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Fulltext Challenges and future perspectives for 3D cerebral organoids as amodel for complex brain disorders

Cheah, Pike-See, Mason, John O., Ling, King-Hwa

Neuroscience Research Notes, 2019;2(1):1-6.
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The human brain is made up of billions of neurons and glial cells which are interconnected and organized into specific patternsof neural circuitry, and hence is arguably the most sophisticated organ in human, both structurally and functionally.Studying the underlying mechanisms responsible for neurologicalor neurodegenerativedisorders and the developmental basis of complex brain diseases such as autism, schizophrenia, bipolar disorder, Alzheimer’s and Parkinson’s disease has proven challenging due to practical and ethical limitations on experiments with human material and the limitationsof existing biological/animal models. Recently,cerebral organoids havebeen proposed as apromisingand revolutionary model for understanding complex brain disorders and preclinical drug screening.
Fulltext Pax6 mutant cerebral organoids partially recapitulate phenotypes of Pax6 mutant mouse strains

Ferdaos N, Lowell S, Mason JO

PLoS One, 2022;17(11):e0278147.
PMID: 36441708 DOI: 10.1371/journal.pone.0278147

Cerebral organoids show great promise as tools to unravel the complex mechanisms by which the mammalian brain develops during embryogenesis. We generated mouse cerebral organoids harbouring constitutive or conditional mutations in Pax6, which encodes a transcription factor with multiple important roles in brain development. By comparing the phenotypes of mutant organoids with the well-described phenotypes of Pax6 mutant mouse embryos, we evaluated the extent to which cerebral organoids reproduce phenotypes previously described in vivo. Organoids lacking Pax6 showed multiple phenotypes associated with its activity in mice, including precocious neural differentiation, altered cell cycle and an increase in abventricular mitoses. Neural progenitors in both Pax6 mutant and wild type control organoids cycled more slowly than their in vivo counterparts, but nonetheless we were able to identify clear changes to cell cycle attributable to the absence of Pax6. Our findings support the value of cerebral organoids as tools to explore mechanisms of brain development, complementing the use of mouse models.
Fulltext Global Retinoblastoma Presentation and Analysis by National Income Level

Global Retinoblastoma Study Group, Fabian ID, Abdallah E, Abdullahi SU, Abdulqader RA, Adamou Boubacar S, et al.

JAMA Oncol, 2020 May 01;6(5):685-695.
PMID: 32105305 DOI: 10.1001/jamaoncol.2019.6716

IMPORTANCE: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.
OBJECTIVES: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis.
DESIGN, SETTING, AND PARTICIPANTS: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017.
MAIN OUTCOMES AND MEASURES: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis.
RESULTS: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]).
CONCLUSIONS AND RELEVANCE: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

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