Citations

We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53. However, patient-matched germline DNA was not sequenced which is critical for identification of true somatic mutations. Furthermore, the FoundationOne panel doesn't measure genomic rearrangements which have been shown to be abundant in sarcomas and are associated with sarcoma tumorigenesis and progression. In the current study, we carried out comprehensive genomic sequencing of the tumor, adjacent normal tissues, and patient-matched blood, in an effort to understand the genomic makeup of this rare extranodal FDCS and to identify potential therapeutic targets. Eighty-one somatic point mutations were identified in tumor but not in adjacent normal tissues or blood. A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes. The fusion gene HDGFRP3→SHC4 led to a 200-fold increase in the expression of oncogene SHC4 which is a potential target of the commercial drug Dasatinib. Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.

Cumulative evidence demonstrates that most RNAs exhibit specific subcellular distribution. However, the mechanisms regulating this phenomenon and its functional consequences are still under investigation. Here, we reveal that cadherin complexes at the apical zonula adherens (ZA) of epithelial adherens junctions recruit the core components of the RNA-induced silencing complex (RISC) Ago2, GW182, and PABPC1, as well as a set of 522 messenger RNAs (mRNAs) and 28 mature microRNAs (miRNAs or miRs), via PLEKHA7. Top canonical pathways represented by these mRNAs include Wnt/β-catenin, TGF-β, and stem cell signaling. We specifically demonstrate the presence and silencing of MYC, JUN, and SOX2 mRNAs by miR-24 and miR-200c at the ZA. PLEKHA7 knockdown dissociates RISC from the ZA, decreases loading of the ZA-associated mRNAs and miRNAs to Ago2, and results in a corresponding increase of MYC, JUN, and SOX2 protein expression. The present work reveals a mechanism that directly links junction integrity to the silencing of a set of mRNAs that critically affect epithelial homeostasis.

Abstract Training adult learners to use ultrasound in clinical practice relies on the ability of the learner to apply visuospatial concepts to the anatomy of the human body. We describe a visuospatial trainer that replicates the housing of an ultrasound transducer, through which a linear laser projects light in the same plane and orientation as the ultrasonic sound waves. We use this trainer in combination with a porcine heart dissection laboratory to teach bedside cardiac ultrasound and transthoracic echocardiography (TTE). Off-the-shelf components, including an on/off switch, a laser, and 2 ampere batteries are connected in series and placed inside the 3-dimensional (3D)–printed housing. The trainer's laser emission projects a red line that visually represents the ultrasound's field. Learners project the laser against a porcine or human heart in the orientation of the TTE window they wish to obtain and then dissect the heart in that plane, allowing for visualization of how grayscale images are obtained from 3D structures. Previous research has demonstrated that visuospatial aptitude is correlated with ultrasound procedural performance. We present this trainer and educational method as a specific training intervention that could enhance the visuospatial ability of the ultrasound learner. This visuospatial trainer and educational method present a novel process for enhancing learner understanding of 2-dimensional ultrasound images as they relate to 3D structures. Having a clear understanding of how images are generated in cross section may translate into more proficient adaptation of cardiac ultrasound and TTE.

AbstractThe treatment of peripheral nerve injuries remains a major problem worldwide despite the availability of a number of Food and Drug Administration (FDA) approved devices which fail to match the efficacy of autografts. Different strategies are used to improve regeneration and functional recovery using biomaterial nerve conduits. However, there is little investigation of the transcriptomic and proteomic changes which occur as a result of these interventions, particularly regarding transection injuries. This study explores differences between autograft‐mediated repair and conduit‐material‐mediated repair of peripheral nerve injuries to understand fundamental differences in their repair mechanisms at the proteomics level at the proximal, middle, and distal components in the early stages of repair. Pathway analysis demonstrates that each material selectively activates different regenerative pathways and alters different biological functions spatially throughout the biomaterial conduits. The analysis highlights some of the deficiencies in conduit‐mediated repair in comparison to autograft (e.g., recycling of myelin and cholesterol, reduction in reactive oxygen species, and higher expression of regenerative proteins). These findings thus suggest that by supplementing the expression of these proteins on the biomaterial of choice, this study can potentially attain regeneration equivalent to autograft. This approach paves the way for incorporating future biomaterial‐specific functionalities in nerve guidance conduits.

Objective Olfactory preservation after resection of esthesioneuroblastoma (ENB) has been reported, however, the ability to predict tumor involvement of the olfactory system is critical to this surgical strategy. This study aims to answer the question: Can a surgeon predict, based on preoperative imaging, whether there is unilateral involvement of the olfactory system allowing for safe attempt of olfactory preservation? Methods This is a retrospective review of post-resection ENB meeting inclusion criteria of having bilateral olfactory tracts and bulbs submitted at the time of primary resection for pathologic margins. Five board-certified skull base surgeons blinded to the pathology individually reviewed the preoperative MRI scans to predict degree of tumor involvement. Results Olfactory bulb involvement occurred in both bulbs in 35% of cases and unilateral in 39% of cases, and there was no involvement in 26% of cases sampled. When comparing physician prediction of involved tracts or bulbs, involvement was appropriate or over-called (i.e., called positive when pathology was in fact negative) in 96% of cases. Conclusion This study demonstrates unilateral or no pathologic olfactory involvement of the olfactory system in 65% of cases. Our ability to predict this involvement, which may allow for a management strategy that attempts to preserve olfactory function, was accurate at 96%. Therefore, interpretation of imaging and proceeding with smell preservation in ENB appears reasonable in this cohort.Level of Evidence: Level 2b.

Pulmonary toxoplasmosis is a serious pulmonary condition caused by the protozoan Toxoplasma gondii. It typically affects immunocompromised patients presenting acutely with cough, fever, myalgias, arthralgias and lymphadenopathy, and chronically with persistent cough and dyspnoea. Because of its protean features, it can mimic many more common lung conditions in the immunocompromised patient, including atypical pneumonia, Pneumocystis pneumonia and interstitial lung disease. In this article, we present the case of a 55-year-old woman who presented to our hospital with persistent dyspnoea and cough, initially suspected to have an arthritis-related interstitial lung disease. She received a final diagnosis of pulmonary toxoplasmosis after lung biopsy demonstrated Toxoplasma cysts, later confirmed by serology. Treatment with trimethoprim–sulfamethoxazole resulted in significant improvement of her respiratory symptoms after 3 months.

AbstractIntroductionTakotsubo syndrome (TTS), also known as Takotsubo cardiomyopathy or stress‐induced cardiomyopathy, has been described following a variety of surgeries and disease states. The relationship between intra‐operative anesthesia management and the development of this syndrome has never been fully elucidated.ObjectivesThe primary objective of this study was to determine the relationship of multiple intra‐operative factors on the pathogenesis of TTS.MethodsA single‐center retrospective review of all liver transplants performed at Mayo Clinic Florida from January 2005 to December 2014. Patients developing left ventricular dilation and a concomitant decrease in ejection fraction, a negative cardiac catheterization, or stress test within 30 days of transplantation were identified. Cases were matched 2:1 to controls with respect to MELD, age, sex, and indication for transplantation. Our evaluation included liver graft characteristics, intra‐operative medications, and intra‐operative hemodynamic measurements.ResultsWe identified 24 cases of TTS from a pool of 1752 transplants, for an incidence of 1.4%. No statistically significant differences in intra‐operative measures between the two groups were identified (all P ≥ .08).ConclusionOur exploratory, single‐center retrospective review evaluating 46 intra‐operative characteristics found no association with the development of TTS.