Citations

Abstract Numerous reports have suggested that infectious agents could play a role in neurodegenerative diseases, but specific etiological agents have not been convincingly demonstrated. To search for candidate agents in an unbiased fashion, we have developed a bioinformatic pipeline that identifies microbial sequences in mammalian RNA-seq data, including sequences with no significant nucleotide similarity hits in GenBank. Effectiveness of the pipeline was tested using publicly available RNA-seq data and in a reconstruction experiment using synthetic data. We then applied this pipeline to a novel RNA-seq dataset generated from a cohort of 120 samples from amyotrophic lateral sclerosis patients and controls, and identified sequences corresponding to known bacteria and viruses, as well as novel virus-like sequences. The presence of these novel virus-like sequences, which were identified in subsets of both patients and controls, were confirmed by quantitative RT-PCR. We believe this pipeline will be a useful tool for the identification of potential etiological agents in the many RNA-seq datasets currently being generated.

No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2–induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion–activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.

Abstract The objective of this clinical practice guideline (CPG) is to provide recommendations for healthcare personnel working with patients with epilepsy on the use of wearable devices for automated seizure detection in patients with epilepsy, in outpatient, ambulatory settings. The Working Group of the International League Against Epilepsy (ILAE) and the International Federation of Clinical Neurophysiology (IFCN) developed the CPG according to the methodology proposed by the ILAE Epilepsy Guidelines Working Group. We reviewed the published evidence using The Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) statement and evaluated the evidence and formulated the recommendations following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We found high level of evidence for the accuracy of automated detection of generalized tonic‐clonic seizures (GTCS) and focal‐to‐bilateral tonic‐clonic seizures (FBTCS) and recommend the use of wearable automated seizure detection devices for selected patients when accurate detection of GTCS and FBTCS is recommended as a clinical adjunct. We also found a moderate level of evidence for seizure types without GTCS or FBTCS. However, it was uncertain whether the detected alarms resulted in meaningful clinical outcomes for the patients. We recommend using clinically validated devices for automated detection of GTCS and FBTCS, especially in unsupervised patients, where alarms can result in rapid intervention (weak/conditional recommendation). At present, we do not recommend clinical use of the currently available devices for other seizure types (weak/conditional recommendation). Further research and development are needed to improve the performance of automated seizure detection and to document their accuracy and clinical utility.

PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .

We clarify that DNA damage triggers autophagy by CHK2-FOXK axis, and misregulation of this pathway leads to chemoresistance.

Marrow adipocytes reprogrammed by myeloma cells induce bone lesions.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

Three-dimensional (3D) printing is an additive manufacturing method that holds great potential in a variety of future patient-specific medical technologies. This project validated a novel crosslinked polyvinyl alcohol (XL-PVA) 3D printed stent infused with collagen, human placental mesenchymal stem cells (PMSCs), and cholangiocytes. The biofabrication method in the present study examined 3D printing and collagen injection molding for rapid prototyping of customized living biliary stents with clinical applications in the setting of malignant and benign bile duct obstructions. XL-PVA stents showed hydrophilic swelling and addition of radiocontrast to the stent matrix improved radiographic opacity. Collagen loaded with PMSCs contracted tightly around hydrophilic stents and dense choloangiocyte coatings were verified through histology and fluorescence microscopy. It is anticipated that design elements used in these stents may enable appropriate stent placement, provide protection of the stent-stem cell matrix against bile constituents, and potentially limit biofilm development. Overall, this approach may allow physicians to create personalized bio-integrating stents for use in biliary procedures and lays a foundation for new patient-specific stent fabrication techniques.