microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a rare pediatric neuromuscular disease caused by loss-of-function variants in myotubularin ). With novel therapies entering clinical trials, the discovery of robust biomarkers that reflect disease severity and therapeutic efficacy is critically required. Using high-throughput and directed approaches, we identified a decrease in miR-133a expression as a marker of XLMTM disease in skeletal muscle and plasma of a mouse model of XLMTM ( KO).

Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.

Biallelic pathogenic variants in the nebulin (NEB) gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in NEB. Previously, a mouse model of Neb was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients.

Generation of a novel mouse model of nemaline myopathy due to recurrent exon 55 deletion.

Biallelic pathogenic variants in the nebulin () gene lead to the congenital muscle disease nemaline myopathy. In-frame deletion of exon 55 (ΔExon55) is the most common disease-causing variant in . Previously, a mouse model of was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in transcript expression that is not observed in exon 55 patients.

CASCADES, a novel SOX2 super-enhancer-associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence. In fact, the property of "stemness" itself may be responsible for treatment resistance.

Combination treatment with histone deacetylase and carbonic anhydrase 9 inhibitors shows therapeutic potential in experimental diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) remains a significant therapeutic challenge due to the lack of effective and safe treatment options. This study explores the potential of combining histone deacetylase (HDAC) and carbonic anhydrase 9 (CA9) inhibitors in treating DIPG. Analysis of RNA sequencing data and tumor tissue from patient samples for the expression of the carbonic anhydrase family and hypoxia signaling pathway activity revealed clinical relevance for targeting CA9 in DIPG.

Biallelic pathogenic variants in the mitochondrial form of phosphoenolpyruvate carboxykinase cause peripheral neuropathy.

Phosphoenolpyruvate carboxykinase (PCK) plays a critical role in cytosolic gluconeogenesis, and defects in cause a fasting-aggravated metabolic disease with hypoglycemia and lactic acidosis. However, there are two genes encoding PCK, and the role of the mitochondrial resident PCK (encoded by ) is unclear, since gluconeogenesis is cytosolic. We identified three patients in two families with biallelic variants in .

Biallelic loss-of-function variants in RABGAP1 cause a novel neurodevelopmental syndrome.

Purpose: RABGAP1 is a GTPase-activating protein implicated in a variety of cellular and molecular processes, including mitosis, cell migration, vesicular trafficking, and mTOR signaling. There are no known Mendelian diseases caused by variants in RABGAP1.

Methods: Through GeneMatcher, we identified 5 patients from 3 unrelated families with homozygous variants in the RABGAP1 gene found on exome sequencing.

X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition.

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition.

Natural history of a mouse model of X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO).

MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy.

Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions.

Glioblastoma (GBM) is the most common malignant primary brain tumour originating in the CNS. Median patient survival is <15 months with standard treatment which consists of surgery alongside radiation therapy and temozolomide chemotherapy. However, because of the aggressive nature of GBM, and the significant toxicity of these adjuvant therapies, long-term therapeutic effects are unsatisfactory.

Tamoxifen therapy in a murine model of myotubular myopathy.

Myotubular myopathy (MTM) is a severe X-linked disease without existing therapies. Here, we show that tamoxifen ameliorates MTM-related histopathological and functional abnormalities in mice, and nearly doubles survival. The beneficial effects of tamoxifen are mediated primarily via estrogen receptor signaling, as demonstrated through in vitro studies and in vivo phenotypic rescue with estradiol.

Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma.

Brainstem blood brain barrier disruption using focused ultrasound: A demonstration of feasibility and enhanced doxorubicin delivery.

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy.

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models.

Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process.

A role for activated Cdc42 in glioblastoma multiforme invasion.

Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines.

Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance.

Object: Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore.

A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma.

Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas.

Gene-expression profiling elucidates molecular signaling networks that can be therapeutically targeted in vestibular schwannoma.

Object: Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown.

Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-Cofilin pathway.

Malignant gliomas are highly proliferative and invasive neoplasms where total surgical resection is often impossible and effective local radiation therapy difficult. Consequently, there is a need to develop a greater understanding of the molecular events driving invasion and to identify novel treatment targets. Using microarray analysis comparing normal brain samples and mesenchymal glioblastoma multiforme (GBM), we identified over 140 significant genes involved in cell migration and invasion.

ATM regulates 3-methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents.

Unlabelled: Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity.

Conditional knockout of pik3c3 causes a murine muscular dystrophy.

Abnormalities in phosphoinositide metabolism are an emerging theme in human neurodegenerative disease. Myotubular myopathy is a prototypical disorder of phosphoinositide dysregulation that is characterized by profound muscle pathology and weakness and that is caused by mutations in MTM1, which encodes a phosphatase that targets 3-position phosphoinositides, including phosphatidylinositol 3-phosphate. Although the association between MTM1 and muscle disease has become increasingly clarified, the normal role(s) of phosphatidylinositol 3-phosphate metabolism in muscle development and homeostasis remain poorly understood.