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PurposeThe aim of this study was to explore a radiomics-clinical model for predicting the response to initial superselective arterial embolization (SAE) in renal angiomyolipoma (RAML).Materials and methodsA total of 78 patients with RAML were retrospectively enrolled. Clinical data were recorded and evaluated. Radiomic features were extracted from preoperative contrast-enhanced CT (CECT). Least absolute shrinkage and selection operator (LASSO) and intra- and inter-class correlation coefficients (ICCs) were used in feature selection. Logistic regression analysis was performed to develop the radiomics, clinical, and combined models where the fivefold cross-validation method was used. The predictive performance and calibration were evaluated by the receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was used to measure clinical usefulness.ResultsThe tumor shrinkage rate was 29.7% in total, and both fat and angiomyogenic components were significantly reduced. In the radiomics model, 12 significant features were selected. In the clinical model, maximum diameter (p = 0.001), angiomyogenic tissue ratio (p = 0.032), aneurysms (p = 0.048), and post-SAE time (p = 0.002) were significantly associated with greater volume reduction after SAE. Because of the severe linear dependence between radiomics signature and some clinical parameters, the combined model eventually included Rad-score, aneurysm, and post-SAE time. The radiomics-clinical model showed better discrimination (mean AUC = 0.83) than the radiomics model (mean AUC = 0.60) and the clinical model (mean AUC = 0.82). Calibration curve and DCA showed the goodness of fit and clinical usefulness of the radiomics-clinical model.ConclusionsThe radiomics-clinical model incorporating radiomics features and clinical parameters can potentially predict the positive response to initial SAE in RAML and provide support for clinical treatment decisions.

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.

Early-onset epileptic encephalopathies are severe disorders often associated with specific genetic mutations. In this context, the CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by early-onset seizures, intellectual delay, and motor dysfunction. Although crucial for proper brain development, the precise targets of CDKL5 and its relation to patients' symptoms are still unknown. Here, induced pluripotent stem cells derived from individuals deficient in CDKL5 protein were used to generate neural cells. Proteomic and phosphoproteomic approaches revealed disruption of several pathways, including microtubule-based processes and cytoskeleton organization. While CDD-derived neural progenitor cells have proliferation defects, neurons showed morphological alterations and compromised glutamatergic synaptogenesis. Moreover, the electrical activity of CDD cortical neurons revealed hyperexcitability during development, leading to an overly synchronized network. Many parameters of this hyperactive network were rescued by lead compounds selected from a human high-throughput drug screening platform. Our results enlighten cellular, molecular, and neural network mechanisms of genetic epilepsy that could ultimately promote novel therapeutic opportunities for patients.

Accumulating evidence has suggested that prenatal exposure to methadone causes multiple adverse effects on human brain development. Methadone not only suppresses fetal neurobehavior and alters neural maturation, but also leads to long-term neurological impairment. Due to logistical and ethical issues of accessing human fetal tissue, the effect of methadone on brain development and its underlying mechanisms have not been investigated adequately and are therefore not fully understood. Here, we use human cortical organoids which resemble fetal brain development to examine the effect of methadone on neuronal function and maturation during early development. During development, cortical organoids that are exposed to clinically relevant concentrations of methadone exhibited suppressed maturation of neuronal function. For example, organoids developed from 12th week till 24th week have an about 7-fold increase in AP firing frequency, but only half and a third of this increase was found in organoids exposed to 1 and 10 μM methadone, respectively. We further demonstrated substantial increases in I Na (4.5-fold) and I KD (10.8-fold), and continued shifts of Na+ channel activation and inactivation during normal organoid development. Methadone-induced suppression of neuronal function was attributed to the attenuated increase in the densities of I Na and I KD and the reduced shift of Na+ channel gating properties. Since normal neuronal electrophysiology and ion channel function are critical for regulating brain development, we believe that the effect of prolonged methadone exposure contributes to the delayed maturation, development fetal brain and potentially for longer term neurologic deficits.