Modeling Extraordinary Response Through Targeting Secondary Alterations in Fusion-Associated Sarcoma.

Purpose: Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes (, /). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical fusion.

Generating in vitro models of NTRK-fusion mesenchymal neoplasia as tools for investigating kinase oncogenic activation and response to targeted therapy.

The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has led to new personalized therapies in oncology. Recent studies investigating NTRK fusions among mesenchymal neoplasms have identified several emerging soft tissue tumor entities displaying various phenotypes and clinical behaviors. Among them, tumors resembling lipofibromatosis or malignant peripheral nerve sheath tumors often harbor intra-chromosomal NTRK1 rearrangements, while most infantile fibrosarcomas are characterized by canonical ETV6::NTRK3 fusions.

Maternal ethanol consumption before paternal fertilization: Stimulation of hypocretin neurogenesis and ethanol intake in zebrafish offspring.

There are numerous clinical and pre-clinical studies showing that exposure of the embryo to ethanol markedly affects neuronal development and stimulates alcohol drinking and related behaviors. In rodents and zebrafish, our studies show that embryonic exposure to low-dose ethanol, in addition to increasing voluntary ethanol intake during adolescence, increases the density of hypothalamic hypocretin (hcrt) neurons, a neuropeptide known to regulate reward-related behaviors. The question addressed here in zebrafish is whether maternal ethanol intake before conception also affects neuronal and behavioral development, phenomena suggested by clinical reports but seldom investigated.

Embryonic Ethanol Exposure Affects the Early Development, Migration, and Location of Hypocretin/Orexin Neurons in Zebrafish.

Background: Embryonic ethanol (EtOH) exposure is known to increase alcohol drinking later in life and have long-term effects on neurochemical systems in the brain. With zebrafish having marked advantages for elucidating neural mechanisms underlying brain disorders, we recently tested and showed in these fish, similar to rodents, that low-dose embryonic EtOH stimulates voluntary consumption of EtOH while increasing expression of hypocretin/orexin (hcrt) neurons, a neuropeptide that promotes consummatory and reward-related behaviors. The goal of the present study was to characterize how embryonic EtOH affects early development of the hcrt system and produces persistent changes at older ages that may contribute to this increase in EtOH consumption.