Faculty Bibliography

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK₁R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK₁R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK₁R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK₁R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

OBJECTIVE. Masculinizing genital surgeries for transgender individuals are currently performed at only a select few centers; however, radiologists in any geographic region may be confronted with imaging studies of transgender patients. The imaging findings of internal and external genital anatomy of a transgender patient may differ substantially from the imaging findings of a cisgender patient. This article provides the surgical and anatomic basis to allow appropriate interpretation of preoperative and postoperative imaging findings. We also expand on the most common complications and associated imaging findings. CONCLUSION. As these procedures become more commonplace, radiologists will have a growing role in the care of transgender patients and will be faced with new anatomic variants and differential diagnoses. Familiarity with these anatomic variations and postoperative complications is crucial for the radiologist to provide an accurate and useful report.

Janus kinase (JAK2)V617F is the most common mutation found in patients with Philadelphia chromosome negative myeloproliferative neoplasms (Ph- MPNs). The discovery of this mutation over 15 years ago revolutionised MPN diagnosis and inspired the development of JAK inhibitors as new therapeutic interventions. However, despite extensive structural and biophysical studies using JAK2 domains in isolation, the exact molecular mechanisms of JAK2XX activation remains elusive. We have previously demonstrated that expression of the thrombopoietin (TPO) receptor, MPL, which interacts directly with JAK2, is essential for disease development in a mouse model of a JAK2XX-positiveMPN (Blood 2014 124:3956-3963). Using total internal reflection fluorescence (TIRF) microscopy, we visualized MPL interaction dynamics in live cells on single molecule level. Effective cell surface MPL fluorescence labelling and dual-color imaging allowed us to determine the level of MPL dimerization under various experimental conditions. Using this assay, we clearly established that MPL is monomeric at physiologically relevant receptor densities. However, TPO stimulation results in significant dimerization of MPL (>50%) and an equilibrium between monomers and dimers. This counters the current dogma that MPL exists at the membrane as a pre-formed dimer. Strikingly, we found that JAK2XX shifts this monomer-dimer equilibrium leading to significant TPO-independent MPL dimerization providing a novel mechanistic model of oncogenic JAK2 activation. To highlight the role of ligand-independent receptor dimerization in JAK2 activation, we compared three groups of autoactivating mutations in the PK domain covering the FERM-SH2 (FS2)-PK linker region (Group I), residues in the proximity of the alphaC helix (Group II) and at the autoinhibitory PK-TK interface (Group III). Consistent MPL dimerization was only observed for mutations in groups I and II. Mutations in these groups both localize to a potential homomeric PK/PK interface that has been implicated as a switch of JAK activation. Using MD simulations, we also found that the FERM domain of JAK2 strongly interacts with the inner leaflet of the lipid bilayer of the plasma membrane via a single hydrophobic residue (L224) surrounded by several positively charged residues that allows the region to act as a membrane anchor. This tight coupling to the membrane enforces an appropriate orientation between the JAKs within the receptor dimers required for optimal intermolecular PK/PK interaction that is critical for receptor dimerization. To interfere with membrane anchoring, we introduced a negative charge in this position (L224E). Strikingly, ligand-independent MPL dimerization and activation by JAK2XX was dramatically reduced upon introducing L224E, supporting the vital importance of L224 for orienting JAK2 at the membrane to allow productive PK-PK interactions. Here, we demonstrate that JAK2XX mutation acts by altering and strengthening the intermolecular interactions involving the PK/PK dimerization interface. In essence, these mutations drive cytoplasmic stabilization of receptor-JAK dimers, bypassing extracellular stabilization of dimers via cytokine binding. These results provide critical and entirely novel mechanistic insights into signal initiation in MPNs and readdress the roles of receptor-associated proteins. Disclosures: Hubbard: Ajax Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder.XXCopyright

BACKGROUND:Surgical fixation of implants into bone for the correction of bone deformities or defects is a traditional approach for skeletal stabilization. Important measures of efficacy of implants include implant stability and osseointegration-the direct interaction between living bone and an implant. Osseointegration depends on successful implant placement and subsequent bone remodeling. This study utilized osseodensification drilling (OD) in a low bone density model using trabecular metal (TM) implants. MATERIAL AND METHODS/METHODS:Three osteotomy sites, Regular, OD-CW (clockwise), and OD-CCW (counterclockwise), were prepared in each ilium of three female sheep. Drilling was performed at 1100rpm with saline irrigation. Trabecular metal (TM) (Zimmer, Parsippany, NJ, USA) implants measuring 3.7mm in diameter x 10mm length were placed into respective osteotomies. A three-week period post-surgery was given to allow for healing to take place after which all three sheep were euthanized and the ilia were collected. Samples were prepared, qualitatively and quantitatively analyzed using histology micrographs and image analysis software (ImageJ, NIH, Bethesda, MD). Bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) were quantified to evaluate the osseointegration parameters. RESULTS:All implants exhibit successful bone formation in the peri-implant environment as well as within the open spaces of the trabecular network. Osseointegration within the TM (quantified by %BIC) as a function of drilling technique was more pronounced in OD samples(p>0.05). The %BAFO however shows a significant difference (p=0.036) between the CCW and R samples. Greater bone volume and frequency of bone chips are observed in OD samples. CONCLUSION/CONCLUSIONS:The utilization of OD as a design for improved fixation of hardware was supported by increased levels of stability, both primary and secondary. Histological data with OD provided notably different results from those of the regular drilling method.

Facial transplantation has gained increasing acceptance as a treatment option to improve quality of life (QoL) for persons suffering from severe facial disfigurement. Despite its growth, the field has yet to establish a consistent approach to assessing QoL in face transplant candidates and recipients that includes integration of meaningful patient-reported outcomes. The published literature suggests that face transplant programs currently use a wide variety of assessment tools and strategies. Moreover, confusion remains as to how best to weigh patients' lived experiences and incorporate them into QoL assessments. Qualitative research can illuminate the dimensions of QoL that are meaningful to face transplant candidates and recipients. Coupled with collaboration and data sharing across face transplant programs, qualitative research will help to bring conceptual clarity and transparency to the assessment process.

The "Wide Awake Local Anesthesia No Tourniquet" (WALANT) technique is gaining popularity in hand surgery owing to its benefits of reduced cost, shorter hospital stay, improved safety, and the ability to perform active intraoperative examinations. The aim of this study is to analyze the cost savings and efficiency of performing A1 pulley release for treatment of trigger finger using the WALANT technique in a major city hospital procedure room (PR) as compared with the standard tourniquet, operating room (OR) approach.

BACKGROUND:From infancy to adulthood, the mandible develops increased ramus height, prominence of the chin, and laterally widened gonial angles. In Crouzon and Apert syndromes, both relative retrognathia and prognathic jaws have been reported. Growth is influenced by a variety of factors, including the growth and relative position of the skull base, functional coordination, and the spatial influence of the laryngopharynx. Thus, this study aimed to explore in detail the evolution of the mandible in both syndromes and its relationship with the entire facial structure and skull base. METHODS:One hundred twenty-three preoperative computed tomographic scans (Crouzon, n = 36; Apert, n = 33; control, n = 54) were included and divided into 5 age subgroups. Computed tomographic scans were measured using Materialise software. Cephalometrics relating to the mandible, facial structures, and cranial base were collected. Statistical analyses were performed using t test and statistical power analysis. RESULTS:In Crouzon syndrome, the angle between the cranial base and gnathion was increased prior to 6 months of age by 10.29 degrees (P < 0.001) and by adulthood to 11.95 degrees (P = 0.003) compared with normal. After 6 months of age, the distance between bilateral mandibular condylions (COR-COL) was narrower by 15% (P < 0.001) in Crouzon syndrome compared with control subjects. Before 6 months of age, Apert COR-COL decreased 16% (P < 0.001) compared with control subjects and 13% (P = 0.006) narrower than Crouzon. During 2 to 6 years of age, Apert mandibular ramus height caught up to, and became longer than, Crouzon by 12% (P = 0.011). The nasion-sella-articulare angle of the Apert skull was 5.04 degrees (P < 0.001) less than Crouzon overall. CONCLUSIONS:In Crouzon syndrome, the changes of the spatial relationship of the mandible to the cranial base develop earlier than the mandibular shape deformity, whereas in Apert syndrome, the spatial and morphological changes are synchronous. The morphological changes of the mandible are disproportional in 3 directions, initially significant shortening of the mandibular width and length, and, subsequently, reduced height. Crouzon has more shortening in mandibular height compared with Apert, reflecting the more shortened posterior cranial base length. The narrowed angle between the mandible and the posterior cranial base in Apert skulls is consistent with the more limited nasopharyngeal and oropharyngeal airway space.

BACKGROUND:Based on an established classification system of Apert syndrome subtypes, detailed regional morphology and volume analysis may be useful to provide additional clarification to individual Apert cranial structure characteristics, and treatment planning. METHODS:Computed tomography scans of 32 unoperated Apert syndrome and 50 controls were included and subgrouped as: type I, bilateral coronal synostosis; type II, pansynostosis; type III, perpendicular combination synostosis. Three-dimensional analysis of craniometric points was used to define structural components using Materialise Mimics and 3-Matics software. RESULTS:Occipitofrontal circumference of all subtypes of Apert syndrome patients is normal. Intracranial volumes of types I and II were normal, but type III was 20% greater than controls. Middle cranial fossa volume was increased in all 3 types, with the greatest increase in type II (86%). Type II developed a 69% increase in anterior cranial fossa volume, whereas type III had 39% greater posterior cranial fossa volume. Increased cranial fossa depth contributed most to above increased volume. The anteroposterior lengths of middle and posterior cranial fossae were reduced in type I (15% and 17%, respectively). However, only the anterior cranial fossa was significantly shortened in type III. CONCLUSIONS:Occipitofrontal circumference and overall intracranial volume is not always consistent in individual subunits of Apert syndrome. Detailed and segmental anterior, middle, and posterior cranial fossae volumes and morphology should be analyzed to see what impact this may have related to surgical planning.

Face transplantation has evolved into a viable reconstructive option for patients with extensive facial disfigurement. Because the first face transplant procedure was described in 2005, the safety and feasibility of the procedure have been validated, and the focus of the field has shifted toward refining functional and esthetic outcomes. Recovery of muscle function following facial transplantation is critical to achieving optimal facial function and restoring facial expression. Assessment of facial muscle function in face transplant recipients has traditionally relied on clinical evaluation. In this study, we describe longitudinal changes in facial muscle volumes captured through quantitative magnetic resonance imaging in a face transplant recipient and compare these findings with functional outcomes evaluated through clinical assessment.