A platform for rapid patient-derived cutaneous neurofibroma organoid establishment and screening.

Localized cutaneous neurofibromas (cNFs) are benign tumors that arise in the dermis of patients affected by neurofibromatosis type 1 syndrome. cNFs are benign lesions: they do not undergo malignant transformation or metastasize. Nevertheless, they can cover a significant proportion of the body, with some individuals developing hundreds to thousands of lesions. cNFs can cause pain, itching, and disfigurement resulting in substantial socio-emotional repercussions. Currently, surgery and laser desiccation are the sole treatment options but may result in scarring and potential regrowth from incomplete removal. To identify effective systemic therapies, we introduce an approach to establish and screen cNF organoids. We optimized conditions to support the ex vivo growth of genomically diverse cNFs. Patient-derived cNF organoids closely recapitulate cellular and molecular features of parental tumors as measured by immunohistopathology, methylation, RNA sequencing, and flow cytometry. Our cNF organoid platform enables rapid screening of hundreds of compounds in a patient- and tumor-specific manner.

Sex and menstrual cycle effects on chronic oral cocaine self-administration in rhesus monkeys: Effects of a nondrug alternative reward.

BACKGROUND: In previous studies, female monkeys self-administered more oral phencyclidine (PCP) than males, and PCP intake differed by phase of menstrual cycle. OBJECTIVES: The purpose of this study was to examine sex and hormonal influences on oral cocaine self-administration in male and female rhesus monkeys in the follicular vs. luteal phases of the menstrual cycle, with concurrent access to an alternative nondrug reward, saccharin (SACC) vs. water. MATERIALS AND METHODS: Concurrent access to cocaine (0.2, 0.4, and 0.8 mg/ml) and SACC or water was available from two drinking spouts under concurrent fixed-ratio (FR) 2, 4, and 8 schedules during daily 3-h sessions. RESULTS: Cocaine deliveries were similar in males and females in the females' luteal phase, but cocaine deliveries were higher in females during the follicular phase than the luteal phase and compared to males. When SACC was available, cocaine deliveries were reduced in females in the follicular phase of the cycle, and cocaine intake (mg/kg) was reduced in males and in females' follicular and luteal phases. CONCLUSIONS: Access to concurrent SACC (vs. water) reduced cocaine intake (mg/kg) in males and in females during both menstrual phases, and the magnitude of the reduction in cocaine intake was greatest during the females' follicular phase. Thus, a nondrug alternative reward, SACC, is a viable alternative treatment for reducing cocaine's rewarding effects on male and female monkeys, and reductions in cocaine seeking were optimal in the females' luteal phase.

Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase.

BACKGROUND: In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females. OBJECTIVES: The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle. MATERIALS AND METHODS: In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7-11) or the late luteal phase (days 24-28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases. RESULTS: PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration. CONCLUSIONS: PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys.