👤 Mercedes Robledo

Pheochromocytomas and paragangliomas (PPGLs) exhibit the highest degree of heritability among all human tumors, yet the genetics of urinary bladder paragangliomas (UBPGLs) remains poorly understood. The present study aims to examine the characteristics of a cohort of Chinese patients with UBPGLs, focusing particularly on genetics. The study included 70 Chinese patients with UBPGLs from 15 centers in China, 240 patients with non-head and neck PGLs (non-HNPGLs) outside the urine bladder, and 16 Caucasian patients with UBPGLs. Tumor DNA samples were sequenced by next generation sequencing. All identified pathogenic variants (PVs) were confirmed by Sanger sequencing. Among the 70 Chinese patients, PVs were identified in 38 cases: 23 in cluster 1 A (13 SDHB, 1 SDHD, 1 SDHA, 4 IDH1, 2 SLC25A11, and 2 FH), 4 in cluster 1B (3 EPAS1 and 1 EGLN1), and 11 in cluster 2 genes (7 HRAS, 1 FGFR1, 2 NF1, and 1 H3F3A). Compared with other non-HNPGLs, UBPGLs had more PVs in cluster 1 A genes (32.9% vs. 14.2%, p < 0.001), but fewer in cluster 1B (5.7% vs. 19.2%, p = 0.002) and cluster 2 genes (15.7% vs. 42.5%, p < 0.001). PVs in SDHB (18.6%) was the most common in Chinese patients with UBPGLs, followed by HRAS (10.0%). No PVs was found in 45.7% of all UBPGLs. PVs in HRAS, SLC25A11, EPAS1, and FH were also identified in Caucasians with UBPGLs. Chinese patients with UBPGLs have a diverse genetic profile. PVs in cluster 1 A genes underlie nearly 1/3 of patients, highlighting the importance of genetic testing. Diverse germline and somatic PVs are also present in Caucasian patients with UBPGLs. Show less

Severe burn injuries can cause long-term cognitive impairments, potentially driven by lipid-mediated neuroinflammation in the central nervous system (CNS). The disruption of lipid homeostasis may contribute to neuroinflammatory responses, exacerbating neuronal damage. This study investigates whether acipimox, an anti-lipolytic agent, modulates lipid accumulation and neuroinflammation in the prefrontal cortex following severe burns. Sprague Dawley rats were randomized into four groups: sham vehicle, sham acipimox, burn vehicle, and burn acipimox. A scald injury covering 40-60% of total body surface area was induced, and rats were treated with acipimox (50 mg/kg/day, intraperitoneally) or vehicle for seven days. Lipidomic analysis assessed alterations in lipid profiles, while machine learning (XGBoost) identified key lipid drivers of burn-induced neuroinflammation. Additionally, mRNA expression of inflammatory markers, including interleukin-1β (IL-1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and toll-like receptor 4 (TLR4), was quantified to evaluate neuroinflammatory responses. Cytokine-lipid correlations were also examined using Spearman analysis. Lipidomic analysis identified significant alterations in a subset of the 21 lipid classes analyzed, particularly long-chain and very-long-chain fatty acids, including lysophosphatidylethanolamines, lysophosphatidylcholines, phosphatidylglycerols, phosphatidylethanolamines, and triacylglycerols ( These findings suggest that severe burns induce significant lipid dysregulation in the CNS, contributing to neuroinflammation and potential cognitive impairment. By targeting lipolysis, acipimox mitigates lipid accumulation, suppresses inflammatory pathways, and normalizes lipid levels, highlighting a potential therapeutic mechanism. This study establishes a mechanistic link between elevated lipolysis and CNS inflammation following severe burns. Acipimox effectively modulates lipid profiles and reduces neuroinflammation, underscoring its potential for managing burn-induced neurological complications. Further studies are needed to validate these findings and explore clinical applications. Show less

Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG. Show less

Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM. Show less