Feasibility of percutaneous dural sac puncture via a posterior trans-sacral foraminal conduit approach: a CT morphometric analysis.

We assess the theoretical feasibility of percutaneous posterior sacral foramen (pSF) needle puncture of the sacral dural sac (DS) by studying the three-dimensional imaging anatomy of pSFs relative to the sacral canal (SC). On CT images of 40 healthy subjects, we retrospectively studied sacral alae passageways from SC to pSFs in all three planes to determine if an imaginary spinal needle could theoretically traverse S1 or S2 pSFs in a straight path toward DS. If not straight, we measured multiplane angulations and morphometrics of this route. We found no straight connections between S1 or S2 pSFs and SC. Instead, there were bilateral spatially complex dorsoventral M-shaped "foraminal conduits" (FCs; common, ventral, and dorsal) from SC to anterior SFs and pSFs that would prevent percutaneous straight needle puncture of the DS. This detailed knowledge of the sacral FCs will be useful for accurate imaging interpretation and interventional procedures on the sacrum.

Caudolenticular gray bridges of the brain: A magnetic resonance imaging study.

The caudolenticular (or transcapsular) gray bridges (CLGBs) connect the caudate nucleus (CN) and putamen across the internal capsule. The CLGBs function as the main efferent terminus from premotor and supplementary motor area cortex to the basal ganglia (BG). We conjectured if inherent variations in numbers and sizes of CLGBs could contribute to abnormal cortical-subcortical connectivity in Parkinson's disease (PD), a neurodegenerative disorder featuring a hindrance of BG processing. However, there are no literature accounts of normative anatomy and morphometry of CLGBs. We therefore retrospectively analyzed axial and coronal 3T fast spoiled gradient-echo magnetic resonance images (MRIs) of 34 healthy individuals for bilateral CLGBs symmetry, their numbers, dimensions of thickest and longest bridge, and axial surface areas of CN head and putamen. We calculated Evans' index (EI) to account for any brain atrophy. We statistically tested associations between sex or age and measured dependent variables, and linear correlations between all measured variables (significance at p < 0.05). Study subjects were F:M = 23:11 with mean age 49.9 years. All EI's were normal (<0.3). All but three CLGBs were bilaterally symmetrical with a mean 7.4 CLGBs per side. Mean CLGBs thickness and lengths were 1.0 and 4.6 mm, respectively; CN head and putamen areas were 205 and 382.0 mm2 , respectively. Females had thicker CLGBs (p = 0.02) but we found no significant interactions between sex or age and measured dependent variables, and no correlations between CN head or putamen areas and CLGBs dimensions. These normative MRI dimensions of the CLGBs will help guide future studies on the possible role of CLGBs morphometry in PD predisposition.

Atavistic and vestigial anatomical structures in the head, neck, and spine: an overview.

Organisms may retain nonfunctional anatomical features as a consequence of evolutionary natural selection. Resultant atavistic and vestigial anatomical structures have long been a source of perplexity. Atavism is when an ancestral trait reappears after loss through an evolutionary change in previous generations, whereas vestigial structures are remnants that are largely or entirely functionless relative to their original roles. While physicians are cognizant of their existence, atavistic and vestigial structures are rarely emphasized in anatomical curricula and can, therefore, be puzzling when discovered incidentally. In addition, the literature is replete with examples of the terms atavistic and vestigial being used interchangeably without careful distinction between them. We provide an overview of important atavistic and vestigial structures in the head, neck, and spine that can serve as a reference for anatomists and clinical neuroscientists. We review the literature on atavistic and vestigial anatomical structures of the head, neck, and spine that may be encountered in clinical practice. We define atavistic and vestigial structures and employ these definitions consistently when classifying anatomical structures. Pertinent anatomical structures are numerous and include human tails, plica semilunaris, the vomeronasal organ, levator claviculae, and external ear muscles, to name a few. Atavistic and vestigial structures are found throughout the head, neck, and spine. Some, such as human tails and branchial cysts may be clinically symptomatic. Literature reports indicate that their prevalence varies across populations. Knowledge of atavistic and vestigial anatomical structures can inform diagnoses, prevent misrecognition of variation for pathology, and guide clinical interventions.

Feasibility of intrathecal therapeutic injections in spinal muscular atrophy patients via a percutaneous transsacral hiatus route: An initial neuroimaging morphometric study.

INTRODUCTION/AIMS: Standard fluoroscopic lumbar puncture (LP) can be impossible in patients with severe spinal deformities from spinal muscular atrophy (SMA) who require intrathecal nusinersen therapy. There usually exists a straight trajectory in the lower sacral canal (SC) that could allow image-guided percutaneous transsacral hiatus puncture of the lumbosacral dural sac. In this study we determine whether sacra are comparatively straighter in SMA patients (SMAps) vs healthy controls (HCs), which may facilitate unhindered transsacral hiatus spinal needle insertion for intrathecal nusinersen therapy. METHODS: We retrospectively analyzed lumbosacral spine computed tomograms (CTs) or CT-myelogram images of 38 SMAps and age- and sex-matched HCs. We digitally measured ventrodorsal sacral curvatures, SC surface areas, dural sac termination levels, and distances from sacral hiatus to the most caudad aspects of dural sacs ("needle distance"). RESULTS: Mean ages of HCs and SMAps were 32.7 and 31.7 years, respectively, with dural sacs terminating at similar levels. Mean values for morphometrics were: (a) midsagittal SC surface area for HCs = 701.2 mm2 , and for SMAps = 601.5 mm2 (not statistically significant [ns]); (b) using a "line method," sacral curvature for HCs = 61.9°, and SMAp = 35.7° (P = .0009), and was similar when using an "angle summation method"; (c) width of sacral hiatus for HCs = 14.9 mm, and SMAps = 15.0 mm (ns); and (d) "needle distance" for HCs = 54.7 mm, and SMAps = 49.9 mm (ns). DISCUSSION: SMAps have significantly straighter sacra compared with HCs, which theoretically renders them more amenable to percutaneous transsacral hiatus puncture of the dural sac.

A New Nrf2 Inhibitor Enhances Chemotherapeutic Effects in Glioblastoma Cells Carrying p53 Mutations.

TP53 tumor suppressor gene is a commonly mutated gene in cancer. p53 mediated senescence is critical in preventing oncogenesis in normal cells. Since p53 is a transcription factor, mutations in its DNA binding domain result in the functional loss of p53-mediated cellular pathways. Similarly, nuclear factor erythroid 2-related factor 2 (Nrf2) is another transcription factor that maintains cellular homeostasis by regulating redox and detoxification mechanisms. In glioblastoma (GBM), Nrf2-mediated antioxidant activity is upregulated while p53-mediated senescence is lost, both rendering GBM cells resistant to treatment. To address this, we identified novel Nrf2 inhibitors from bioactive compounds using a molecular imaging biosensor-based screening approach. We further evaluated the identified compounds for their in vitro and in vivo chemotherapy enhancement capabilities in GBM cells carrying different p53 mutations. We thus identified an Nrf2 inhibitor that is effective in GBM cells carrying the p53 (R175H) mutation, a frequent clinically observed hotspot structural mutation responsible for chemotherapeutic resistance in GBM. Combining this drug with low-dose chemotherapies can potentially reduce their toxicity and increase their efficacy by transiently suppressing Nrf2-mediated detoxification function in GBM cells carrying this important p53 missense mutation.

Anatomy of the Orbit.

Each orbit is a complex structure housing the globe, multiple cranial nerves, muscles, vascular structures, which support the visual sense. Many of these structures have been delineated in careful detail by anatomists but remain beyond the resolution of conventional imaging techniques. With the advances of higher resolution MR, surface coil usage, and thinner section computed tomographic images, the ability to resolve these small structures continues to improve, allowing radiologists to provide more detailed anatomic descriptions for preoperative and pretreatment planning.

Oral Cavity and Salivary Glands Anatomy.

Knowledge of anatomy is essential to the understanding of disease and conditions of the oral cavity and salivary glands. This article is intended to serve as an overview of the oral cavity, its subsites, and that of the neighboring salivary glands. The authors cover the anatomy of the lips, tongue, floor of mouth, hard palate, teeth, various mucosal areas, and salivary ducts. When appropriate, radiological imaging along with figures serves as a companion to highlight the clinical relevance and practical applications of specific anatomic locations.

Root of the Neck and Extracranial Vessel Anatomy.

The root of the neck is the junctional anatomic structure between the thoracic inlet, the axilla, and the lower neck. The detailed radiological anatomy of this critical area is discussed in this review.

Thoracic and Lumbosacral Spine Anatomy.

We review anatomy of the thoracic, lumbar, and sacral spine. Knowledge of normal anatomy is vital when reviewing imaging of the spine because it allows for the detection of abnormal findings. We emphasize the normal appearance of the thoracic and lumbosacral spine on imaging, focusing on the most common imaging techniques of computed tomography and magnetic resonance imaging, as well as highlighting a few less common and emerging imaging techniques that can evaluate the spine.

Anatomy of the Spinal Cord, Coverings, and Nerves.

The spinal cord is an elegant structure that serves as a conduit for the transfer of information between the brain and the peripheral nervous system. To enable the reader to understand its complex microstructural anatomy, we have created a detailed yet approachable anatomic reference for clinicians. We review gross and structural features of the spinal cord, its coverings, and nerves while also discussing spinal cord development, microscopic organization, and common anatomic variants. We detail how this anatomy appears on current neuroimaging techniques, with special attention to MR imaging.

Inhaled Gold Nano-star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to Lung Metastases: Development and Validation in a Small Animal Model.

Pulmonary metastases pose significant treatment challenges for many cancers, including triple-negative breast cancer (TNBC). We developed and tested a novel suicide gene and therapeutic microRNAs (miRs) combination therapy against lung metastases in vivo in mouse models after intranasal delivery using nontoxic gold nanoparticles (AuNPs) formulated to carry these molecular therapeutics. We used AuNPs coated with chitosan-ß-cyclodextrin (CS-CD) and functionalized with a urokinase plasminogen activator (uPA) peptide to carry triple cancer suicide genes (thymidine kinase-p53-nitroreductase: TK-p53-NTR) plus therapeutic miRNAs (antimiR-21, antimiR-10b and miR-100). We synthesized three AuNPs: 20nm nanodots (AuND), and 20nm or 50nm nanostars (AuNS), then surface coated these with CS-CD using a microfluidic-optimized method. We sequentially coated the resulting positively charged AuNP-CS-CD core with synthetic miRNAs followed by TK-p53-NTR via electrostatic interactions, and added uPA peptide through CD-adamantane host-guest chemistry. A comparison of transfection efficiencies for different AuNPs showed that the 50nm AuNS allowed ∼4.16-fold higher gene transfection than other NPs. The intranasal delivery of uPA-AuNS-TK-p53-NTR-microRNAs NPs (pAuNS@TK-p53-NTR-miRs) in mice predominantly accumulated in lungs and facilitated ganciclovir and CB1954 prodrug-mediated gene therapy against TNBC lung metastases. This new nanosystem may serve as an adaptable-across-cancer-type, facile, and clinically scalable platform to allow future inhalational suicide gene-miR combination therapy for patients harboring pulmonary metastases.

A rationally identified panel of microRNAs targets multiple oncogenic pathways to enhance chemotherapeutic effects in glioblastoma models.

Glioblastoma (GBM) is the most common malignant brain tumor. Available treatments have limited success because most patients develop chemoresistance. Alternative strategies are required to improve anticancer effects of current chemotherapeutics while limiting resistance. Successful targeting of microRNAs (miRNAs) as regulators of gene expression can help reprogram GBM cells to better respond to chemotherapy. We aimed to identify a panel of miRNAs that target multiple oncogenic pathways to improve GBM therapy. We first identified differentially expressed miRNAs and tested if their target genes play central roles in GBM signaling pathways by analyzing data in the Gene Expression Omnibus and The Cancer Genome Atlas databases. We then studied the effects of different combinations of these miRNAs in GBM cells by delivering synthetic miRNAs using clinically compatible PLGA-PEG nanoparticles prior to treatment with temozolomide (TMZ) or doxorubicin (DOX). The successful miRNA panel was tested in mice bearing U87-MG cells co-treated with TMZ. We identified a panel of five miRNAs (miRNA-138, miRNA-139, miRNA-218, miRNA-490, and miRNA-21) and their oncogenic targets (CDK6, ZEB1, STAT3, TGIF2, and SMAD7) that cover four different signaling pathways (cell proliferation and apoptotic signaling, invasion and metastasis, cytokine signaling, and stemness) in GBM. We observed significant in vitro and in vivo enhancement of therapeutic efficiency of TMZ and DOX in GBM models. The proposed combination therapy using rationally selected miRNAs and chemotherapeutic drugs is effective owing to the ability of this specific miRNA panel to better target multiple genes associated with the hallmarks of cancer.

BRET Sensors for Imaging Membrane Integrity of Microfluidically Generated Extracellular Vesicles.

Extracellular vesicles (EVs) derived from various cell lines have been extensively used as natural nanodelivery vehicles for drug, protein, and nucleic acid deliveries in therapeutic applications for cancer. Recently, we developed a microfluidic-based reconstruction strategy as a novel method to generate microRNA-loaded membrane vesicles for cancer therapy in vivo. We used EVs and cell membranes isolated from different source of cells for this reconstruction process. The microfluidic system produced reconstructed vesicles of uniform sizes with high microRNA loading efficiency independent of input membrane sources (EVs or cell membranes). To address the functional integrity of the membrane structure and of proteins in the reconstructed EVs, we introduce a membrane-insertable bioluminescence resonance energy transfer (BRET) sensor system. This sensor, with its membrane-insertable palmitoylation signal peptide sequence derived from a growth-associated protein 43 (GAP43), helps in trafficking the fusion protein to the cell membrane upon its expression in cells and allows for imaging reconstructed membrane vesicles using optical imaging. In this chapter, we detail the stepwise methods used for the engineering of cells using this sensor, isolation of EVs from the engineered cells, preparation of reconstructed EVs by microfluidic processing, and BRET imaging of reconstructed EVs for membrane integrity evaluation.

Anatomy of the Calvaria and Skull Base.

A thorough understanding of the skull anatomy is of key importance to radiologists as well as specialist physicians and surgeons. We describe the anatomy of the neurocranium comprising calvaria (the skull vault) and the skull base and discuss the most common and clinically relevant anatomic variants.