Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.

Coibamide A (CbA) is a cyanobacterial lariat depsipeptide that selectively inhibits multiple secreted and integral membrane proteins from entering the endoplasmic reticulum secretory pathway through binding the alpha subunit of the Sec61 translocon. As a complex peptide-based macrocycle with 13 stereogenic centers, CbA is presumed to adopt a conformationally restricted orientation in the ligand-bound state, resulting in potent antitumor and antiangiogenic bioactivity. A stereochemical structure-activity relationship for CbA was previously defined based on cytotoxicity against established cancer cell lines.

AAV9 transduction mediated by systemic delivery of vector via retro-orbital injection in newborn, neonatal and juvenile mice.

Adeno-associated virus (AAV)-based gene therapy is gaining popularity owing to its excellent safety profile and effective therapeutic outcomes in a number of diseases. Intravenous (IV) injection of AAV into the tail vein, facial vein and retro-orbital (RO) venous sinus have all been useful strategies to infuse the viral vector systemically. However, tail vein injection is technically challenging in juvenile mice, and injection at young ages (≤ postnatal day-(P)21) is essentially impossible.

Post-COVID-19 Acute Disseminated Encephalomyelitis in a 17-Month-Old.

Neurologic manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric patients have been reported in the acute and postinfectious stages of coronavirus disease 2019. Acute disseminated encephalomyelitis (ADEM) typically presents in children after a viral illness at a mean age of 3 to 7 years. A total of 60% to 90% of literature-reported pediatric patients with ADEM have minimal to no neurologic deficits at long-term follow-up.

A multiplexed bioluminescent reporter for sensitive and non-invasive tracking of DNA double strand break repair dynamics in vitro and in vivo.

Tracking DNA double strand break (DSB) repair is paramount for the understanding and therapeutic development of various diseases including cancers. Herein, we describe a multiplexed bioluminescent repair reporter (BLRR) for non-invasive monitoring of DSB repair pathways in living cells and animals. The BLRR approach employs secreted Gaussia and Vargula luciferases to simultaneously detect homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively.

Obtusaquinone: A Cysteine-Modifying Compound That Targets Keap1 for Degradation.

We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex.

Patient-Derived Glioma Models: From Patients to Dish to Animals.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults associated with a poor survival. Current standard of care consists of surgical resection followed by radiation and chemotherapy. GBMs are highly heterogeneous, having a complex interaction among different cells within the tumor as well as the tumor microenvironment.

Erratum: Author Correction: Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition.

[This corrects the article DOI: 10.1038/s41420-019-0155-9.].

Stearoyl CoA Desaturase Is Essential for Regulation of Endoplasmic Reticulum Homeostasis and Tumor Growth in Glioblastoma Cancer Stem Cells.

Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%-100% cure rate in xenograft mouse models.

Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition.

Glioblastoma is an incurable and highly aggressive brain tumor. Understanding therapeutic resistance and survival mechanisms driving this tumor type is key to finding effective therapies. Smac mimetics (SM) emerged as attractive cancer therapeutics particularly for tumor populations that are highly resistant to conventional apoptosis-inducing therapies.

Dissecting inherent intratumor heterogeneity in patient-derived glioblastoma culture models.

Background: Molecular profile of glioblastoma multiforme (GBM) revealed 4 subtypes, 2 of which, proneural and mesenchymal, have been predominantly observed, with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Single-cell RNA sequencing revealed that multiple subtypes actually reside within the same tumor, suggesting cellular heterogeneity in GBM. Further, plasticity between these 2 subtypes is observed during tumor recurrence and in response to radiation therapy.

New methods for investigation of neuronal migration in embryonic brain explants.

Background: Proper migration of neurons is essential for the formation and normal functioning of the nervous system. Defects in neuronal migration underlie a number of neurologic diseases in humans. Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration remain to be elucidated fully.

Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A.

Early-onset dystonia is associated with the deletion of one of a pair of glutamic acid residues (c.904_906delGAG/c.907_909delGAG; p.

Microfluidic platform to evaluate migration of cells from patients with DYT1 dystonia.

Background: Microfluidic platforms for quantitative evaluation of cell biologic processes allow low cost and time efficient research studies of biological and pathological events, such as monitoring cell migration by real-time imaging. In healthy and disease states, cell migration is crucial in development and wound healing, as well as to maintain the body's homeostasis.

New Method: The microfluidic chambers allow precise measurements to investigate whether fibroblasts carrying a mutation in the TOR1A gene, underlying the hereditary neurologic disease--DYT1 dystonia, have decreased migration properties when compared to control cells.

TorsinA participates in endoplasmic reticulum-associated degradation.

TorsinA is an AAA+ ATPase located within the lumen of the endoplasmic reticulum and nuclear envelope, with a mutant form causing early onset torsion dystonia (DYT1). Here we report a new function for torsinA in endoplasmic reticulum-associated degradation (ERAD). Retro-translocation and proteosomal degradation of a mutant cystic fibrosis transmembrane conductance regulator (CFTRΔF508) was inhibited by downregulation of torsinA or overexpression of mutant torsinA, and facilitated by increased torsinA.