A Report of a Rare Case of BCOR (B-cell Line 6 Corepressor)-Altered Sarcoma of the Lung in a Child.

Ewing sarcoma is one of the small round blue cell tumors of childhood that typically affects bone. Recently, a subgroup of undifferentiated round-cell sarcomas has been genetically identified as BCOR (B-cell Line 6 Corepressor)-altered sarcomas (BAS). We present a case of a six-year-old male child who presented with a chief complaint of shortness of breath and tachypnea and was found to have a large mediastinal mass concerning sarcoma. Preliminary biopsy results were positive for small round blue cells, possibly Ewing sarcoma. After six cycles of chemotherapy, with subsequent shrinkage of mediastinal mass, the patient was able to undergo wedge resection and excision of the mass with en bloc resection of the fifth and sixth rib, preserving his right lung. Final tissue pathology was positive for BAS. There have been only four reported cases of BAS of the chest wall and zero reported cases of primary tumor presentation of the lung, making this a rare presentation of the disease.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ9-tetrahydrocannabinol (Δ9-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60%  of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ9-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ9-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ9-THC-induced reduction in oICSS and Δ9-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ9-THC-induced hypoactivity and catalepsy but failed to alter Δ9-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.

PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice.

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ 9 -tetrahydrocannabinol (Δ 9 -THC) is a PPARg agonist and some endocannabinoids are natural activators of PPAR a and PPARg. Therefore, both the receptors are putative cannabinoid receptors. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are highly expressed in ~70% midbrain dopamine (DA) neurons and in ~50% GABAergic and ~50% glutamatergic neurons in the amygdala. However, no PPARα/γ signal was detected in GABAergic neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ 9 -THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ 9 -THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS, suggesting that dopaminergic PPARγ modulates DA-dependent behavior. Surprisingly, pretreatment with PPARα or PPARγ antagonists dose-dependently attenuated the Δ 9 -THC-induced reduction in oICSS and anxiogenic effects. In addition, a PPARγ agonist increased, while PPARa or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARa or PPARγ antagonists potentiated Δ 9 -THC-induced hypoactivity and catalepsy but failed to alter Δ 9 -THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARa/g in DA-dependent behavior and cannabinoid action.

Involvement of the ghrelin system in the maintenance and reinstatement of cocaine-motivated behaviors: a role of adrenergic action at peripheral ß1 receptors.

Cocaine addiction is a significant medical and public concern. Despite decades of research effort, development of pharmacotherapy for cocaine use disorder remains largely unsuccessful. This may be partially due to insufficient understanding of the complex biological mechanisms involved in the pathophysiology of this disorder. In the present study, we show that: (1) elevation of ghrelin by cocaine plays a critical role in maintenance of cocaine self-administration and cocaine-seeking motivated by cocaine-conditioned stimuli; (2) acquisition of cocaine-taking behavior is associated with the acquisition of stimulatory effects of cocaine by cocaine-conditioned stimuli on ghrelin secretion, and with an upregulation of ghrelin receptor mRNA levels in the ventral tegmental area (VTA); (3) blockade of ghrelin signaling by pretreatment with JMV2959, a selective ghrelin receptor antagonist, dose-dependently inhibits reinstatement of cocaine-seeking triggered by either cocaine or yohimbine in behaviorally extinguished animals with a history of cocaine self-administration; (4) JMV2959 pretreatment also inhibits brain stimulation reward (BSR) and cocaine-potentiated BSR maintained by optogenetic stimulation of VTA dopamine neurons in DAT-Cre mice; (5) blockade of peripheral adrenergic ß1 receptors by atenolol potently attenuates the elevation in circulating ghrelin induced by cocaine and inhibits cocaine self-administration and cocaine reinstatement triggered by cocaine. These findings demonstrate that the endogenous ghrelin system plays an important role in cocaine-related addictive behaviors and suggest that manipulating and targeting this system may be viable for mitigating cocaine use disorder.