plant species had a significant effect on DHC of C. perspectalis. Despite higher total hemocyte number when fed on B. microphylla, the PLs% and ELs% were significantly higher in sixth‐instar larvae fed on B. hyrcana compared with B. microphylla. Oppositely, the percentage of GRs was 17% less in larvae reared on B. hyrcana than on B. microphylla. As hemocyte types are responsible for different immune functions, these findings on instar‐ and host plant‐dependent variation in their relative abundance would be critical to understand the immune response of this specialist herbivore.

Primary Hyperparathyroidism Across the Age Spectrum: A Comparative Study of Clinical and Biochemical Profiles in Older and Younger Patients

Primary Hyperparathyroidism Across the Age Spectrum: A Comparative Study of Clinical and Biochemical Profiles in Older and Younger Patients

P0973 Early infliximab use is associated with less disease progression in luminal Crohn’s disease: a real-world tertiary centre experience

Abstract Background The PROFILE study demonstrated clear benefits of early advanced therapy in luminal Crohn’s disease (CD) in the trial setting. We retrospectively evaluated the relationship between timing of onset of infliximab as first advanced therapy and disease outcomes in a real-world single centre cohort at Oxford University Hospitals NHS Trust. Methods A pharmacy database was searched to identify patients who received infliximab as first advanced therapy in CD. Electronic patient records (Cerner) were searched to capture the following: demographics, Montreal classification, timing of onset of infliximab, biochemical, endoscopic and radiological parameters. The primary outcome was persistence on therapy. Secondary outcomes were survival without surgery or hospitalisation, progression of disease phenotype and steroid use. Data was analysed using GraphPad Prism. Results 247 patients prescribed infliximab as first advanced therapy were identified (F:M = 112:135). Median duration (IQR) from diagnoses to first infliximab dose was 2.83 (0.25 – 10.02) years. 117 patients had inflammatory luminal disease at therapy onset (Montreal B1P0), with median first therapy from diagnosis of 2.67 (0.25 – 9.91) years. When reviewing all cases, and those with exclusively inflammatory luminal disease, persistence on therapy, survival without surgery and survival without hospitalisation did not vary with time to first advanced therapy (p&amp;gt;0.05 all comparisons, figure 1). However, in patients with luminal inflammatory CD who started therapy within 2 years of disease onset there was less disease progression, defined as extension in location, behaviour or new perianal disease (2/52 vs 10/65 chi sq 4.18 p=0.04), and a trend towards less systemic corticosteroid use (4/52 vs 13/65 chi sq 3.53 p=0.06). Conclusion Early infliximab therapy in luminal CD is associated with less disease progression and less use of systemic corticosteroids. The lack of variation in other outcomes may be due to historical case selection for advanced therapies. References Noor NM et al. PROFILE. Gastro Lancet Hep 2024 Figure 1: Persistence on therapy, surgery and hospitalisation free survival, categorised by duration from diagnosis until first infliximab dose. *luminal = Montreal B1P0

Targeting EPHB2/ABL1 restores antitumor immunity in preclinical models of ependymoma

Ependymoma (EPN) is a common form of brain tumor in children, often resistant to available cytotoxic therapies. Molecular profiling studies have led to a better understanding of EPN subtypes and revealed a critical role of oncogenes ZFTA-RELA fusion and EPHB2 in supratentorial ependymoma (ST-EPN). However, the immune system's role in tumor progression and response to therapy remains poorly understood. New treatments for various molecular subtypes of EPN are desperately needed. Using ST-EPN-ZFTA subtype-specific syngeneic mouse models, we found an increased frequency of M2-like tumor-associated macrophages (TAMs), which proportionally increased with tumor size during tumor progression. Transcriptomic profiling of ST-EPN-ZFTA and analysis of a human EPN dataset revealed multiple protein kinases as potential druggable targets. By matching transcriptomic signatures with the target spectrum of FDA-approved drugs, we found that the multikinase inhibitor dasatinib potently inhibited the growth of EPN both in vitro and in vivo, mainly through blocking EPHB2 and ABL1. Treatment with dasatinib reprogrammed the EPN immune microenvironment by polarizing TAMs toward an M1-like phenotype and increasing CD8 T cell activation. Furthermore, dasatinib treatment induced complete regression of established EPN tumors in 78% of the animals and protected survivors against tumor recurrence. Depletion of CD8 cells compromised the durability of EPN responses and reduced overall survival. These data indicate that dasatinib has the potential to be an effective therapy for ST-EPN-ZFTA molecular subgroup of EPN and support further investigation of dasatinib in clinical trials.

P0488 The course of Crohn’s Disease in the Biologics Era: an in depth Single-Center Tertiary Cohort Study in Belgium

Abstract Background Since 1999, Biologics have become a cornerstone in the management of Crohn’s Disease (CD), enabling complete mucosal healing in a significant proportion of patients, with measurable changes in major outcomes in large phase III/IV clinical trials. This holds true particularly when patients were exposed early at diagnosis to biologics, as reported in the recent PROFILE study. However, their real-world impact on the long-term course of the disease remains uncertain. This retrospective study aims to characterize the natural history of CD before and during the biologic era, in a single tertiary center in Belgium. Methods Based on inclusion criteria, 516 CD patients were included and stratified in two subpopulations, according to the date of CD diagnosis (before or after 1999). All events were recorded from date of diagnosis to maximum follow-up (FU), to achieve high granularity, from disease characteristics to treatment adaptations. Statistical analyses were performed using Prism. Results Among 516 CD patients included, 87 and 429 were diagnosed before and after 1999, respectively. There was no significant difference in demographics or disease characteristics at diagnosis. Patients diagnosed after 1999 were exposed to biologics for a larger portion of their FU compared to those diagnosed before 1999 [51% vs 11%, p&amp;lt;0.0001]. At maximum FU, more patients diagnosed before 1999 had progressed to B2/B3 phenotypes (69% vs 39%, p&amp;lt;0.0001), reflecting their longer disease duration compared to patients diagnosed after 1999 (Median FU 27 years [22-30] vs 12 years [6-15], p&amp;lt;0.0001). Indeed, 10 years after CD diagnosis, disease progression to B2/B3 phenotypes was similar in both groups (27% vs 23%, p=0.6), (Figure 1a). Changes in phenotype were diagnosed sooner in patients diagnosed after 1999 compared to those diagnosed before 1999 (Median 4.8 years [1.8-9.9] vs 12.3 years [6-16.8], p&amp;lt;0.0001] (Figure 1b). They were also operated sooner than patients diagnosed before 1999 (Median 5.9 years [2.1-10.2] vs 12.5 years [6.6-18.2], p&amp;lt;0.0001] (Figure 1c). Conclusion The proportion of patients progressing to a B2/B3 phenotype at 10 years of disease course is similar for CD patients diagnosed before and during the Biological Era. The detection of complications occured earlier in patients diagnosed after 1999, which suggests a shift toward more proactive monitoring since the advent of biologics. Based on these findings, it remains uncertain whether biological therapies have significantly altered the course of the disease and phenotype progression in CD patients. However, while these results are based on objective outcomes, they do not fully capture the impact of biological treatments on patients quality of life and disease burden.

A computational study of novel CsYMSe3 (M = Cd, Zn) materials: for their potential optoelectronic and thermoelectric application

Abstract The thermoelectric performance and adjustable optical properties of chalcogenides are noteworthy. Density functional theory is employed to study the electrical, optical, and thermoelectric properties of the novel CsYMSe3 (M = Cd, Zn) quaternary chalcogenides. A direct band gap nature was predicted based on the band profile study. Using Perdew–Burke–Ernzerhof generalized gradient approximation and TB-modified Becke–Johnson, the reported band gaps are 2.12 and 2.92 eV for CsYZnSe3 and 2.11 and 3.07 eV for CsYCdSe3, respectively. The results showed that in both materials, the hybridization of the orbital Cs–p/d and the Se–p were responsible for direct energy losses. The complex dielectric function and the important linear optical parameters were investigated for possible usage in optoelectronic devices. These materials exhibit stronger absorption of photons. These materials could be employed as particularly effective UV-reflecting materials from the noticed peaks in the reflectivity spectra. Because of their negative Seebeck coefficient values, both materials show n-type conductivity across the whole temperature range. CsYZnSe3 possesses better electrical conductivity than CsYCdSe3, which results in a larger ZT value.

Study of the Edge Metallization Profile of Optically Transparent Windows Formed by Magnetron Sputtering

Study of the Edge Metallization Profile of Optically Transparent Windows Formed by Magnetron Sputtering