Histoplasty Modification of the Tumor Microenvironment in a Murine Preclinical Model of Breast Cancer.

PURPOSE: To develop a noninvasive therapeutic approach able to alter the biophysical organization and physiology of the extracellular matrix (ECM) in breast cancer. MATERIALS AND METHODS: In a 4T1 murine model of breast cancer, histoplasty treatment with a proprietary 700-kHz multielement therapy transducer using a coaxially aligned ultrasound (US) imaging probe was used to target the center of an ex vivo tumor and deliver subablative acoustic energy. Tumor collagen morphology was qualitatively evaluated before and after histoplasty with second harmonic generation. Separately, mice bearing bilateral 4T1 tumors (n = 4; total tumors = 8) were intravenously injected with liposomal doxorubicin. The right flank tumor was histoplasty-treated, and tumors were fluorescently imaged to detect doxorubicin uptake after histoplasty treatment. Next, 4T1 tumor-bearing mice were randomized into 2 treatment groups (sham vs histoplasty, n = 3 per group). Forty-eight hours after sham/histoplasty treatment, tumors were harvested and analyzed using flow cytometry. RESULTS: Histoplasty significantly increased (P = .002) liposomal doxorubicin diffusion into 4T1 tumors compared with untreated tumors (2.12- vs 1.66-fold increase over control). Flow cytometry on histoplasty-treated tumors (n = 3) demonstrated a significant increase in tumor macrophage frequency (42% of CD45 vs 33%; P = .022) and a significant decrease in myeloid-derived suppressive cell frequency (7.1% of CD45 vs 10.3%; P = .044). Histoplasty-treated tumors demonstrated increased CD8+ (5.1% of CD45 vs 3.1%; P = .117) and CD4+ (14.1% of CD45 vs 11.8%; P = .075) T-cell frequency. CONCLUSIONS: Histoplasty is a nonablative focused US approach to noninvasively modify the tumor ECM, increase chemotherapeutic uptake, and alter the tumor immune microenvironment.

Increased expression of SLC25A1/CIC causes an autistic-like phenotype with altered neuron morphology.

N ε-lysine acetylation within the lumen of the endoplasmic reticulum is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the endoplasmic reticulum acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter and ATP citrate lyase, which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder, suggesting that aberrant cytosolic-to-endoplasmic reticulum flux of acetyl-CoA can be a mechanistic driver for the development of autism spectrum disorder. We therefore generated a SLC25A1 neuron transgenic mouse with overexpression specifically in the forebrain neurons. The mice displayed autistic-like behaviours with a jumping stereotypy. They exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia and altered synaptic plasticity and morphology. Finally, quantitative proteomic and acetyl-proteomic analyses revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosolic-to-endoplasmic reticulum acetyl-CoA flux and the development of an autistic-like phenotype.

Clinical translational neuroimaging of the antioxidant effect of N-acetylcysteine on neural microstructure.

PURPOSE: Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N-acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. METHODS: Male and female Disc1 svΔ2 rats and age-matched, sex-matched Sprague-Dawley wild-type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region-specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early-life stress to test how gene-environment interactions might alter effectiveness of NAC therapy. RESULTS: The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early-life, sex-specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early-life stress reduced the ability of NAC to restore microstructural deficits. CONCLUSION: These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.

Recurrent natural killer/T-cell lymphoma of the lacrimal sac and nasolacrimal duct in a 59-year-old Caucasian woman.

A 59-year-old Caucasian woman with past medical history significant for Natural Killer (NK)/T-cell lymphoma of the right nasal septum in remission for nine months presented after surveillance PET-CT imaging revealed increased metabolic activity in the right nasolacrimal duct. She also reported ipsilateral epiphora starting around this time. The lacrimal sac and nasolacrimal ductal mucosa were biopsied via an external approach. Pathologic evaluation revealed a proliferation of lymphoid cells with necrotic tissue. Immunohistochemical staining demonstrated predominantly CD3+, EBER+, and CD56+ cells indicating recurrent NK/T-cell lymphoma. This case describes an unusual presentation of recurrent NK/T-cell lymphoma involving the lacrimal excretory system in a Caucasian adult. Recurrent malignancy should be considered in the differential of any patient with a history of a lymphoproliferative disorder near the lacrimal drainage system who presents with new onset epiphora.

PHACE syndrome and congenitally absent thyroid gland at MR imaging.

PHACE syndrome is a rare neurocutaneous disorder characterized by posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, and abnormalities of the eye. Thyroid disorders associated with PHACE syndrome have been described, although there are limited reports of this rare occurrence. We report a case of PHACE syndrome with congenital hypothyroidism in an infant, for which absent thyroid gland was diagnosed at magnetic resonance imaging.

Disruption of Radiologist Workflow.

The effect of disruptions has been studied extensively in surgery and emergency medicine, and a number of solutions-such as preoperative checklists-have been implemented to enforce the integrity of critical safety-related workflows. Disruptions of the highly complex and cognitively demanding workflow of modern clinical radiology have only recently attracted attention as a potential safety hazard. In this article, we describe the variety of disruptions that arise in the reading room environment, review approaches that other specialties have taken to mitigate workflow disruption, and suggest possible solutions for workflow improvement in radiology.

Template-driven computed tomography radiation dose reporting: implementation of a radiology housestaff quality improvement project.

RATIONALE AND OBJECTIVES: Radiation exposure from medical imaging has received increasing attention in recent years. Ongoing calls to report radiation doses received during radiology studies as a means of recording cumulative exposure and identifying rare over-exposures have culminated in the State of California passing a mandatory reporting requirement effective July 1, 2012. Herein we describe a radiology housestaff-led quality improvement project to track radiation dose reporting a full year prior to state reporting mandates using a template-driven reporting system and our results over the first 12 months of its implementation. MATERIALS AND METHODS: Effective July 2011, all radiology trainees were instructed to use a standard computed tomography (CT) report template that included a CT dose measurement derived from dose information routinely displayed on our picture archiving and communication system. Consecutive reports from July 1, 2011, to June 30, 2012, of patients who underwent CT examinations at our institution were then retrospectively reviewed. Compliance of each study with the reporting requirement was assessed based on the presence or absence of a radiation dose statement within the finalized report. RESULTS: A total of 36,217 eligible consecutive CT reports were identified within the review period. Of these, 91.9% reported the radiation dose for the examination, greatly exceeding the initial goal of 80% compliance with the dose reporting requirement. CONCLUSION: Successful reporting of CT radiation doses resulted from template-driven reporting, readily accessible calculation tools to facilitate dose calculation, and minimization of reporting burden on the radiologist a full year prior to state regulatory mandates.

Heterogeneous 18F-FDG uptake in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) describes an infection of the upper aerodigestive tract by the human papilloma virus most commonly affecting the larynx with rare lung involvement in 1%-2% of affected patients. We describe an unusual case of a 28-year-old male patient with a longstanding history of RRP where a whole-body PET/CT obtained for disease staging revealed multiple cavitary pulmonary nodules in addition to the more typical tracheobronchial papillomas. In the case described herein, we report heterogeneous uptake of 18F-FDG among these RRP lesions, suggesting significant unexpected variability in the underlying metabolic behavior of these lesions.

Incidental aortic valve calcification on CT scans: significance for bicuspid and tricuspid valve disease.

RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the role of incidental aortic valve calcification on routine computed tomographic scans as a marker for stenosis, as assessed by echocardiography, in patients with bicuspid aortic valve (BAV) and tricuspid aortic valve. MATERIALS AND METHODS: Computed tomographic and echocardiographic studies were retrospectively reviewed for 182 consecutive, unselected patients and 426 patients identified by a record search for "aortic valve calcification." Location and severity of valve calcification were correlated with aortic valve morphology and stenosis. Differences between subgroups were assessed using χ(2) or Fisher's exact tests. RESULTS: In unselected patients, calcification was present in 25.8% with tricuspid aortic valves (46 of 178) and 75% (three of four) with BAV. In patients selected for valve calcification, the average age of those with tricuspid aortic valves (n = 395) was 14.3 years older than those with BAV (n = 31). Patients with BAV were more likely to have severe calcification (87% vs 50%, P < .001), and if severe calcification was present, it was more likely to involve only the valve leaflets (41% vs 9%, P < .001) and result in aortic stenosis (85% vs 58%, P = .006). Patients aged < 60 years with severe calcification were more likely to have BAV (56% vs 7%; odds ratio, 7.9; 95% confidence interval, 3.4-18.7). CONCLUSIONS: Aortic valve calcification was found 14 years earlier in patients with BAV and was more severe and strongly linked to aortic stenosis. Valve calcification on computed tomographic scans should be considered a marker for BAV if found before the seventh decade.

Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis.

Nisin is a posttranslationally modified antimicrobial peptide that is widely used as a food preservative. It contains five cyclic thioethers of varying sizes that are installed by a single enzyme, NisC. Reported here are the in vitro reconstitution of the cyclization process and the x-ray crystal structure of the NisC enzyme. The structure reveals similarities in fold and substrate activation with mammalian farnesyl transferases, suggesting that human homologs of NisC posttranslationally modify a cysteine of a protein substrate.