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Pharmacological Treatment for Adamantinomatous Craniopharyngioma.
No full textPURPOSE OF REVIEW: Adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive tumor arising from Rathke\u27s pouch remnants, which is molecularly distinct from the other subtype, papillary craniopharyngioma (PCP). Despite advancements in surgery and radiotherapy, treatment outcomes remain unsatisfactory due to the tumor\u27s invasiveness and resistance to conventional therapies. This review systematically examines the molecular pathogenesis of ACP and evaluates current and emerging therapeutic strategies to improve clinical management.
RECENT FINDINGS: ACP is driven by CTNNB1 mutations and dysregulated Wnt/β-catenin signaling, alongside inflammatory and senescence-associated pathways. Current pharmacological approaches, including interferon-α, IL-6 inhibitors (e.g., tocilizumab), and intracystic agents (e.g., bleomycin), exhibit limited efficacy. Promising emerging therapies target the angiogenesis (e.g., bevacizumab) and MAPK/ERK pathway, which is activated by somatic BRAF V600E mutations in PCP, has been successfully targeted with BRAF/MEK inhibitors, demonstrating significant efficacy in the majority of treated PCP patients. whereas immune checkpoint inhibitors and SHH pathway modulators face significant challenges. Additionally, ACP-related endocrine dysfunction and hypothalamic obesity require tailored interventions, such as GLP-1 receptor agonists and MC4R-targeted therapies. Precision medicine, informed by molecular subtyping and multi-omics data, holds transformative potential for ACP treatment. Future strategies should focus on combinatorial therapies to address tumor heterogeneity, microenvironment modulation, and senolytic approaches. Collaborative multidisciplinary efforts are crucial to translating these insights into clinical practice, ultimately enhancing patient outcomes and quality of life
Single-cell landscape of sex-specific drivers of Alzheimer\u27s disease.
No full textINTRODUCTION: We investigated sex-specific gene expression associations with the neuropathology and cognitive manifestation of Alzheimer\u27s disease (AD) leveraging single-nucleus transcriptomic datasets including 2.84 million nuclei from the dorsolateral prefrontal cortex (DLPFC).
METHODS: We delineated the full scope of sex-specific transcript associations, differential gene expression, signaling pathway, and cell-cell communication network changes in eight major DLPFC cell types.
RESULTS: Nine female-specific associations were identified and replicated, involving ADGRV1, OR3A3, IFI27L1, LYRM1, STAP2, TSTD2, PDYN, and TMEM50B. We observed the preponderance of protective female-specific associations in neurons. Sex-specific genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals that may contribute to female-specific risk of Aβ accumulation were also highlighted.
DISCUSSION: Our study highlights the transcriptome-wide, single-cell landscape of sex-specific molecular associations with AD neuropathology and cognitive decline, with identifying and replicating several female-specific gene associations in neurons to help direct future mechanistic studies.
HIGHLIGHTS: Single-nucleus transcriptomic association analysis identified 2660 sex-specific associations involving 2110 genes with four AD endophenotypes. The majority of female-specific associations link to better endophenotype outcomes were from neurons. Nine female-specific associations were replicated, including ADGRV1 and OR3A3 with Aβ; IFI27L1, LYRM1, STAP2, and TSTD2 with tau; PDYN with global cognition; and TMEM50B with longitudinal cognitive trajectory. Sex-specific effect genes were enriched in the immune-, inflammation-, and damage-related stress-response pathways. Six ITGB1-mediated microglia-specific incoming signals may play roles in female-specific risk for Aβ accumulation
Clonal dynamics and somatic evolution of haematopoiesis in mouse.
Get PDFHaematopoietic stem cells maintain blood production throughout life1 . Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they independently self-renew in parallel over life, evenly contributing to differentiated progenitors and peripheral blood. The stem cell pool grows steadily over the mouse lifespan to about 70,000 cells, self-renewing about every 6 weeks. Aged mice did not display the profound loss of clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing showed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations, exhibiting a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse
The contribution of de novo coding mutations to meningomyelocele.
No full textMeningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele . Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin- modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis
Non-homologous sequence interactions during meiosis: meiotic challenges and evolutionary opportunities.
Get PDFA hallmark of meiosis is pairing of homologous chromosomes, an event that ensures proper segregation into the gametes. Homology pairing is crucial to the formation of normal gametes, the maintenance of genomic integrity, and avoidance of aneuploidy. However, chromosomes are not completely homologous. Here we discuss two notable exceptions to homology: the mammalian sex chromosomes and centromeres. In themselves, these exceptions illustrate meiotic adaptations that both ensure correct chromosome segregation and present evolutionary opportunities. More broadly, such examples of non-homology provide a window for viewing normal mechanisms of meiotic pairing and chromosome modifications. Current analyses of mammalian meiotic chromosome dynamics suggest that the basis for the initial recognition of homology early in meiosis may be based in epigenetic chromatin modifications. Chromatin units may both form pairing sites and provide the modifications that allow non-homologous sequences to be tolerated. Despite recent research progress, we have yet to understand why some non-homologies are tolerated, while others lead to aneuploidy. Understanding how genomes evolve strategies to subvert the usual rules of meiosis will benefit from studies focused on the identification and characterization of meiosis in species with recently acquired non-homology. Looking forward, we are now armed with technologies and tools suited to precisely measure the extent of nonhomology across mammalian chromosomes and to probe the molecular and biophysical steps required for the initiation of homologous chromosome recognition and pairing. These goals are important for elucidating an essential mechanism of meiosis and ultimately for advancing the clinical diagnosis of gametic and embryo aneuploidy
Physiological role and mechanisms of action for a long noncoding haplotype region.
Get PDFDirect targeting of noncoding genomic regions harboring common sequence variants associated with human traits through in vivo animal model studies and precise genome editing in human cells is essential for closing the critical gap between genetic discoveries and physiological understanding. However, such investigation has been impractical for many of these variants as they are in haplotypes containing multiple single-nucleotide polymorphisms (SNPs) spanning thousands of base pairs and have small effect sizes. We developed an integrated approach to address this challenge, combining an efficient two-step technique to precisely edit large haplotypes in human induced pluripotent stem cells and orthologous region deletion in phenotypically permissive animal models. As proof of principle, we applied this approach to examine a blood pressure-associated locus with a noncoding haplotype containing 11 SNPs spanning 17.4 kbp. We found a robust blood pressure effect of nearly 10 mmHg and identified the physiological and molecular mechanisms involved
Biological modifications of the immune response to COVID-19 vaccine in patients treated with rituximab and immune checkpoint inhibitors.
Get PDFUnderstanding how immune-modulating therapies affect mRNA vaccine responses is essential for optimizing immunization strategies in cancer and immunocompromised patients. In this work, we investigate the immune response to the third dose of COVID-19 mRNA vaccine in cancer-free individuals, patients with non-Hodgkin lymphoma treated with rituximab (RTX), and patients with solid tumors receiving immune checkpoint inhibitors (ICIs). By integrating blood RNA sequencing, SARS-CoV-2 serology, and interferon-γ release assessment, we chart the vaccine-induced immunity over a 6-month time frame. Our findings reveal that RTX-treated patients exhibit profound immune dysfunction, characterized by a blunted type I interferon response, upregulation of transcripts pertaining to regulatory T cells, and widespread impairment of humoral immunity. In contrast, ICI-treated patients have preserved vaccine-induced immunity, displaying adaptive B cell and T cell responses akin to those of cancer-free volunteers. These results provide critical insights into immunization strategies for immunocompromised populations and may inform future vaccination protocols
Metformin reduces the competitive advantage of Dnmt3a
No full textClonal haematopoiesis arises when a haematopoietic stem cell (HSC) acquires a mutation that confers a competitive advantage over wild-type HSCs, resulting in its clonal expansion. Individuals with clonal haematopoiesis are at increased risk of developing haematologic neoplasms and other age-related inflammatory illnesses 1–4 . Suppressing the expansion of mutant HSCs may prevent these outcomes; however, such interventions have not yet been identified. The most common clonal haematopoiesis driver mutations are in the DNMT3A gene, with arginine 882 (R882) being a mutation hotspot 1–3,5–7 . Here we show that mouse haematopoietic stem and progenitor cells (HSPCs) carrying the Dnmt3aR878H/+ mutation, equivalent to human DNMT3AR882H/+ , have increased mitochondrial respiration compared with wild-type cells and are dependent on this metabolic reprogramming for their competitive advantage. Treatment with metformin, an anti-diabetic drug that inhibits mitochondrial respiration 8 , reduced the competitive advantage of Dnmt3aR878H/+ HSCs. Through a multi-omics approach, we found that metformin acts by enhancing methylation potential in Dnmt3aR878H/+ HSPCs and reversing the aberrant DNA CpG methylation and histone H3 K27 trimethylation profiles in these cells. Metformin also reduced the competitive advantage of human DNMT3AR882H HSPCs generated by prime editing. Our findings provide preclinical rationale for investigating metformin as a preventive intervention against DNMT3A R882 mutation-driven clonal haematopoiesis in humans
Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models.
Get PDFBACKGROUND: Despite significant therapeutic progress, many lymphoma subtypes remain difficult to manage due to resistance, relapse, and dose-limiting toxicity.
METHODS: To elucidate the mechanism of action of the semi-synthetic flavonoid derivative (SND) compounds, we conducted a screening of cancer cell lines using proliferation, cell cycle, and apoptosis assays. We then performed computational modeling of the compounds\u27 binding to tubulin, and finally evaluated in vivo activity using nanoNail technology alongside xenograft experiment.
RESULTS: Here, we describe a series of SNDs that exhibit low-nanomolar to picomolar cytotoxicity across multiple lymphoma models, including those resistant to BTK and PI3K inhibitors. Mechanistic studies show that these compounds trigger robust apoptosis via cytoskeletal disruption and mitochondrial dysfunction. Notably, SND207 also potently inhibits Protein Kinase N1, suggesting a synergistic link between kinase blockade and cytoskeletal interference. High-throughput profiling places them near classical microtubule agents, although tubulin assays indicate more nuanced mechanisms than straightforward stabilization or depolymerization. In murine xenografts, SND207 significantly reduced tumor burden, and its combination with a BTK inhibitor demonstrates potential synergy. Furthermore, localized NanoNail delivery achieves high intratumoral drug concentrations at low doses, underscoring a favorable therapeutic index.
CONCLUSIONS: Overall, these findings highlight the translational promise of the SND series for future studies in the lymphoma field.
CLINICAL TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission
Reproductive experience drives changes in behaviour and physiology in male California mice, Peromyscus californicus
Get PDFPaternal experience improves memory and reduces anxiety-like behaviour in males, but it is unclear whether these changes are due to mating, siring offspring or caregiving behaviour. Likewise, paternal males have larger testes, a measure of sperm production, but again, the effects of siring and caregiving experience are difficult to disentangle. We examined behavioural and physiological outcomes in three groups of male mice: (1) virgins, (2) males paired with sterile females (‘nonfathers’) and (3) experienced fathers (experiment 1). Compared to virgins and nonfathers, experienced fathers exhibited increased recognition memory (novel object recognition) and decreased anxiety-like behaviour (elevated plus maze). Virgin males, however, had smaller testes and fewer sperm compared to nonfathers. We then compared the same traits in three additional groups of male mice (nonfathers, nonfathers with experience caring for unrelated pups (‘pup-sensitized nonfathers’) and first-time fathers) to determine whether the behavioural and physiological observations in experiment 1 were due to siring offspring or caregiving, and how rapidly these changes occur (experiment 2). Recognition memory and anxiety-like behaviour did not differ among these three groups, suggesting that caring for a single litter does not recapitulate the behavioural changes observed in experienced fathers (experiment 1). Despite equal mating opportunity, we observed larger testes in first-time fathers compared to nonfathers, suggesting that investment in sperm production may be more plastic than behavioural changes. Finally, we compared pup interactions in pup-sensitized nonfathers and first-time fathers. While pup-sensitized nonfathers were slower to approach pups than first-time fathers, they spent more time grooming pups, whereas first-time fathers invested more time in nest building, suggesting different caregiving behaviours in pup-sensitized males and biological fathers. Taken together, our study reveals that mating, siring and caregiving experience contributes to changes in memory, anxiety-like behaviour and reproductive investment in males of a biparental species