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.

New autonomous and self-signaling biosensing device for sarcosine detection.

An early diagnosis is the gold standard for cancer survival. Biosensors have proven their effectiveness in monitoring cancer biomarkers but are still limited to a series of requirements. This work proposes an integrated power solution, with an autonomous and self-signaling biosensing device.

Evaluation parameters for evidence-based practices for people with autism spectrum disorder: a narrative review of group and single-subject design studies.

Recommendations for using evidence-based practices have become increasingly common in services for individuals diagnosed with autistic spectrum disorder (ASD). The aim of this study was to conduct a narrative literature review to identify differences and similarities in evidence-evaluation criteria for group and single-subject designs that empirically support interventions for people with ASD. Data sources used in this analysis were reports and articles elaborated by different clearinghouses (i.

The role of dietary factors on blood lead concentration in children and adolescents - Results from the nationally representative German Environmental Survey 2014-2017 (GerES V).

In industrialized nations, human lead exposure has decreased significantly in recent decades. Nevertheless, due to its toxic effects, this heavy metal remains a public health concern with children and adolescents being particularly at risk. In Europe nowadays, oral intake via food and drinking water is the predominant exposure pathway for lead.

Lead, cadmium, mercury, and chromium in urine and blood of children and adolescents in Germany - Human biomonitoring results of the German Environmental Survey 2014-2017 (GerES V).

Metals reach humans through food and drinking water intake and inhalation of airborne particles and can have detrimental health effects in particular for children. The metals presented here (lead, cadmium, chromium, and mercury) could lead to toxic effects such as neurotoxicity, mutagenicity, and have been classified as (possible) carcinogens. Using population representative data from the German Environmental Survey 2014-2017 (GerES V) from 3- to 17-year-old children on lead and cadmium in blood (n = 720) and on cadmium, chromium, and mercury in urine (n = 2250) we describe current internal exposure levels, and socio-demographic and substance-specific exposure determinants.

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.

Cognitive correlates of visual hallucinations in non-demented Parkinson's disease patients.

Background: Visual hallucinations (VH) in Parkinson's disease (PD) are associated with PD dementia and have been related to cognitive impairments in non-demented PD patients. Reports on the specific cognitive domains affected are conflicting. The aim of the present study was to investigate the presence of specific cognitive impairments in non-demented PD patients with VH, compared to those without VH.

Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function.

Unlabelled: The histidine triad nucleotide-binding (HINT2) protein is a mitochondrial adenosine phosphoramidase expressed in the liver and pancreas. Its physiological function is unknown. To elucidate the role of HINT2 in liver physiology, the mouse Hint2 gene was deleted.

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.

Acute medical assessment units: an efficient alternative to in-hospital acute medical care.

Acute Medical Assessment Units (AMAUs) are being proposed as an alternative to congested Emergency Departments (EDs for the assessment of patients with a range of acute medical problems. We retrospectively reviewed the discharge destination of patients referred to a newly established AMAU during a six-month period. During the same period we contrasted activity in the ED for a similar group of patients.

Effect of sorafenib on murine liver regeneration.

Unlabelled: Hepatocellular carcinoma (HCC) is a common cause of cancer-related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor-beta 1/2 (PDGFR-β) and the kinase RAF.

Ablation of the tumor suppressor histidine triad nucleotide binding protein 1 is protective against hepatic ischemia/reperfusion injury.

Unlabelled: The identification of cellular pathways capable of limiting ischemia/reperfusion (I/R) injury remains a frontier in medicine, and its clinical relevance is urgent. Histidine triad nucleotide binding protein 1 (HINT1) is a tumor suppressor that influences apoptosis. Because apoptotic pathways are a feature of I/R injury, we asked whether Hint1 influences hepatic I/R injury.

Connective tissue growth factor, steatosis and fibrosis in patients with chronic hepatitis C.

Background/aim: Both steatosis and insulin resistance have been linked to accelerated fibrosis in chronic hepatitis C. Connective tissue growth factor (CTGF) plays a major role in extracellular matrix production in fibrotic disorders including cirrhosis, and its expression is stimulated in vitro by insulin and glucose. We hypothesized that CTGF may link steatosis, insulin resistance and fibrosis.

Impact of concentrations of glycated hemoglobin, alpha-tocopherol, copper, and manganese on oxidation of low-density lipoproteins in patients with type I diabetes, type II diabetes and control subjects.

The late organ complications in diabetic patients are associated with enhanced oxidation of low-density lipoproteins (LDL). The role of vitamin and trace metal concentrations in this process is not clear. Therefore, we compared the oxidative susceptibility and alpha-tocopherol concentration of LDL with the levels of glycated hemoglobin (HbA1c), copper and manganese.