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Summary: Adaptor chimeric antigen receptor (CAR) T‐cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T‐cell therapy in myeloid malignancies. The adaptor CAR T‐cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well‐tolerated, rapidly switchable, CD123‐directed UniCAR T‐cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti‐tumour responses, underlining the need to further design alternative AML‐specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS‐like tyrosine kinase 3 (FLT3)‐directed UniCAR T‐cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half‐life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3‐specific UniCAR T cells for the therapy of AML. [ABSTRACT FROM AUTHOR]

Magnetic and fluorescent hydroxyapatite nanoparticles were synthesised using Al(OH)3-stabilised MnFe2O4 or Fe3O4 nanoparticles as precursors. They were readily and efficiently radiolabelled with 18F. Bisphosphonate polyethylene glycol polymers were utilised to endow the nanoparticles with excellent colloidal stability in water and to incorporate cyclam for high affinity labelling with 64Cu. [ABSTRACT FROM AUTHOR]

Biomarkers are emerging as important tools in the detection and monitoring of various diseases. A major limitation and challenge to effectively utilize biomarker signals is the limited understanding of factors contributing to their variance. As genetic variation is a major contributor to phenotypic variation, exploring genetic contributions is of great importance. Copy number variants (CNVs) offer an alternative genomic framework to understand contributions to phenotypic variance. A copy-number variation genome-wide association study was performed using 116 serum inflammatory biomarkers as quantitative trait in elderly normal controls to test the hypothesis that CNVs contribute to the phenotypic heterogeneity of serum biomarkers. Three chromosomal regions were associated with four biomarkers in trans. Transforming growth factor alpha (TG-alpha) serum levels were associated with CNV dosage at chr11:5,788 kb, soluble levels of receptor for advanced glycation endproducts (sRAGE) was associated with CNV dosage at chr8:40,183 kb and both thrombospondin-1 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were associated with CNV dosage at chr11:18,961 kb. The CNV at chr11:5,788 kb harbors 2 olfactory genes and the introns of Tripartite motif-containing (TRIM) gene cluster TRIM5&22 while the CNV at chr11:18,961 includes the Mas-related G-protein coupled receptor member X1. These trans associations may identify novel relationships in the relevant pathways and suggest that genetic variation can contribute to biomarker levels. The detected trans-association between MRGPRX1 and thrombospondin-1/TIMP-1 could implicate a novel pathway between pain/itching and inflammation. Cataloguing all genetic variants with an effect on biomarkers will serve as a tool to interpret epidemiological studies and establish causal relationships through Mendelian randomization. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high prevalence, which imposes a substantial public health problem. The heritability of AD is estimated at 60-80% forecasting the potential use of genetic biomarkers for risk stratification in the future. Several large scale genome-wide association studies using high frequency variants identified 10 loci accountable for only a fraction of the estimated heritability. To find the missing heritability, systematic assessment of various mutational mechanisms needs to be performed. This copy number variation (CNV) genome-wide association study with age at onset (AAO) of AD identified 5 CNV regions that may contribute to the heritability of AAO of AD. Two CNV events are intragenic causing a deletion in CPNE4. In addition, to further study the mutational load at the 10 known susceptibility loci, CNVs overlapping with these loci were also catalogued. We identified rare small events overlapping CR1 and BIN1 in AD and normal controls with opposite CNV dosage. The CR1 events are consistent with previous reports. Larger scale studies with deeper genotyping specifically addressing CNV are needed to evaluate the significance of these findings. [ABSTRACT FROM AUTHOR]

Jumping translocations (JTs) are very rare chromosome aberrations, usually identified in tumors. We report a constitutional JT between donor chromosome 21q21.3→qter and recipients 13qter and 18qter, resulting in an ∼15.5-Mb proximal deletion 21q in a girl with mild developmental delay and minor dysmorphic features. Using fluorescence in situ hybridization (FISH) studies, we identified an ∼550-kb complex inter- and intra-chromosomal low-copy repeat (LCR) adjacent to the 21q21.3 translocation breakpoint. On the recipient chromosomes 13qter and 18qter, the telomeric sequences TTAGGG were retained. Genotyping revealed that the deletion was of maternal origin. We propose that genome architecture involving LCRs may be a major mechanism responsible for the origin of jumping translocations. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca 2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored., Methods: Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca 2+ dynamics and decoders to elucidate the pathway from receptor to phenotype., Findings: CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca 2+ influx and prolonged channel closed state. This shifts the Ca 2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca 2+ dynamic changes. Ca 2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation., Interpretation: CHRFAM7A introduces an additional, human specific, layer to Ca 2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis., Funding: This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: CHRFAM7A , a uniquely human fusion gene, has been associated with neuropsychiatric disorders including Alzheimer's disease, schizophrenia, anxiety, and attention deficit disorder. Understanding the physiological function of CHRFAM7A in the human brain is the first step to uncovering its role in disease. CHRFAM7A was identified as a potent modulator of intracellular calcium and an upstream regulator of Rac1 leading to actin cytoskeleton reorganization and a switch from filopodia to lamellipodia implicating a more efficient neuronal structure. We performed a neurocognitive-MRI correlation exploratory study on 46 normal human subjects to explore the effect of CHRFAM7A on human brain., Methods: Dual locus specific genotyping of CHRFAM7A was performed on genomic DNA to determine copy number (TaqMan assay) and orientation (capillary sequencing) of the CHRFAM7A alleles. As only the direct allele is expressed at the protein level and affects α7 nAChR function, direct allele carriers and non-carriers are compared for neuropsychological and MRI measures. Subjects underwent neuropsychological testing to measure motor (Timed 25-foot walk test, 9-hole peg test), cognitive processing speed (Symbol Digit Modalities Test), Learning and memory (California Verbal Learning Test immediate and delayed recall, Brief Visuospatial Memory Test-Revised immediate and delayed recall) and Beck Depression Inventory-Fast Screen, Fatigue Severity Scale. All subjects underwent MRI scanning on the same 3 T GE scanner using the same protocol. Global and tissue-specific volumes were determined using validated cross-sectional algorithms including FSL's Structural Image Evaluation, using Normalization, of Atrophy (SIENAX) and FSL's Integrated Registration and Segmentation Tool (FIRST) on lesion-inpainted images. The cognitive tests were age and years of education-adjusted using analysis of covariance (ANCOVA). Age-adjusted analysis of covariance (ANCOVA) was performed on the MRI data., Results: CHRFAM7A direct allele carrier and non-carrier groups included 33 and 13 individuals, respectively. Demographic variables (age and years of education) were comparable. CHRFAM7A direct allele carriers demonstrated an upward shift in cognitive performance including cognitive processing speed, learning and memory, reaching statistical significance in visual immediate recall (FDR corrected p  = 0.018). The shift in cognitive performance was associated with smaller whole brain volume (uncorrected p  = 0.046) and lower connectivity by resting state functional MRI in the visual network (FDR corrected p  = 0.027) accentuating the cognitive findings., Conclusion: These data suggest that direct allele carriers harbor a more efficient brain consistent with the cellular biology of actin cytoskeleton and synaptic gain of function. Further larger human studies of cognitive measures correlated with MRI and functional imaging are needed to decipher the impact of CHRFAM7A on brain function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jakimovski, Dorn, Regno, Bartnik, Bergsland, Ramanathan, Dwyer, Benedict, Zivadinov and Szigeti.)