RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in vitro in affected individuals' fibroblasts and skeletal muscle and in vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161∗). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

For over two centuries, clinicians have been aware of various conditions affecting white matter which had come to be grouped under the umbrella term multiple sclerosis. Within the last 20 years, specific scientific advances have occurred leading to more accurate diagnosis and differentiation of several of these conditions including, neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody disease. This new understanding has been coupled with advances in disease-modifying therapies which must be accurately applied for maximum safety and efficacy.

Tumor volume as a predictor of survival in advanced laryngeal cancer treated with total laryngectomy.

BACKGROUND: Recent literature shows that tumor volume (TV) in T3 laryngeal squamous cell carcinoma (LSCC) is associated with response to radiation therapy. The aim of this study was to evaluate the effect of TV on survival outcomes in patients undergoing total laryngectomy (TL). METHODS: One hundred and seventeen patients with LSCC undergoing TL between 2013 and 2020 at the University of Florida were included. TV was measured using a previously validated method on preoperative-CT scans. Multivariable CoxPH models for overall survival (OS) and disease-specific survival (DSS), metastasis-free survival (MFS), and recurrence-free survival (RFS) were developed with TV. RESULTS: Mean age was 61.5 years and 81.2% were male. Higher TV was associated with decreased OS, MFS, DSS, and RFS with adjusted hazard ratios 1.02 (95%CI: 1.01, 1.03), 1.01, (95%CI: 1.00, 1.03), 1.03 (95%CI: 1.01, 1.06), and 1.02 (95%CI: 1.00, 1.03) respectively. TV >7.1 cc had worse prognoses. CONCLUSIONS: TV appears associated with decreased survival in LSCC treated with TL.

Detailed imaging of abducens nerve anatomy using contrast-enhanced 3D-TOF MR angiography.

PURPOSE: Cranial nerves (CNs), particularly CN IV and VI are difficult to visualize with conventional MRI techniques, particularly within the cavernous sinus region. The aim of this study was to evaluate the capacity of high-resolution contrast enhanced 3D time-of-flight (TOF) MR angiography using new generation 3 T imaging technology to provide detailed visualization of CN VI anatomy, particularly within the cavernous sinus and petroclival regions. METHODS: Two neuroradiologists conducted bilateral evaluation of CN VI visibility in 23 patients for nerve segments located in the petroclival segment (dural cave and Dorello's canal), and three divisions of the cavernous sinus. All images were collected using contrast enhanced TOF MR angiography using a new generation 3 T machine. RESULTS: Of the CN VI segments assessed, average visibility of CN VI was best achieved in Dorello's canal. Overall visibility of CN VI within the regions inspected was best achieved in the axial view, with the exception of the dural cave, which was best assessed using the coronal view. We also identified strong agreement in assessment of nerve visibility between the two reviewers. We also identified a putative CN6 duplication and a small schwannoma, highlighting the fidelity of our approach. CONCLUSION: Contrast enhanced 3D TOF MR angiography can visualize CN VI anatomy, particularly within the petrocavernosal region and cavernous sinus with simultaneous visualization of arterial and venous structures. This cannot be easily achieved using traditional MRI techniques. This imaging technique might be used with new generation machines to evaluate CN VI anatomy and pathologies within the petrocavernosal region and cavernous sinus, especially relating to vascular pathologies.

Comparison of metal artifact reduction using single-energy CT and dual-energy CT with various metallic implants in cadavers.

OBJECTIVES: The purpose of this study was to compare the effectiveness of metal artifact reduction using Single Energy Metal Artifact Reduction (SEMAR) and Dual Energy CT (DECT). MATERIALS AND METHODS: Six cadavers containing metal implants in the head, neck, abdomen, pelvis, and extremities were scanned with Standard, SEMAR, and DECT protocols on a 320-slice CT scanner. Four specialized radiologists blinded to acquisition methods rated severity of metal artifacts, visualization of anatomic structures, diagnostic interpretation, and image preference with a 5-point grading scale. RESULTS: Scores were significantly better for SEMAR than Standard images in the hip, knee, pelvis, abdomen, and maxillofacial scans (3.25 ±â€¯0.88 versus 2.14 ±â€¯0.93, p < 0.001). However, new reconstruction artifacts developed in SEMAR images that were not present in Standard images. Scores for severity of metal artifacts and visualization of smooth structures were significantly better for DECT than Standard images in the cervical spine (3.50±0.50 versus 2.0±0.58, p < 0.001) and was preferred over Standard images by one radiologist. In all other cases, radiologists preferred the Standard image over the DECT image due to increased image noise and reduced low-contrast resolution with DECT. In all cases, SEMAR was preferred over Standard and DECT images. CONCLUSION: SEMAR was more effective at reducing metal artifacts than DECT. Radiologists should be aware of new artifacts and review both the original and SEMAR images. When the anatomy or implant is relatively small, DECT may be superior to SEMAR without additional artifacts. However, radiologist should be aware of a reduction in soft tissue contrast.