Subclinical immune reactions to viral infections may correlate with child and adolescent diagnosis of attention-deficit/hyperactivity disorder: A preliminary study from Turkey

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neuro-developmental disorders of childhood and  adolescence. Studies focusing on the relationship of infectious agents and ADHD are scarce. It is also known that cerebellar injury may lead to  hyperactive behavior. This study aimed to evaluate the relationship  between viral agents of cerebellitis and the diagnosis of ADHD.Methods: The study group was formed of 60 consecutive ADHD patients and 30 healthy children. IgG levels for VZV; HSV-1, CMV, Measles, Mumps, Rubella and EBV were evaluated.Results: Males were significantly higher among patients with ADHD (65% vs. 40%, p=0.025). Patients with ADHD displayed significantly higher positivity for measles IgG (80% vs. 60%, p=0.044). When patients with ADHD were classified according to their pubertal status, adolescents with ADHD displayed higher positivity for mumps (100% vs. 74.4%, p=0.043). Most of the patients were diagnosed with ADHD-Combined or  Hyperactive/Impulsive Subtypes (56.6%) while 43.3% were diagnosed with ADHD-predominantly inattentive type. When patients with subtypes of ADHD were compared in terms of seropositivity, it was found that patients with ADHD-Combined/ Hyperactive-Impulsive subtypes had significantly elevated reactions for Rubella (100% vs. 88.5%, p=0.044).Conclusion: Although limited to a single center and may be prone to sampling biases, our results may support the notion that immune reactions may be related with ADHD among children and adolescents. Further,  prospective studies from multiple centers are needed to support our  findings and establish causality.Key words: ADHD, infection, immunology, measles, rubella, mumps, Ig

Pericyte FAK negatively regulates Gas6/Axl signalling to suppress tumour angiogenesis and tumour growth

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK.</p

Two-dimensional Schr\"odinger Hamiltonians with Effective Mass in SUSY Approach

The general solution of SUSY intertwining relations of first order for two-dimensional Schr\"odinger operators with position-dependent (effective) mass is built in terms of four arbitrary functions. The procedure of separation of variables for the constructed potentials is demonstrated in general form. The generalization for intertwining of second order is also considered. The general solution for a particular form of intertwining operator is found, its properties - symmetry, irreducibility, separation of variables - are investigated.Comment: 16 page

METhodological RadiomICs Score (METRICS): a quality scoring tool for radiomics research endorsed by EuSoMII

Purpose: To propose a new quality scoring tool, METhodological RadiomICs Score (METRICS), to assess and improve research quality of radiomics studies. Methods: We conducted an online modified Delphi study with a group of international experts. It was performed in three consecutive stages: Stage#1, item preparation; Stage#2, panel discussion among EuSoMII Auditing Group members to identify the items to be voted; and Stage#3, four rounds of the modified Delphi exercise by panelists to determine the items eligible for the METRICS and their weights. The consensus threshold was 75%. Based on the median ranks derived from expert panel opinion and their rank-sum based conversion to importance scores, the category and item weights were calculated. Result: In total, 59 panelists from 19 countries participated in selection and ranking of the items and categories. Final METRICS tool included 30 items within 9 categories. According to their weights, the categories were in descending order of importance: study design, imaging data, image processing and feature extraction, metrics and comparison, testing, feature processing, preparation for modeling, segmentation, and open science. A web application and a repository were developed to streamline the calculation of the METRICS score and to collect feedback from the radiomics community. Conclusion: In this work, we developed a scoring tool for assessing the methodological quality of the radiomics research, with a large international panel and a modified Delphi protocol. With its conditional format to cover methodological variations, it provides a well-constructed framework for the key methodological concepts to assess the quality of radiomic research papers. Critical relevance statement: A quality assessment tool, METhodological RadiomICs Score (METRICS), is made available by a large group of international domain experts, with transparent methodology, aiming at evaluating and improving research quality in radiomics and machine learning. Key points: • A methodological scoring tool, METRICS, was developed for assessing the quality of radiomics research, with a large international expert panel and a modified Delphi protocol. • The proposed scoring tool presents expert opinion-based importance weights of categories and items with a transparent methodology for the first time. • METRICS accounts for varying use cases, from handcrafted radiomics to entirely deep learning-based pipelines. • A web application has been developed to help with the calculation of the METRICS score (https://metricsscore.github.io/metrics/METRICS.html) and a repository created to collect feedback from the radiomics community (https://github.com/metricsscore/metrics). Graphical Abstract: [Figure not available: see fulltext.

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5(+) CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF ‘memory’ sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5(+) states in isolation is constrained by their functional redundancy. Although the canonical LGR5(+) state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment

Genomic basis for RNA alterations in cancer

Transcript alterations often result from somatic changes in cancer genomes1. Various forms of RNA alterations have been described in cancer, including overexpression2, altered splicing3 and gene fusions4; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)5. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed ‘bridged’ fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer