Diverse Subtypes Research Articles

Identifying potential drug targets for seborrheic keratosis through druggable genome-wide Mendelian randomization and colocalization analysis.

Seborrheic keratosis (SK) is the most prevalent benign epidermal tumor in adults, characterized by complex pathogenesis and diverse clinical subtypes. This study systematically evaluated the genetic susceptibility and identified novel therapeutic targets for SK. We applied two-sample Mendelian randomization (MR) using cis-eQTL data for druggable genes in blood and SK genome-wide association study (GWAS) data to identify causal genes. Sensitivity and colocalization analyses were performed to assess MR reliability and estimate the likelihood of shared causal variants between cis-eQTLs of druggable genes and SK. For additional validation, we conducted enrichment analysis, phenome-wide association analysis, and candidate drug prediction to further interpret our findings. The expression levels of 18 druggable genes were significantly associated with SK susceptibility (adjusted p-value [FDR] < 0.05), of which 8 were identified as risk factors for SK, while 10 significantly reduced SK predisposition. The susceptibility of SK was likely linked to a shared causal variant with two significant druggable genes, CASP8 (OR = 0.725, 95%CI: 0.622-0.844, PPH4 = 0.907) and TSSK6 (OR = 0.478, 95%CI: 0.327-0.696, PPH4 = 0.970). Functional analyses revealed CASP8 and TSSK6 may influence SK onset and progression through mechanisms cell differentiation and programmed apoptosis regulation. CASP8 and TSSK6 stand out as the most promising potential drug targets for reducing the susceptibility of SK. Our findings identify potential drug targets and provide valuable insights for future SK drug development.

Untargeted Metabolomics and Liquid Biopsy Investigation of Circulating Biomarkers in Soft Tissue Sarcoma

Background: Soft tissue sarcomas (STSs) are rare, highly malignant mesenchymal tumours, comprising approximately 1% of all adult cancers and about 15% of paediatric solid tumours. STSs exhibit considerable genomic complexity with diverse subtypes, posing significant clinical challenges. Objectives: This study aims to characterise the molecular signature of primary STS through liquid biopsies and the untargeted metabolomic profiling of 75 patients, providing deep insights into cellular processes and potential therapeutic targets. Methods: This study analysed serum samples using nuclear magnetic resonance (NMR) spectroscopy for metabolomic profiling. Multivariate data analysis and machine learning classifiers were employed to identify biomarkers. Results: A panel of eleven significant deregulated metabolites were discovered in serum samples of patients with STS, with potential implications for cancer diagnosis and treatment. Conclusions: Choline decrease emerged as a marker for cancer progression, highlighting the potential of targeting its metabolism for therapeutic approaches in STS. The NMR analysis protocol proved effective for determining circulating biomarkers from liquid biopsies, making it suitable for rare disease research.

From heterogeneity to prognosis: understanding the complexity of tertiary lymphoid structures in tumors.

Tertiary lymphoid structures (TLSs) are aberrant lymphoid tissues found in persistent inflammatory settings, including malignancies, autoimmune disorders, and transplanted organs. The organization and architecture of TLS closely resemble that of secondary lymphoid organs (SLOs). The formation of TLS is an ongoing process, with varying structural features observed at different stages of maturation. The tumor microenvironment (TME) is a multifaceted milieu comprising cells, molecules, and extracellular matrix components in close proximity to the neoplasm. TLS within the TME have the capacity to actively elicit anti-tumor immune responses. TLSs exhibit tumor-specific and individual-specific characteristics, leading to varying immune responses towards tumor immunity based on their distinct cellular components, maturity levels, and spatial distribution. Cell interaction is the foundational elements of tumor immunity. Despite differences in the cellular composition of TLS, B cells and T cells are the main components of tumor-associated TLS。Recent research has highlighted the significance of diverse subtypes of B cells and T cells within TLSs in influencing the therapeutic outcomes and prognostic indicators of individual tumors. This review elucidates the diversity of TLS in terms of cellular composition, developmental stage, anatomical location, and the influence of cytokines on their initiation and progression. Furthermore, the article examines the involvement of B and T cells within TLS and the significance of TLS in relation to tumor prognosis.

Advancements in Artificial Intelligence for Kidney Transplantology: A Comprehensive Review of Current Applications and Predictive Models

Background: Artificial intelligence is rapidly advancing within the domains of medicine and transplantology. In this comprehensive review, we provide an in-depth exploration of current AI methodologies, with a particular emphasis on machine learning and deep learning techniques, and their diverse subtypes. These technologies are revolutionizing how data are processed, analyzed, and applied in clinical decision making. Methods: A meticulous literature review was conducted with a focus on the application of artificial intelligence in kidney transplantation. Four research questions were formulated to establish the aim of the review. Results: We thoroughly examined the general applications of AI in the medical field, such as feature selection, dimensionality reduction, and clustering, which serve as foundational tools for complex data analysis. This includes the development of predictive models for transplant rejection, the optimization of personalized immunosuppressive therapies, the algorithmic matching of donors and recipients based on multidimensional criteria, and the sophisticated analysis of histopathological images to improve the diagnostic accuracy. Moreover, we present a detailed comparison of existing AI-based algorithms designed to predict kidney graft survival in transplant recipients. In this context, we focus on the variables incorporated into these predictive models, providing a critical analysis of their relative importance and contribution to model performance. Conclusions: This review highlights the significant advancements made possible through AI and underscores its potential to enhance both clinical outcomes and the precision of medical interventions in the field of transplantology.

Patterns and variations of copy number alterations in acute myeloid leukemia: insights from the LeukAtlas database.

Recent pan-cancer analysis revealed the global pattern and potential aetiologies of copy number variation signatures in human cancers, particularly those derived from non-hematopoietic tissues. In sharp contrast, the generally low CNV burden in leukemia leaves the CNV landscape and variations largely unexplored, impeding understanding of CNV in leukemia development. Through a comprehensive compilation of public datasets, we constructed LeukAtlas ( https://ngdc.cncb.ac.cn/leukemia ), a user-friendly database encompassing 12,597 CNVs from 1446 AML samples across diverse subtypes and age groups, providing tools for multidimensional CNV analysis. Our analyses suggested the CNV levels significantly varied among AML patients. We discovered two previously unknown CNV patterns in adult AML patients, dominated by segmental LOH and/or minor gain, which have been shown to be associated with chromosomal instability in solid tumors. Additionally, we defined two potential new AML subgroups based on CNVs status, providing new stratification markers within the existing karyotype framework. Representing the most extensive CNV collection in AML, LeukAtlas is a valuable resource for exploring the role of CNVs in the pathogenesis and prognosis stratification of leukemia. Interrogation of this database uncovers novel subclasses with unique CNV profiles and reveals heterogeneous CNV patterns in AML, demonstrating the potential role of chromosomal instability in AML progression.

Genetic diversity and prevalence of Blastocystis subtypes in Alborz Province, Iran: A molecular epidemiological study.

The primary objective of this study was to evaluate the genetic diversity of Blastocystis. Additionally, it aimed to explore, for the first time in Iran, the potential association between Blastocystis infection and ABO blood groups. Another focus was to examine the relationship between Blastocystis subtypes and blood groups, an often overlooked risk factor, within the population of Alborz Province, Iran. 450 stool samples were collected from diagnostic facilities across Alborz Province between June 2022 and April 2024. The presence of Blastocystis was confirmed in 64 out of 450 samples (14.22 %) using the Nested PCR-RFLP technique. Among the 64 positive samples, nine (2 %) were classified as indeterminate. Two distinct Blastocystis subtypes were identified in 55 isolates, accounting for 12.22 % of the total samples. ST1 was detected in 44 isolates (9.77 %), rendering it the most prevalent subtype, while ST3 was identified in 11 isolates (2.44 %). Phylogenetic trees were constructed using sequencing data and compared against genotypes available in GenBank. Significant differences between infected and non-infected individuals were observed regarding educational attainment, marital status, and blood type (p < 0.05). A significant association was found between ABO blood groups and the prevalence of Blastocystis infection (p = 0.019). However, when examining the correlation between Blastocystis subtypes (ST1 and ST3) and ABO blood groups, no significant overall association was observed. Nonetheless, specific associations were found for blood groups O+ and B-, with subtype ST1 being more prevalent in these groups.

CSGO: A Deep Learning Pipeline for Whole-Cell Segmentation in Hematoxylin and Eosin Stained Tissues

Accurate whole-cell segmentation is essential in various biomedical applications, particularly in studying the tumor microenvironment. Despite advancements in machine learning for nuclei segmentation in hematoxylin and eosin (H&E)-stained images, there remains a need for effective whole-cell segmentation methods. This study aimed to develop a deep learning-based pipeline to automatically segment cells in H&E-stained tissues, thereby advancing the capabilities of pathological image analysis. The Cell Segmentation with Globally Optimized boundaries (CSGO) framework integrates nuclei and membrane segmentation algorithms, followed by postprocessing using an energy-based watershed method. Specifically, we used the You Only Look Once (YOLO) object detection algorithm for nuclei segmentation and U-Net for membrane segmentation. The membrane detection model was trained on a data set of 7 hepatocellular carcinomas and 11 normal liver tissue patches. The cell segmentation performance was extensively evaluated on 5 external data sets, including liver, lung, and oral disease cases. CSGO demonstrated superior performance over the state-of-the-art method Cellpose, achieving higher F1 scores ranging from 0.37 to 0.53 at an intersection over union threshold of 0.5 in 4 of the 5 external datasets, compared to that of Cellpose from 0.21 to 0.36. These results underscore the robustness and accuracy of our approach in various tissue types. A web-based application is available at https://ai.swmed.edu/projects/csgo, providing a user-friendly platform for researchers to apply our method to their own data sets. Our method exhibits remarkable versatility in whole-cell segmentation across diverse cancer subtypes, serving as an accurate and reliable tool to facilitate tumor microenvironment studies. The advancements presented in this study have the potential to significantly enhance the precision and efficiency of pathologic image analysis, contributing to better understanding and treatment of cancer.

Design and assessment of two broad-spectrum multi-epitope vaccine candidates against bovine viral diarrhea virus based on reverse vaccinology.

Bovine viral diarrhea virus (BVDV) is a significant pathogen that exerts substantial economic influence on the global cattle industry. Developing a safe and effective novel vaccine targeting various BVDV subtypes is critical for controlling BVDV infection. In the study, we created two distinct multi-epitope vaccines by linking highly conserved and dominant cytotoxic T-lymphocytes (CTL), helper T-lymphocytes (HTL), and B-cell epitopes from either the E0 or E2 envelope glycoprotein of diverse BVDV subtypes. To enhance immunogenicity, β-defensin-3 was fused to the N-terminus of these constructs as an adjuvant. Using multiple immunoinformatics tools, we conducted an analysis and assessment of the vaccine constructs' physicochemical properties and immunological features. Consequently, two prospective vaccine candidates named BVDV-M1 and BVDV-M2 were successfully designed and shown to be stable, antigenic, non-allergenic, and non-toxic. The optimized vaccine 3D models exhibit excellent structural quality. Molecular docking revealed a strong interaction between the vaccines with bovine TLR2 and TLR4. The stability of the docked vaccine-TLR complexes was confirmed through molecular dynamics simulation. Immune simulation analyses indicated that both vaccines have the potential to induce high levels of antibodies IgM, IgG and the cytokines IFN-γ and IL-2. Furthermore, the vaccine's efficient expression in the E.coli system was secured through codon optimization coupled with in silico cloning. Summarily, the designed multi-epitope vaccines have the potential to elicit robust humoral and cellular immune responses, positioning them as hopeful broad-spectrum vaccine candidates against the currently prevalent BVDV subtypes.

P-463. Diversity of KSHV Subtypes in People Living with HIV in a Large Urban Center in Dallas, Texas

Abstract Background Human herpesvirus-8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), causes Kaposi’s sarcoma (KS) and other KSHV-associated disease (KAD). We previously described high KSHV seroprevalence and high KS incidence in a population of men who have sex with men (MSM) with HIV in Dallas, Texas. We now describe viral genetics in the same population.Table 1:Participant Characteristics Methods We analyzed samples from participants recruited in 2 different studies, one enrolling MSM with HIV with and without KAD, and the other enrolling MSM with HIV and KAD. We measured KSHV IgG in serum using a combination of ELISA and a bead-based multiplex assay. Oral fluid samples of all individuals with KAD and seropositive individuals with no KAD were analyzed by RT-PCR to detect and quantify KSHV DNA. Samples with detectable KSHV underwent Sanger and/or next generation sequencing to determine K1 subtype.Figure 1:Phylogenetic Tree of Participant Samples Results Overall, 281 participants were recruited; 59 shed enough virus for K1 subtyping. Of these, 37 did not have KAD, and 22 had KAD, all had KS. Table 1 describes the demographic characteristics of these participants. Notably, those with KS had lower median CD4 countsthan those without KS (p &amp;lt; 0.01). All known K1 subtypes, except for D, were identified in this cohort, including the rare E and F subtypes. The latter, which only recently had been described outside Africa was identified in 6 individuals. Four participants had mixed infections with 2 or more KSHV subtype (Figure 1). Figure 2 illustrates clinical presentations by KSHV subtype. Limitations in sequencing technology and study design permit no inferences on possible associations between KSHV subtype and KS onset or severity. We observed a larger proportion of subtypes B and F, typical of African populations, in participants with KS, than those with no KAD (8/27 subtypes detected vs 3/37). However, A and C were the most commonly identified subtypes in KS (19/27 subtypes in those with KS vs 32/37 subtypes in those without KS), including in advanced cases (i.e. T1 stage, 10/13).Figure 2:KSHV Subtypes and Clinical Presentation Conclusion In conclusion, we observed extreme diversity in KSHV genomes sequenced in a single institution in Dallas, TX. Further studies are needed to better understand the relationship between viral genetics and KSHV epidemiology and disease risk in the southern US. Disclosures Ank E. Nijhawan, MD, MPH, MSCS, Gilead Sciences: Grant/Research Support

Olfactory ensheathing cells from adult female rats are hybrid glia that promote neural repair.

Olfactory ensheathing cells (OECs) are unique glial cells found in both central and peripheral nervous systems where they support continuous axonal outgrowth of olfactory sensory neurons to their targets. Previously we reported that following severe spinal cord injury, OECs transplanted near the injury site modify the inhibitory glial scar and facilitate axon regeneration past the scar border and into the lesion. To better understand the mechanisms underlying the reparative properties of OECs, we used single-cell RNA-sequencing of OECs from adult rats to study their gene expression programs. Our analyses revealed five diverse OEC subtypes, each expressing novel marker genes and pathways indicative of progenitor, axonal regeneration, secreted molecules, or microglia-like functions. We found substantial overlap of OEC genes with those of Schwann cells, but also with microglia, astrocytes, and oligodendrocytes. We confirmed established markers on cultured OECs, and localized select top genes of OEC subtypes in olfactory bulb tissue. We also show that OECs secrete Reelin and Connective tissue growth factor, extracellular matrix molecules which are important for neural repair and axonal outgrowth. Our results support that OECs are a unique hybrid glia, some with progenitor characteristics, and that their gene expression patterns indicate functions related to wound healing, injury repair and axonal regeneration.

CAR T-Cell Therapy Unveiled: Navigating Beyond CRS and ICANS to Address Delayed Complications and Optimize Management Strategies

Chimeric antigen receptor (CAR) T-cell therapy has ushered in a transformative era in the management of relapsed/refractory hematologic malignancies. The extensive phase II trials targeting relapsed/refractory non-Hodgkin lymphoma, including diverse subtypes such as diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, along with multiple myeloma and B-cell acute lymphoblastic leukemia, have culminated in the endorsement of various CAR T-cell products for these specific indications by the US Food and Drug Administration. Although CAR T-cell therapy has achieved remarkable success, it is important to recognize that this innovative approach often gives rise to notable toxicities and is frequently associated with a distinctive pattern of adverse effects. Advanced practice providers, including advanced practice nurses and physician associates, involved in the care of these patients should be able to recognize these toxicities and be versed in treatment strategies to mitigate their impact.

Orbital inflammatory disease: a joint clinical experience in rheumatology and ophthalmology.

This retrospective study aimed to characterize the clinical features, histopathological findings, and treatment outcomes of patients diagnosed with orbital inflammatory disease (OID) co-managed by the rheumatology and ophthalmology departments in a tertiary hospital. Medical records of 14 patients with OID were analyzed. Data on demographics, clinical presentation, laboratory investigations, radiological imaging, histopathological results, treatment regimens, and disease outcomes were collected and reviewed. The mean age of the patients was 34.5years, with a female (71.4%) predominance. Periorbital pain (62.5%), periorbital edema (50%) and diplopia (50%) were the most common presenting symptoms. Histopathological evaluation revealed diverse subtypes, including non-specific orbital inflammation (NSOI) (42.8%), orbital myositis (28.5%) and IgG4-related disease (14.3%). Initial treatment with systemic corticosteroids achieved remission in 14.3% of patients, while 85.7% required additional immunosuppressive therapy. Radiotherapy was effective in one patient unresponsive to steroid and azathioprine treatment. OID presents with diverse clinical manifestations and histopathological subtypes, often requiring multidisciplinary management. While corticosteroids remain the first-line therapy, adjunctive immunosuppressive agents or radiotherapy may be necessary in refractory cases.

A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses

Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region’s highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity. Methods: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&amp;2 (V1V2) scaffold proteins and linear V2 peptides. Results: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at 169K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site (179LDV/I181) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions. Conclusions: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.

Transcriptome-Based Survival Analysis Identifies MAP4K4 as a Prognostic Marker in Gastric Cancer with Microsatellite Instability

Background/Objectives: Gastric cancer (GC) is a highly aggressive malignancy with diverse molecular subtypes. While microsatellite instability (MSI) GC generally carries a favorable prognosis, a subset of patients experiences poor outcomes, highlighting the need for refined prognostic markers. Methods: This study utilized transcriptomic and clinical data from two independent cohorts, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG), to identify novel prognostic genes in MSI-GC. Results: Through rigorous survival analysis, we identified high MAP4K4 expression (MAP4K4high) as an independent and robust predictor of poor overall survival (OS) and disease-free survival (DFS) specifically within the MSI-GC subtype. MAP4K4high was associated with increased hazard ratios for both OS and DFS in both cohorts, even after adjusting for clinicopathological factors. Further analysis revealed that MAP4K4high MSI-GC tumors exhibit a distinct molecular profile characterized by increased extracellular matrix remodeling, epithelial–mesenchymal transition, and a microenvironment enriched in monocytes and cancer-associated fibroblasts (CAFs). Notably, a subgroup of MSI-GC patients with a CIN-like phenotype and high MAP4K4 expression exhibited particularly dismal outcomes. Conclusions: Our findings establish MAP4K4 as a promising prognostic biomarker for risk stratification in MSI-GC and suggest its potential role in driving aggressive tumor behavior through modulation of the tumor microenvironment.

Impulse control disorders in Parkinson's disease: What's new?

Impulse Control Disorders (ICDs) are increasingly recognized as a significant non-motor complication in Parkinson's disease (PD), impacting patients and their caregivers. ICDs in PD are primarily associated with dopaminergic treatments, particularly dopamine agonists, though not all patients develop these disorders, indicating a role for genetic and other clinical factors. Studies over the past few years suggest that the mesocorticolimbic reward system, a core neural substrate for impulsivity, is a key contributor to ICDs in PD. Recent advances in neuroimaging have begun to unravel the neurobiological diversity of ICD subtypes. Moreover, recent studies provide valuable insights into the clinical and biologic risk factors for ICDs that could be used as indicators for the development of future preventive strategies or targeted interventions. Indeed, current treatment strategies, which often involve reducing or discontinuing dopamine agonists, are limited in efficacy. Emerging therapies, including behavioral interventions and continuous drug delivery methods, show promise, though further research is needed. This paper provides an updated review of ICD prevalence, mechanisms, assessment, and novel management approaches.

Highly pathogenic bovine viral diarrhea virus BJ-11 unveils genetic evolution related to virulence in calves.

Bovine viral diarrhea virus (BVDV) is the causative agent of bovine viral diarrhea, which causes significant economic loss to the global livestock industry. Despite the widespread use of inactivated BVDV vaccines, highly pathogenic strains continue to emerge. In China, regional variations in BVDV subtypes, morbidities, and symptoms, however, only the BVDV 1a subtype vaccine is currently approved. Therefore, this study is to gain insight into the biological characteristics and genetic variation of BVDV strains prevalent in Beijing. Meanwhile, this will provide a theoretical foundation and technical support for the prevention and control of BVDV, as well as raise awareness of the potential for virulence enhancement caused by the unregulated use of BVDV vaccines. In this study, A BVDV strain, BJ-11, was isolated from calves that died of diarrhea and vaccinated of BVDV. To evaluate its virulence, newborn calves were experimentally infected with the BJ-11. Clinical signs included fever, diarrhea, bloody stools, anorexia, and death in some cases. A marked reduction in leukocyte and lymphocyte counts were observed, accompanied by an increase in neutrophil counts. Histopathological changes manifested as severe lung lesions. Phylogenetic analysis indicated that BJ-11 belongs to the BVDV 1b subtype, genetically closest to the JL-1 strain. Analysis of the E2 glycosylation site disappeared (298SYT) in one of the four common glycosylation sites in the BVDV-1, which has been reported to affect the ability of the virus to infect and an additional glycosylation site (122NGS). These results indicate that BJ-11 is a highly pathogenic strain evolved from a low-virulence ancestor and should be served as a challenge strain. Simultaneously, these results contribute to a broader understanding of BVDV and whether imperfect vaccination strategies lead to reversal of immunosuppressive virulence.

Computational pathology applied to clinical colorectal cancer cohorts identifies immune and endothelial cell spatial patterns predictive of outcome.

Colorectal cancer (CRC) is a histologically heterogeneous disease with variable clinical outcome. The role the tumour microenvironment (TME) plays in determining tumour progression is complex and not fully understood. To improve our understanding, it is critical that the TME is studied systematically within clinically annotated patient cohorts with long-term follow-up. Here we studied the TME in three clinical cohorts of metastatic CRC with diverse molecular subtype and treatment history. The MISSONI cohort included cases with microsatellite instability that received immunotherapy (n = 59, 24 months median follow-up). The BRAF cohort included BRAF V600E mutant microsatellite stable (MSS) cancers (n = 141, 24 months median follow-up). The VALENTINO cohort included RAS/RAF WT MSS cases who received chemotherapy and anti-EGFR therapy (n = 175, 32 months median follow-up). Using a Deep learning cell classifier, trained upon >38,000 pathologist annotations, to detect eight cell types within H&E-stained sections of CRC, we quantified the spatial tissue organisation and colocalisation of cell types across these cohorts. We found that the ratio of infiltrating endothelial cells to cancer cells, a possible marker of vascular invasion, was an independent predictor of progression-free survival (PFS) in the BRAF+MISSONI cohort (p = 0.033, HR = 1.44, CI = 1.029-2.01). In the VALENTINO cohort, this pattern was also an independent PFS predictor in TP53 mutant patients (p = 0.009, HR = 0.59, CI = 0.40-0.88). Tumour-infiltrating lymphocytes were an independent predictor of PFS in BRAF+MISSONI (p = 0.016, HR = 0.36, CI = 0.153-0.83). Elevated tumour-infiltrating macrophages were predictive of improved PFS in the MISSONI cohort (p = 0.031). We validated our cell classification using highly multiplexed immunofluorescence for 17 markers applied to the same sections that were analysed by the classifier (n = 26 cases). These findings uncovered important microenvironmental factors that underpin treatment response across and within CRC molecular subtypes, while providing an atlas of the distribution of 180 million cells in 375 clinically annotated CRC patients. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Analyzing Mood Structures in the Quranic Stories of Nuh: A Comparative Study of Quranic Translations

To properly translate rhetorical questions, the paper addresses how to preserve and analyze thematic structures in translations of religious texts. It mainly concentrates on how translators understand and communicate the interpersonal mood structures found in the Quranic Nuh stories in the Quranic translations by Abdullah Yusuf Ali and by Muhammad Taqi-ud-Din Al-Hilali and Muhammad Muhsin Khan. Nuh's stories were chosen mainly because they provide a rich tapestry of divine pronouncements, pleas, and rhetorical inquiries and highlight how clear mood rules conversations, aiming at explaining the impact of translation choices on mood distribution and potential interpretive nuances. Employing the Systemic Functional Linguistics (SFL) framework, the study analyzes the distribution of declarative, imperative, and interrogative moods within the Nuh stories across both translations. The analysis revealed a consistent dominance of the declarative mood across the two translations, reflecting the narrative's primary focus on conveying information and pronouncements. However, significant variations emerge in the usage of imperative and interrogative moods. The study identifies translator-specific tendencies, highlighting how confident choices amplify or subdue the urgency of commands or the intensity of rhetorical questions. Furthermore, the findings show that linguistic variations exist across languages regarding how declarative is constructed. Findings also articulated the diverse subtypes that help realize emerging declarations within different translation approaches. Moreover, Nuh's stories show high imperative usage by reflecting the guidance-oriented themes. Conversely, the blend of declarative, imperatives, and interrogatives at the particular stage of Nuh's spreading Allah’s message hints at a dynamic interplay of information, instruction, and rhetorical questioning.

IDH-mutant gliomas in children and adolescents - from biology to clinical trials.

Gliomas account for nearly 30% of all primary central nervous system (CNS) tumors in children and adolescents and young adults (AYA), contributing to significant morbidity and mortality. The updated molecular classification of gliomas defines molecularly diverse subtypes with a spectrum of tumors associated with age-distinct incidence. In adults, gliomas are characterized by the presence or absence of mutations in isocitrate dehydrogenase (IDH), with mutated IDH (mIDH) gliomas providing favorable outcomes and avenues for targeted therapy with the emergence of mIDH inhibitors. Despite their rarity, IDH mutations have been reported in 5-15% of pediatric glioma cases. Those with primary mismatch-repair deficient mIDH astrocytomas (PMMRDIA) have a particularly poor prognosis. Here, we describe the biology of mIDH gliomas and review the literature regarding the emergence of mIDH inhibitors, including clinical trials in adults. Given the paucity of clinical trial data from pediatric patients with mIDH glioma, we propose guidelines for the inclusion of pediatric and AYA patients with gliomas onto prospective trials and expanded access programs as well as the potential of combined mIDH inhibition and immunotherapy in the treatment of patients with PMMRDIA at high risk of progression.

Serum metabolomic profiling for predicting therapeutic response and toxicity in breast cancer neoadjuvant chemotherapy: a retrospective longitudinal study

BackgroundNeoadjuvant chemotherapy (NACT) is the standard-of-care treatment for patients with locally advanced breast cancer (LABC), providing crucial benefits in tumor downstaging. Clinical parameters, such as molecular subtypes, influence the therapeutic impact of NACT. Moreover, severe adverse events delay the treatment process and reduce the effectiveness of therapy. Although metabolic changes during cancer treatment are crucial determinant factors in therapeutic responses and toxicities, related clinical research remains limited.MethodsOne hundred paired blood samples were collected from 50 patients with LABC before and after a complete NACT treatment cycle. Untargeted metabolomics was used by liquid chromatography-mass spectrometry (LC–MS) to investigate the relationship between dynamically changing metabolites in serum and the responses and toxicities of NACT.ResultsFirstly, we observed significant alterations in serum metabolite levels pre- and post-NACT, with a predominant enrichment in the sphingolipid and amino acid metabolism pathways. Second, pre-treatment serum metabolites successfully predicted the therapeutic response and hematotoxicities during NACT. In particular, molecular subtype variations in favorable treatment responses are linked to acyl carnitine levels. Finally, we discovered that the therapeutic effects of NACT could be attributed to essential amino acid metabolism.ConclusionThis study elucidated the dynamic changes in metabolism during NACT treatment, providing a possibility for developing responsive metabolic signatures for personalized NACT treatment.