Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.

Durability of an endoscopic management strategy for recurrent choroid plexus carcinoma with a comprehensive molecular characterization: illustrative case.

OBJECTIVE: Choroid plexus carcinoma (CPC) is a rare, primarily intraventricular neoplasm. Extent of resection correlates with improved outcomes but is limited due to tumor vascularity and size. Evidence on optimal surgical management and molecular drivers of recurrence remains limited. Here the authors characterize a case of multiply recurrent CPC treated with sequential endoscopic removals over 10 years and highlight its genomic properties. OBSERVATIONS: Five years after standard treatment, a 16-year-old female presented with a distant intraventricular recurrence of CPC. Whole exome sequencing revealed NF1, PER1, and SLC12A2 mutations, FGFR3 gain, and no TP53 alterations. Repeat sequencing on recurrences 4 and 5 years later showed persistent NF1 and FGFR3 alterations. Methylation profiling was consistent with plexus tumor, subclass pediatric B. Short-term magnetic resonance imaging detected four total isolated recurrences, all treated with complete endoscopic resections at 5, 6.5, 9, and 10 years after initial diagnosis. Mean hospital stay for all recurrences was 1 day with no complications. LESSONS: The authors describe a patient with four isolated recurrences of CPC over a decade, each treated with complete endoscopic removal, and identify unique molecular alterations that persisted without TP53 alterations. These outcomes support frequent neuroimaging to facilitate endoscopic surgical removal following early detection of CPC recurrence.

Acute vagus nerve stimulation enhances reversal learning in rats.

Cognitive flexibility is a prefrontal cortex-dependent neurocognitive process that enables behavioral adaptation in response to changes in environmental contingencies. Electrical vagus nerve stimulation (VNS) enhances several forms of learning and neuroplasticity, but its effects on cognitive flexibility have not been evaluated. In the current study, a within-subjects design was used to assess the effects of VNS on performance in a novel visual discrimination reversal learning task conducted in touchscreen operant chambers. The task design enabled simultaneous assessment of acute VNS both on reversal learning and on recall of a well-learned discrimination problem. Acute VNS delivered in conjunction with stimuli presentation during reversal learning reliably enhanced learning of new reward contingencies. Enhancement was not observed, however, if VNS was delivered during the session but was not coincident with presentation of to-be-learned stimuli. In addition, whereas VNS delivered at 30 HZ enhanced performance, the same enhancement was not observed using 10 or 50 Hz. Together, these data show that acute VNS facilitates reversal learning and indicate that the timing and frequency of the VNS are critical for these enhancing effects. In separate rats, administration of the norepinephrine reuptake inhibitor atomoxetine also enhanced reversal learning in the same task, consistent with a noradrenergic mechanism through which VNS enhances cognitive flexibility.

The Mechanism of Action of cTIND for Minimally Invasive Ischemic Incision of the Prostate: In Vivo Study.

OBJECTIVES: To understand the histologic changes of prostate tissue induced by temporary implantable nitinol device (cTIND) in a canine model. METHODS: The cTIND is a small, symmetric device comprised of nitinol wire loops welded together on an axis, which exert radial force on the tissue to induce a targeted ischemic effect. The cTIND was implanted in three live canine models, which were monitored for 14 days post-index procedure. Device placement was monitored via serial fluoroscopy and biologic effects of cTIND were studied via histopathology. RESULTS: The cTIND was successfully placed in the canine models and remained securely in position until the animal was sacrificed on postoperative day 14. The cTIND treated tissue demonstrated an abrupt transition from normal, viable prostatic glandular tissue to an area of shrunken necrosis and fibrosis between the two. CONCLUSION: In the canine models, the cTIND created focal areas of ischemic necrosis resulting in incisions in the peri-urethral prostate with minimal inflammation.

Effects of a high-fat diet on impulsive choice in rats.

INTRODUCTION: Obesity and binge eating disorder are associated with high levels of impulsivity, but the causal role of eating and palatable food in these associations is unclear. Studies in rodents show that a high-fat diet can increase one aspect of impulsivity (impulsive action); it is less clear, however, whether a dissociable aspect of impulsivity (impulsive choice) is similarly affected. Hence, the aim of this study was to ascertain whether chronic exposure to a high-fat diet would alter impulsive choice. METHODS: Male rats were maintained on either a high-fat or control chow diet for two weeks ad libitum. They then underwent equi-caloric food restriction for the duration of the experiment, with each group maintained on their respective diet. To measure impulsive choice, rats were trained on a delay discounting task (DDT) in which they made discrete choices between a lever that delivered a small food reward immediately and a lever that delivered a large food reward accompanied by systematically increasing delays. Upon reaching stable performance on the DDT, rats were given acute systemic injections of amphetamine prior to testing in the DDT to determine whether increased monoamine transmission affected impulsive choice differently in the two diet groups. Lastly, subjects were tested on a progressive ratio schedule of reinforcement to assess motivation for a sucrose reward. RESULTS: There was no significant effect of the high-fat diet on impulsive choice. Further, amphetamine decreased choice of the large, delayed reward (increased impulsive choice) to the same extent in both groups. Exposure to the high-fat diet did, however, increase motivation to obtain a sucrose reward. CONCLUSIONS: These experiments reveal that, under conditions that do not promote weight gain, a chronic high-fat diet does not affect impulsive choice in a delay discounting task. The data are surprising in light of findings showing that this same diet alters impulsive action, and highlight the necessity of further research to elucidate relationships between palatable food consumption and impulsivity.

Regulation of risky decision making by gonadal hormones in males and females.

Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.

Contributions of medial prefrontal cortex to decision making involving risk of punishment.

The prefrontal cortex (PFC) plays an important role in several forms of cost-benefit decision making. Its contributions to decision making under risk of explicit punishment, however, are not well understood. A rat model was used to investigate the role of the medial PFC (mPFC) and its monoaminergic innervation in a Risky Decision-making Task (RDT), in which rats chose between a small, "safe" food reward and a large, "risky" food reward accompanied by varying probabilities of mild footshock punishment. Inactivation of mPFC increased choice of the large, risky reward when the punishment probability increased across the session ("ascending RDT"), but decreased choice of the large, risky reward when the punishment probability decreased across the session ("descending RDT"). In contrast, enhancement of monoamine availability via intra-mPFC amphetamine reduced choice of the large, risky reward only in the descending RDT. Systemic administration of amphetamine reduced choice of the large, risky reward in both the ascending and descending RDT; however, this reduction was not attenuated by concurrent mPFC inactivation, indicating that mPFC is not a critical locus of amphetamine's effects on risk taking. These findings suggest that mPFC plays an important role in adapting choice behavior in response to shifting risk contingencies, but not necessarily in risk-taking behavior per se.