Mutations In Gene Research Articles

Differentially expressed extracellular matrix genes functionally separate ameloblastoma from odontogenic keratocyst

BackgroundAmeloblastoma and odontogenic keratocyst (OKC) are odontogenic tumors that develop from remnants of odontogenic epithelium. Both display locally invasive growth characteristics and high predilection for recurrence after surgical removal. Most ameloblastomas harbor BRAFV600E mutation while OKCs are associated with PATCH1 gene mutation but distinctive indicators of ameloblastoma growth characteristics relative to OKC are still unclear. The aim of this study was to assess hub genes that underlie ameloblastoma growth characteristics using bioinformatic analysis, ameloblastoma samples and mouse xenografts of human epithelial-derived ameloblastoma cells.MethodsRNA expression profiles were extracted from GSE186489 gene expression dataset acquired from Gene Expression Ominibus (GEO) database. Galaxy and iDEP online analysis tools were used to identify differentially expressed genes that were further characterized by gene ontology (GO) and pathway analysis using ShineyGO. The protein-protein interaction (PPI) network was constructed for significantly upregulated differentially expressed genes using online database STRING. The PPI network visualization was performed using Cytoscape and hub gene identification with cytoHubba. Top ten nodes were selected using maximum neighborhood component, degree and closeness algorithms and analysis of overlap was performed to confirm the hub genes. Epithelial-derived ameloblastoma cells from conventional ameloblastoma were transplanted into immunocompromised mice to recreate ameloblastoma in vivo based on the mouse xenograft model. The top 3 hub genes FN1, COL I and IGF-1 were validated by immunostaining and quantitative analysis of staining intensities to ameloblastoma, OKC samples and mouse ameloblastoma xenografts tissues.ResultsSeven hub genes were identified among which FN1, COL1A1/COL1A2 and IGF-1 are associated with extracellular matrix organization, collagen binding, cell adhesion and cell surface interaction. These were further validated by positive immunoreactivity within the stroma of ameloblastoma samples but both ameloblastoma xenograft and OKC displayed only FN1 and IGF-1 immunoreactivity while COL 1 was unreactive. The expression levels of both FN1 and IGF-1 were much lower in OKC relative to ameloblastoma.ConclusionThis study further validates a differentially upregulated expression of matrix proteins FN1, COL I and IGF-1 in ameloblastoma relative to OKC. It suggests that differential stromal architecture and growth characteristics of ameloblastoma relative to OKC could be an interplay of differentially upregulated genes in ameloblastoma.

An infant case of autosomal recessive polycystic kidney disease-associated dilated cardiomyopathy-like hypertensive cardiomyopathy diagnosed because of urinary tract infection.

We report a case of dilated cardiomyopathy-like hypertensive cardiomyopathy (HTN-CM) with polycystic kidney disease without family history when a 3-month-old boy developed bacteraemia secondary to a urinary tract infection. He was later confirmed as having autosomal recessive inheritance due to the proven PKHD1 gene mutation. The treatment consisted mainly of antihypertensive and anti-heart failure therapies and he was discharged on the 131st day. To prevent the development of heart failure in patients with HTN-CM due to autosomal recessive polycystic kidney disease (ARPKD), it is important to improve the fetal diagnosis rate of ARPKD, detect hypertension early, and strictly control the blood pressure after birth.

CLONAL HEMATOPOIESIS AND ITS ROLE IN THE DEVELOPMENT OF CARDIOVASCULAR DISEASES

Clonal hematopoiesis (CH) is the increase in somatic clones carrying mutations in hematopoietic stem cells. This biological condition can lead to cancer and is implicated in the development of atherosclerosis and cardiovascular diseases. CH of indeterminate potential (CHIP) refers to somatic mutations in genes that are associated with the development of Coronary heart disease (CHD) and leukemia. Now, with next-generation sequencing, we can detect mutations even if they are present in only a small number of cells in the tissue sample being studied. Consequently, numerous studies have shown that mutations in the DNMT3A, TET2, ASXL1, and JAK2 genes found in the blood are associated with coronary heart disease. The purpose of our study is to detect a genetic variant of genes in Kazakh patients with atherosclerosis, which will further allow us to study the role of CHIP in increasing the risk of developing coronary microvascular dysfunction and CHD. We perform high-throughput whole-exome sequencing in patients with atherosclerosis. The object of the study is samples delivered from the clinic “National Scientific Cardiac Surgery Center” in Astana. The study is carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Genomic DNA extraction was performed on 245 samples using the Illustra Blood Kit (Cytiva, USA). Qualitative and quantitative assessment of the extracted genomic DNA was conducted using the NanoDrop 2000 (Thermo Scientific) and Qubit 2.0 (Thermo Fisher Scientific). Subsequently, DNA library preparation was carried out using the Illumina DNA Prep with Exome 2.5 Enrichment kit. Quality control of the resulting DNA libraries was conducted on a 2100 Bioanalyzer system using the Agilent DNA 1000 Kit and High Sensitivity DNA kit (Agilent Technologies). Following assessment of the DNA library concentration on Qubit 2.0, they were loaded onto the high-performance sequencer NovaSeq 6000 (Illumina, USA) following the manufacturer’s protocol. We conducted human whole-exome sequencing on 245 samples to identify somatic clones in the peripheral blood of patients with atherosclerosis. Patients were divided into three groups – low risk, middle, and high risk of atherosclerotic complications. Bioinformatic analysis of sequence data were performed. We created list of genes associated with CH to deep analysis and to interpreter the data in patient groups. Subsequently, DNA extraction from the remaining samples is performed, followed by sequencing on the NovaSeq 6000 platform. Analysis of the resulting sequenced data is currently underway. Further research and monitoring of CHIP will enable us to understand the mechanisms underlying the development of cardiovascular diseases and to devise a comprehensive management plan for patients with this pathology. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome-inhibiting antibiotics.

Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well-established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear-encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2-deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.

Mitochondrial tRNAGlu 14693A>G Mutation, an "Enhancer" to the Phenotypic Expression of Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON), a maternally inherited ocular disease, is predominantly caused by mitochondrial DNA (mtDNA) mutations. Mitochondrial tRNA variants are hypothesized to amplify the pathogenic impact of three primary mutations. However, the exact mechanisms remained unclear. In the present study, the synergistic effect of the tRNAGlu 14693A>G and ND6 14484T>C mutations in three Chinese families affected by LHON is investigated. The m.14693A>G mutation nearly abolishes the pseudouridinylation at position 55 of tRNAGlu, leading to structural abnormalities, decreased stability, aberrant mitochondrial protein synthesis, and increased autophagy. In contrast, the ND6 14484T>C mutation predominantly impairs complex I function, resulting in heightened apoptosis and virtually no induction of mitochondrial autophagy compared to control cell lines. The presence of dual mutations in the same cell lines exhibited a coexistence of both upregulated cellular stress responses to mitochondrial damage, indicating a scenario of autophagy and mutation dysregulation within these dual-mutant cell lines. The data proposes a novel hypothesis that mitochondrial tRNA gene mutations generally lead to increased mitochondrial autophagy, while mutations in genes encoding mitochondrial proteins typically induce apoptosis, shedding light on the intricate interplay between different genetic factors in the manifestation of LHON.

Prevalence of hearing loss in pseudohypoparathyroidism

BackgroundThe main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD.MethodsOur retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db.ResultsThe median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively).ConclusionOur study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present.

MeCP2 deficiency alters the response selectivity of prefrontal cortical neurons to different social stimuli.

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MeCP2 gene, is characterized by cognitive and social deficits. Previous studies have noted hypoactivity in the medial prefrontal cortex (mPFC) pyramidal neurons of MeCP2-deficient mice (RTT mice) in response to both social and nonsocial stimuli. To further understand the neural mechanisms behind the social deficits of RTT mice, we monitored excitatory pyramidal neurons in the prelimbic region of the mPFC during social interactions in mice. These neurons' activity was closely linked to social preference, especially in wild-type mice. However, RTT mice showed reduced social interest and corresponding hypoactivity in these neurons, indicating that impaired mPFC activity contributes to their social deficits. We identified six mPFC neural ensembles selectively tuned to various stimuli, with RTT mice recruiting fewer neurons to ensembles responsive to social interactions and consistently showing lower stimulus-ON ensemble transient rates. Despite these lower rates, RTT mice exhibited an increase in the percentage of social-ON neurons in later sessions, suggesting a compensatory mechanism for the decreased firing rate. This highlights the limited plasticity in the mPFC caused by MeCP2 deficiency and offers insights into the neural dynamics of social encoding. The presence of multifunctional neurons and those specifically responsive to social or object stimuli in the mPFC emphasizes its crucial role in complex behaviors and cognitive functions, with selective neuron engagement suggesting efficiency in neural activation that optimizes responses to environmental stimuli.Significance Statement Unlike previous studies that have only shown altered prefrontal activity in response to stimuli in MeCP2 deficient models, our study identifies specific stimulus-tuned ensembles in the prefrontal cortex and their dysregulated activity patterns underlying social deficits in Rett syndrome. Utilizing innovate neural activity visualization tools, we revealed circuit-level evidence of the impairment caused by MeCP2-deficiency. The current research not only adds to the field of neurodevelopmental disorders and insights into the neurocircuitry of social behavior, but sheds light on the circuit-level mechanisms underlying a key behavioral phenotype of Rett syndrome.

High frequency of silent mutations in gyrA gene of Mycobacterium tuberculosis in Indian isolates.

Reporting any uncommon or untapped changes in bacterial genetics or physiology would be of great importance to support the drug development process. We studied 120 Mycobacterium tuberculosis clinical isolates with different geographical origin within India and their resistance profile and found a significant number of isolates (109) harboring the polymorphism at nucleotide positions 61 and 284 of the gyrA gene. Bioinformatics analysis of these changes for drug binding suggested no significant change in the binding of the drug but have lower binding energies as compared with the wild-type proteins. Although functionally silent for the gyrA gene, these changes are indicating a silent geographical and evolutionary change that needs to be further studied for drug discovery and bacterial fitness.

Staphylococcus capitis: insights into epidemiology, virulence, and antimicrobial resistance of a clinically relevant bacterial species.

SUMMARYStaphylococcus capitis is divided into two subspecies, S. capitis subsp. ureolyticus (renamed urealyticus in 1992; ATCC 49326) and S. capitis subsp. capitis (ATCC 27840), and fits with the archetype of clinically relevant coagulase-negative staphylococci (CoNS). S. capitis is a commensal bacterium of the skin in humans, which must be considered an opportunistic pathogen of interest particularly as soon as it is identified in a clinically relevant specimen from an immunocompromised patient. Several studies have highlighted the potential determinants underlying S. capitis pathogenicity, resistance profiles, and virulence factors. In addition, mobile genetic element acquisitions and mutations contribute to S. capitis genome adaptation to its environment. Over the past decades, antibiotic resistance has been identified for S. capitis in almost all the families of the currently available antibiotics and is related to the emergence of multidrug-resistant clones of high clinical significance. The present review summarizes the current knowledge concerning the taxonomic position of S. capitis among staphylococci, the involvement of this species in human colonization and diseases, the virulence factors supporting its pathogenicity, and the phenotypic and genomic antimicrobial resistance profiles of this species.

Analysis of the Mechanism Underlying Radiotherapy Resistance Caused by Oligodendroglia Cells in Glioblastoma by Applying the Single-cell RNA Sequencing Technology.

Glioblastoma (GBM) is an aggressive malignancy. The inherent resistance of GBM to radiotherapy poses great challenges for clinical treatment. The primary objective of this study is to explore the molecular mechanisms of radiotherapy resistance in GBM and identify the key influencing factors that contribute to this phenomenon. The single-cell RNA sequencing (scRNA-seq) data of GBM were downloaded from the Gene Expression Omnibus (GEO) database. Cells were clustered using the Seurat R package, and the clusters were annotated using the CellMarker database. Pseudotime analysis was conducted using Monocle2. Marker scores were calculated based on the RNA-seq data of GBM from the UCSC database, and the enrichment of Hallmark gene sets was measured with the AUCell package. Furthermore, the most frequently mutated genes were identified using the simple nucleotide variation data from The Cancer Genome Atlas (TCGA) applying the maftools package. This study identified two oligodendrocyte subsets (ODC3 and ODC4) as radiotherapy-resistant groups in GBM. Enrichment and Pseudotime analysis revealed that the inflammatory response and immune activation pathways were enriched in ODC3, while the cell division and interferon response pathways were enriched in ODC4. The enrichment scores of hallmark gene sets further confirmed that ODC3 and ODC4 subpopulations developed radiotherapy resistance via distinct molecular mechanisms. Analysis of gene mutation frequencies showed that TP53 exhibited the most significant change in mutation frequency, indicating that it was an important risk factor involved in radiotherapy resistance in GBM. We identified two ODC subpopulations that exhibited resistance to radiotherapy, providing a new perspective and potential targets for personalized treatment strategies for GBM.

Clinicopathologic Analysis of HPV-Related Primary Squamous Cell Carcinoma of the Thyroid.

This study aims to explore the clinical and pathologic characteristics of HPV-related primary thyroid squamous cell carcinoma (PSCCT), a rare tumor classified by WHO-5 as a subtype of anaplastic thyroid carcinoma (ATC). Clinical data, histomorphology, immunohistochemistry, HPV detection, and B-raf gene point mutations of 3 PSCCT cases were analyzed. Subsequent follow-up was conducted post-treatment. All 3 cases involved female patients aged between 60 and 76. Microscopic examination revealed squamous cell carcinoma in cases 1 and 3, whereas case 2 exhibited both squamous cell carcinoma and papillary thyroid carcinoma components. Immunohistochemistry demonstrated CK19, PAX8, and TTF1 expression in the papillary thyroid carcinoma component, and CK5/6, p63, p40, and PAX8 expression in the squamous cell carcinoma component. P16 exhibited diffuse positivity in both squamous cell carcinoma and classic papillary carcinoma. HPV analysis identified low-risk type 6 positivity in cases 1 and 3, while both squamous cell carcinoma and papillary carcinoma areas in case 2 were positive for HPV-33. B-raf gene mutation was exclusive to case 2. Diagnosis of PSCCT necessitates multidisciplinary assessment, incorporating clinical symptoms, imaging, histomorphology, and immunohistochemistry. This study, for the first time, reveals the presence of HPV DNA in both PTC and PSCCT, occurring concurrently but separately. Given the limited scope of 3 case reports, definitive conclusions cannot be drawn, warranting further investigation.

Epigenotoxicity: Decoding the epigenetic imprints of genotoxic agents and their implications for regulatory genetic toxicology.

Regulatory genetic toxicology focuses on DNA damage and subsequent gene mutations. However, genotoxic agents can also affect epigenetic marks, and incorporation of epigenetic data into the regulatory framework may thus enhance the accuracy of risk assessment. Additionally, epigenetic alterations may identify non-genotoxic carcinogens that are not captured with the current battery of tests. Epigenetic alterations could also explain long-term consequences and potential transgenerational effects in the absence of DNA mutations. Therefore, at the 2022 International Workshops on Genotoxicity Testing (IWGT) in Ottawa (Ontario, Canada), an expert workgroup explored whether including epigenetic endpoints would improve regulatory genetic toxicology. Here we summarize the presentations and the discussions on technical advancements in assessing epigenetics, how the assessment of epigenetics can enhance strategies for detecting genotoxic and non-genotoxic carcinogens and the correlation between epigenetic alterations with other relevant apical endpoints.

Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress

Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress

In-depth analysis of OTC A208T case induced by OTC gene mutation and research on the prediction and simulation of the impact on protein function

In-depth analysis of OTC A208T case induced by OTC gene mutation and research on the prediction and simulation of the impact on protein function

TARGETED SEQUENCING REVEAL TWO PATHOGENIC MUTATIONS IN LDLR AND APOE GENES IN PATIENT WITH FAMILY HYPERCHOLESTEROLEMIA: CASE REPORT

Familial hypercholesterolemia (FH) is a serious inherited disorder that can lead to early development of cardiovascular disease (CVD) due to the high blood cholesterol levels. In our study, we identified in FH patient likely pathogenic variant of LDLR and APOE genes. Interest in the homozygous state of FH is understandable given its rarity and severe health consequences. The homozygous state, when both LDL receptor alleles mutated, demonstrates even higher cholesterol levels and an earlier and more severe clinical course compared with the heterozygous state. In our study, we report an interesting case of homozygous FH due to its rare prevalence. Patient U., 16 years old, woman, admitted to the National Research Cardiac Surgery Center (NRCC), was diagnosed with FH, congenital heart disease (CHD), bicuspidal aortic valve (AV) type 1. Both parents (mother and father) were included for reliable analysis. DNA was isolated from the venous blood sample by using the column method of QIAamp DNA Mini Kit. Targeted NGS using TruSight Cardio panel for 174 genes was performed on MiSeq, Illumina. Identified genetic variants were classified according to the ACMG guidelines. Pathogenic variants were validated by Sanger sequencing. Additionally, databases of the VarSome and ClinVar were used for analysis. Sequencing of 96 genes and bioinformatics analysis identified 2 likely pathogenic variants - C526T:p.R176C in APOE and G295A:p.E99K in LDLR gene, 4 uncertain significance variants in APOB, TTN, COL3A1, NOTCH1 and 90 benign variants in APOB, TTN, LAMA4, MYPN, DMD. LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) were validated and confirmed by Sanger sequencing in patients and her father and mother. The main function of the APOE gene is to make the protein apolipoprotein E, which is involved in fat metabolism. In our study, the patient had a heterozygous variant of СT polymorphism rs7412 in the APOE gene, which indicates the presence of a possible disorder of fat metabolism. LDLR gene encodes a protein called low-density lipoprotein receptor, which is responsible for the uptake of cholesterol-carrying lipoprotein particles in cells. In our study, a patient with a homozygous AA variant of the LDLR gene was found to be pathogenic. Disruption of the uptake of cholesterol-carrying lipoprotein particles in cells can have serious consequences for the body. This can lead to cholesterol accumulation in the blood and tissues, which in turn can contribute to the development of atherosclerosis and other CVD. We found that both parents had a heterozygous genotype of G295A:p.E99K in LDLR gene; and mother had a heterozygous genotype and father had a homozygous genotype of C526T:p.R176C in APOE gene. In our study, we found the genetic mutations - two likely pathogenic genetic variants LDLR (G295A:p.E99K) and APOE (C526T:p.R176C) associated with FH in patient with clinical phenotype of FH using TruSight Cardio targeted panel of 96 genes. Genetic testing using targeted NGS or whole exome sequencing would be useful for right diagnosis and might improve personalize treatment for these patients. To identify other genes associated with FH whole exome sequencing can be recommend. Supported by Committee of Science of the Ministry of Science and Higher Education of Republic of Kazakhstan (AP14869903), (BR21881970) and Nazarbayev University CRP (211123CRP1608).

Big1 is a newly identified autophagy regulator that is critical for a fully functional V-ATPase.

The vacuolar H+-translocating ATPase (V-ATPase) is the major proton pump for intra-organellar acidification. Therefore, the integrity of the V-ATPase is closely associated with cellular homeostasis, and mutations in genes encoding V-ATPase components and assembly factors have been reported in certain types of diseases. For instance, the recurrent mutations of ATP6AP1, a gene encoding a V-ATPase accessory protein, have been associated with cancers and immunodeficiency. With the aim of studying V-ATPase-related mutations using the yeast model system, we report that Big1 is another homolog of ATP6AP1 in yeast cells, and we characterize the role of Big1 in maintaining a fully functional V-ATPase. In addition to its role in acidifying the vacuole or lysosome, our data support the concept that the V-ATPase may function as part of a signaling pathway to regulate macroautophagy/autophagy through a mechanism that is independent from Tor/MTOR.

Composite cellulose/bismuth/PVA nanocrystal for high-performance X-ray radiation shielding

The strong penetrating power of X-rays causes serious health problems. Longer exposure to radiation that penetrates normal cells can result in gene mutations, cancer, and even death. Protection against radiation exposure is necessary to prevent negative impacts from occurring. This research aims to make apron samples using a simple method based on cellulose as a matrix, bismuth as a filler with concentrations of 1 g, 0.75 g, 0.25 g and PVA acts as a binder that helps bind cellulose and bismuth particles into an effective X-ray radiation shield. The characterization carried out includes Fourier transform infrared (FTIR) to determine the functional groups and chemical composition of the sample, x-ray diffraction (XRD) to analyze the crystal size of the sample, and mobile x-ray with energies of 60, 70, and 80 keV to determine the radiation shielding performance. The findings of this study highlight that the optimal shielding properties were attained by employing a sample with the highest concentration of bismuth filler, specifically at 1 g. This material exhibits outstanding characteristics, including a high linear attenuation coefficient and mass attenuation coefficient of 0.68 cm−1 and 2.24 cm2/g respectively for an energy of 60 keV and especially low HVL (1.01 cm) and TVL (3.36 cm) values. These findings have significant implications for developing high-performance X-ray radiation shielding materials, particularly in industries where radiation exposure is a concern, such as the medical industry, research, and laboratories. The high tensile strength (2.83 N/mm2) and elongation (12.09 %) values as well as the low Young's modulus (0.108 N/mm2) values also indicate the flexibility of the resulting material, which could be beneficial for applications that require flexible shielding materials. The practicality of this research makes the audience feel that the findings are applicable and useful in real-world scenarios.

Transcriptomic profiles of myxofibrosarcoma and undifferentiated pleomorphic sarcoma correlate with clinical and genomic features.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are two common and aggressive subtypes of soft tissue sarcoma. The aim of this study was to assess potential transcriptomic differences between MFS and UPS tumours and to evaluate the extent to which differences in gene expression profiles were associated with genomic and clinical features. The study included 162 patients with tumours diagnosed as MFS (N = 62) or UPS (N = 100). The patients had been diagnosed and treated at two Swedish sarcoma centres during a 30-year period. For gene expression profiling and gene fusion detection all tumours were analysed using RNA-sequencing and could be compared with data on clinical outcome (N = 155), global copy number profiles (N = 145), and gene mutations (N = 128). Gene expression profiling revealed three transcriptomic clusters (TCs) without any clear separation of MFS and UPS. One TC was associated with longer metastasis-free survival. These tumours had lower tumour mutation burden (TMB), were enriched for a copy number signature representative of focal LOH and chromosomal instability on a diploid background, and were relatively immune-depleted. MFS and UPS showed extensive genomic overlap, with whole genome doubling occurring more frequently among the latter. The results support the idea that MFS and UPS tumours have largely overlapping genomic and transcriptomic features, with UPS tumours showing more aggressive behaviour and more complex genomes. Independently of the tumour type, clinically relevant subgroups were revealed by gene expression analysis, and the finding of multiple genomic subgroups strongly suggest the existence of subgroups of relevance to treatment stratification. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules.

p53 is known as the guardian of the genome and is one of the most important tumor-suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) have demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in cancer patients who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.

ELP1, the Gene Mutated in Familial Dysautonomia, Is Required for Normal Enteric Nervous System Development and Maintenance and for Gut Epithelium Homeostasis.

Familial dysautonomia (FD) is a rare sensory and autonomic neuropathy that results from a mutation in the ELP1 gene. Virtually all patients report gastrointestinal (GI) dysfunction and we have recently shown that FD patients have a dysbiotic gut microbiome and altered metabolome. These findings were recapitulated in an FD mouse model and moreover, the FD mice had reduced intestinal motility, as did patients. To understand the cellular basis for impaired GI function in FD, the enteric nervous system (ENS; both female and male mice) from FD mouse models was analyzed during embryonic development and adulthood. We show here that not only is Elp1 required for the normal formation of the ENS, but it is also required in adulthood for the regulation of both neuronal and non-neuronal cells and for target innervation in both the mucosa and in intestinal smooth muscle. In particular, CGRP innervation was significantly reduced as was the number of dopaminergic neurons. Examination of an FD patient's gastric biopsy also revealed reduced and disoriented axons in the mucosa. Finally, using an FD mouse model in which Elp1 was deleted exclusively from neurons, we found significant changes to the colon epithelium including reduced E-cadherin expression, perturbed mucus layer organization, and infiltration of bacteria into the mucosa. The fact that deletion of Elp1 exclusively in neurons is sufficient to alter the intestinal epithelium and perturb the intestinal epithelial barrier highlights a critical role for neurons in regulating GI epithelium homeostasis.