Search Results (86)

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine. Full article

Background: CIC-rearranged sarcoma is a rare and aggressive type of undifferentiated round cell tumor characterized by CIC gene fusion, most commonly CIC::DUX4. This study presents a series of eleven cases, highlighting their clinicopathological features. Methods: Pathology records (2019 to 2024) were searched using “sarcoma with CIC”, identifying eleven cases, of which seven referred cases were initially misdiagnosed. Pathological and clinical analysis was conducted. Treatment was dictated upon multidisciplinary panel discussion based on tumor stage. Follow-up data (1–25 months) was available for all patients. Results: The cohort included six males and five females, with a median age of 43 years (range;14–53), with nine in soft tissue and two in bone. Tumor size ranged from 3.5 cm to 20.0 cm (mean: 9.8 cm). Most cases showed sheets of undifferentiated round- to oval-shaped cells. Two cases showed an Ewing-like pattern, and one case showed spindle cells in a fibrotic stroma transitioning to epithelioid cells. Necrosis was present in nine cases, and mitotic count ranged from 2 to 38/ 10HPFs (mean = 14.2). CD99 was positive in (10/11) cases and WT-1 in (6/9). NKX2.2, S100, and MDM2 were positive in rare cases. CIC::DUX4 fusion was detected in four cases. FISH for CIC gene rearrangement was positive in seven cases, two of them confirmed by methylation analysis. Metastasis at diagnosis was common (n = 8), primarily in the lungs, with later metastasis to the brain and bone. At time of final analysis, eight patients died within a median of 10 months (range: 1–19 months), while three were alive, two with stable disease (for a period of 6 and 25 months) and one with progression after 10 months. Significant correlation was seen between overall survival and the presence of metastasis at diagnosis (p value = 0.03). Conclusions: CIC-rearranged sarcomas are rare, high-grade tumors with predilection for soft tissue. Misdiagnosis is frequent, necessitating molecular confirmation. These tumors are treatment-resistant, often present with lung metastasis, and carry a poor prognosis, especially with initial metastasis. Full article

Background: Histamine intolerance, a disorder due to impaired degradation of dietary histamine, is frequently associated with headaches, but the underlying pathophysiology is largely unknown; the sensitization of meningeal afferents appears likely. We approached this issue by examining histamine concentrations in different tissues and meningeal histamine release in a new mouse model of high-histamine diets. Methods: C57BL/6 mice of both sexes were fed with diets containing 3 or 9 g/kg histamine and compared to control groups. After 10–30 days, the histamine concentration was determined in plasma, samples of homogenized ileum, trigeminal ganglia, spinal medulla, and cerebellum using an ELISA. The histamine release from mast cells in the dura mater stimulated with compound 48/80 was also examined. Results: Animals supplied with high dietary histamine showed normal behavior and no signs of suffering. Compared with the controls, the histamine concentration was significantly higher in plasma and ileum of mice fed with 3 g/kg, highest in animals fed with 9 g/kg histamine. In addition, this group of animals showed also higher histamine concentrations in the trigeminal ganglion. The histamine release from the dura mater in mice supplied with 3 g/kg histamine was not significantly different to control animals, but the relative increase in stimulated release was lower in male animals of the high histamine group. Conclusions: High dietary histamine increases histamine levels in blood plasma and the gut, whereas the histamine content of neural tissues is not significantly influenced. The lowered stimulated release in animals subjected to high dietary histamine may indicate compensatory mechanisms. Full article

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. In this study, an analysis of human FSHD muscle biopsies revealed differential expressions of six m6A regulators, including writers, readers and eraser proteins. In immortalized human FSHD myoblasts, we found higher levels of mRNA and protein expression of a major m6A regulator, methyltransferase-like protein 3 (METTL3), in comparison with myoblasts from unaffected siblings (UASbs). Quantification of the overall RNA m6A levels in the FSHD myoblasts revealed significant elevation compared with their UASb, which was reversed to UASb levels following treatment with an antisense oligonucleotide targeting the DUX4 mRNA. Using Oxford Nanopore direct-RNA sequencing, we mapped m6A across the transcriptome and identified genes harboring differential methylated m6A sites, including several involved in iron homeostasis. Western blot protein quantification showed that FSHD myoblasts had higher levels of ferritin-heavy chain-207 isoform and mitoferrin-1. In addition, our data showed elevation in mitochondrial ferrous iron in FSHD myoblasts. Our findings suggest that m6A RNA modifications play a pivotal role in FSHD pathophysiology and may serve as biomarker for this disease. Full article

Background/Objectives: Chronic attention problems occur in approximately 25% of children after acquired brain injury (ABI). When delivered daily, transcranial direct current stimulation (tDCS) may improve attention; however, access to daily in-clinic tDCS treatment can be limited by other commitments, including concurrent therapy, school commitments, and caregiver schedules. Treatment access can be improved through home-based interventions, though these require several practical and safety considerations in a pediatric ABI population. This study evaluated the safety, feasibility, and tolerability of remotely monitored at-home tDCS during online gamified attention training in pediatric ABI. Methods: We conducted a randomized, single-blind, dose-controlled clinical trial of at home tDCS in Brisbane, Australia (10 tDCS sessions; 20 min; 1 mA or 2 mA; bilateral dorsolateral prefrontal cortex). Participants attended our clinic at baseline for clinical assessments, fitting of the personalized tDCS headband, and training in how to use tDCS at home. All sessions were remotely supervised using live videoconferencing. We assessed the feasibility and tolerability of at-home tDCS and our customized, personalized at-home tDCS headband as primary outcomes. As secondary outcomes, we evaluated changes in functional connectivity (fc) and reaction time (RT). Results: Seventy-three participants were contacted over six months (January-June 2023) and ten were enrolled (5 males; mean age: 12.10 y [SD: 2.9]), satisfying a priori recruitment timelines (CONSORT reporting). All families successfully set up tDCS and completed attention training with excellent protocol adherence. There were no serious adverse events over the 100 total sessions. Nine participants completed all stimulation sessions (1 mA: n = 5, 2 mA: n = 4). Participants in the 2 mA group reported greater tingling, itching, and discomfort (all p < 0.05). One participant in the 1 mA group was unable to complete all sessions due to tolerability challenges; however, these challenges were resolved in the second half of the intervention by gradually increasing the stimulation duration across the 10 days alongside additional coaching and support. Conclusions: Overall, daily remotely supervised at-home tDCS in patients with pediatric ABI is safe, feasible, and tolerable. Our results support larger, sham-controlled efficacy trials and provide a foundation for the development of safe and effective at-home stimulation therapeutics that may offer targeted improvement of neurocognitive symptoms in children. Full article

(1) Background: The chorioallantoic membrane (CAM) model has the potential to contribute to the development of personalized medicine based on individual cancer patients. We previously established the CAM model using patient-derived CIC-DUX4 sarcoma cells. We also used the CAM model for characterization and a comparison with the mouse model by examining the tumor accumulation of small-size, highly dispersive mesoporous silica nanoparticles (MSNs). (2) Method: In this study, we transplanted a variety of cancer cell lines, including patient-derived osteosarcoma (OS) and extraskeletal osteosarcoma (ESOS) cells. Patient-derived OS, ESOS and other cell lines were transplanted onto CAMs. The proliferation of cancer cells within CAM tumors was confirmed using H&E staining. For the comparison of the CAM and mouse models, rhodamine B-labeled MSNs were administered intravenously to CAMs and to xenograft mice. Tumor accumulation was evaluated by examining fluorescence and by confocal microscopy. The biodistribution of MSNs was examined by measuring the Si content by ICP. (3) Results: H&E staining demonstrated the proliferation of cancer cells of OS, ESOS and others on CAMs. While growth patterns and morphologies varied among different cancer types, H&E staining confirmed the establishment of tumors. As for the tumor accumulation, both the CAM and mouse models showed that MSNs were selectively accumulated in the tumors in both the CAM and mouse models. (4) Conclusions: We have expanded the range of CAM models by using a variety of cancer cells, including patient-derived cell lines. We also report that the small-size, highly dispersive MSNs exhibit excellent tumor accumulation in both the CAM and mouse models. These results point to the usefulness of the CAM model for patient-derived cancer cells as well as for evaluating drug carriers for tumor targeting. Full article

Embryogenesis and tumorigenesis share several key biological characteristics, such as rapid cell proliferation, high plasticity, and immune evasion. This similarity indicates that developmental pathways can be hijacked, leading to the formation of malignant cell states. With regard to this, cancer can be regarded as a stem cell disease. On the contrary, a fetus, in many ways, has similar characteristics to the “ideal tumor”, such as immune evasion and rapid growth. Therefore, deciphering the molecular mechanisms beneath these phenomena will help us to understand the embryonic origins of cancer. This review discusses the relationship between embryogenesis and tumorigenesis, highlighting the potential roles played by DUX4. DUX4 is involved in the activation of the zygote genome and then facilitates the establishment of totipotency in pre-implantation embryos, whereas the misexpression of DUX4 is associated with different types of cancer. Taken together, this indicates that DUX4 performs analogous functions in these two processes and connects embryogenesis and tumorigenesis. Through examining DUX4, this review underscores the importance of developmental mechanisms in cancer biology, suggesting that the insights gained from studying embryonic processes may provide novel therapeutic strategies. As we continue to explore the complex relationship between cancer and embryogenesis, elucidating the role of DUX4 in linking these two processes will be critical for developing targeted therapies that exploit developmental pathways. Full article

Double homeobox (DUX) genes are key embryonic regulators that are silenced after the early cleavage stages of embryogenesis. Aberrant expression of DUX4 in skeletal muscle is linked to facioscapulohumeral muscular dystrophy (FSHD). A recent study reported that Dux, the murine ortholog of DUX4, contributes to the dystrophic phenotype in mdx mice, a Duchenne muscular dystrophy (DMD) model, and that its deletion enhances muscle regeneration by reducing oxidative stress. However, convincing evidence of Dux expression in either intact or injured muscle of wild-type (WT) and mdx mice remains lacking, raising questions about its role in muscle homeostasis. To investigate this, we assessed Dux expression in WT and mdx mice and used Dux knockout (Dux^Δ/Δ) mice to evaluate its function during regeneration following cardiotoxin (CTX)-induced injury. Contrary to prior reports, Dux was not expressed in either WT or mdx mice. Moreover, Dux deletion did not enhance muscle regeneration or affect the expression of the oxidative stress regulator Nrf2 following CTX injury. Lastly, we confirmed that neither DUX4 nor its target genes were induced in muscle biopsies from DMD patients, excluding a role for DUX4 in DMD pathology. Collectively, our results demonstrate that Dux does not impact skeletal muscle regeneration or DUX4 contribution to the DMD dystrophic phenotype, directly challenging the conclusions of a previously published study. We comment on issues of editorial oversight that led to the publication of that study and highlight the deleterious impact of the growing wave of fraudulent publications. Full article

During embryonic development, zygotic genome activation (ZGA) is a critical event that determines the rational process and the fate of embryonic cells. The tricarboxylic acid cycle (TCA cycle) provides necessary reactants and energy for biological activities such as genome activation, chromatin opening, and epigenetic modifications during ZGA. Recent studies have shown that during ZGA, core enzymes associated with TCA briefly enter the nucleus and participate in initiating the ZGA process. However, the regulatory relationship between ZGA factors, such as Dux, Dppa2, and Dppa4, and the core enzymes of the TCA cycle remains unknown. In this study, we found that Dppa2 plays a key role in ZGA by directly determining the localization of TCA core enzymes, thereby affecting the early embryonic development. To further investigate the effect of Dppa2 on the localization of pyruvate dehydrogenase (PDH), we followed the establishment of an inducible Dppa2 transgenic mouse model. We found that the “chronoectopic” expression of Dppa2 prior to normal ZGA time could lead to the advanced nuclear localization of PDH. In summary, Dppa2 plays a key role in ZGA, directly determining the location of TCA core enzymes in early embryos. This study provides a theoretical basis for early embryonic development at the metabolic regulation level. Full article

DUX4 is typically a repressed transcription factor, but its aberrant activation in Facioscapulohumeral Muscular Dystrophy (FSHD) leads to cell death by disrupting muscle homeostasis. This disruption affects crucial processes such as myogenesis, sarcolemma integrity, gene regulation, oxidative stress, immune response, and many other biological pathways. Notably, these disrupted processes have been associated, in other pathological contexts, with the presence of connexin (Cx) hemichannels—transmembrane structures that mediate communication between the intracellular and extracellular environments. Thus, hemichannels have been implicated in skeletal muscle atrophy, as observed in human biopsies and animal models of Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, and Dysferlinopathies, suggesting a potentially shared mechanism of muscle atrophy that has not yet been explored in FSHD. Despite various therapeutic strategies proposed to manage FSHD, no treatment or cure is currently available. This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function. Additionally, it explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells. Full article

Background/Objectives: Antibiotic-resistant bacteria pose a significant global public health threat that demands serious attention. The proliferation of antimicrobial resistance (AMR) is primarily attributed to the overuse of antibiotics in humans, livestock, and the agro-industry. However, it is worth noting that antibiotic-resistant genes (ARGs) can be found in all ecosystems, even in environments where antibiotics have never been utilized. African great apes (AGAs) are our closest living relatives and are known to be susceptible to many of the same pathogens (and other microorganisms) as humans. AGAs could therefore serve as sentinels for human-induced AMR spread into the environment. They can potentially also serve as reservoirs for AMR. AGAs inhabit a range of environments from remote areas with little anthropogenic impact, over habitats that are co-used by AGAs and humans, to captive settings with close human–animal contacts like zoos and sanctuaries. This provides opportunities to study AMR in relation to human interaction. This review examines the literature on AMR in AGAs, identifying knowledge gaps. Results: Of the 16 articles reviewed, 13 focused on wild AGAs in habitats with different degrees of human presence, 2 compared wild and captive apes, and 1 study tested captive apes alone. Ten studies included humans working with or living close to AGA habitats. Despite different methodologies, all studies detected AMR in AGAs. Resistance to beta-lactams was the most common (36%), followed by resistance to aminoglycosides (22%), tetracyclines (15%), fluoroquinolones (10%), sulphonamides (5%), trimethoprim (5%), macrolide (3%), phenicoles (2%) and fosfomycin (1%). Conclusions: While several studies suggest a correlation between increased human contact and higher AMR in AGAs, resistance was also found in relatively pristine habitats. While AGAs clearly encounter bacteria resistant to diverse antibiotics, significant gaps remain in understanding the underlying processes. Comparative studies using standardized methods across different sites would enhance our understanding of the origin and distribution of AMR in AGAs. Full article

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD. Full article

DUX4 is the major gene responsible for facioscapulohumeral dystrophy (FSHD). Several mouse models expressing DUX4 have been developed, the most commonly used by academic laboratories being ACTA1-MCM/FLExDUX4. In this study, molecular and histological modifications in the tibialis anterior and quadriceps muscles were investigated in this model at different time points. We investigated several changes that could be used as markers of therapeutic efficacy. Our results confirm the progressive muscular dystrophy previously described but also highlight biases associated with tamoxifen injections and the complexity of choosing the genes used to calculate a DUX4-pathway gene composite score. We also developed a comprehensive force test that better reflects the movements made in everyday life. This functional force–velocity–endurance model, which describes the force production capacities at all velocity and fatigue levels, was applied on 12–13-week-old animals without tamoxifen. Our data highlight that previously unsuspected muscle properties are also affected by the expression of DUX4, leading to a weaker muscle with a lower initial muscle force but with preserved power and endurance capacity. Importantly, this force–velocity–endurance approach can be used in humans for clinical evaluations. Full article

Background/Objectives: Microwave ablation (MWA) is the leading therapy method for treating patients with liver cancer. MWA simulation is used to further improve the therapy and to help develop new devices. Methods: A water-cooled ablation needle was reconstructed. MWA simulations of a polyacrylamide phantom were carried out and compared with a representative clinical example (tumor diameter: 8.75 mm). The Arrhenius damage model and a critical temperature approach of 60 °C were applied to assess the necrosis zones. Finally, the simulation results were compared to the corresponding MR measurements. Results: Most of the heating in the simulation took place at a distance of 5 mm along the transverse axis and 20 mm along the longitudinal axis above the needle tip. The calculated Dice scores for the Arrhenius model were 0.77/0.53 for the phantom/clinical case. For the critical temperature approach, Dice scores of 0.60/0.66 for the phantom/clinical case were achieved. Conclusions: The comparison between simulated and measured temperature increases showed an excellent agreement. However, differences in the predicted necrosis volume might be caused by omitting consideration of the heat sink effect, especially in the clinical case. Nevertheless, this workflow enables short MWA simulation times (approximately 3 min) and demonstrates a step towards possible integration into daily clinical use. Full article

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant genetic disease, which is caused by the mistaken expression of double homeobox protein 4 protein 4 (DUX4) in skeletal muscle. Patients with FSHD are usually accompanied by degenerative changes in the face, shoulders, and upper muscles, gradually accumulating in the lower limb muscles. The severity of patients is quite different, and most patients end up using wheelchairs and losing their self-care ability. At present, the exploration of treatment strategies for FSHD has shifted from relieving symptoms to gene therapy, which brings hope to the future of patients, but the current gene therapy is only in the clinical trial stage. Here, we conducted a comprehensive search of the relevant literature using the keywords FSHD, DUX4, and gene therapy methods including ASOs, CRISPR, and RNAi in the PubMed and Web of Science databases. We discussed the current advancements in treatment strategies for FSHD, as well as ongoing preclinical and clinical trials related to FSHD. Additionally, we evaluated the advantages and limitations of various gene therapy approaches targeting DUX4 aimed at correcting the underlying genetic defect. Full article