Faculty Bibliography

The mechanical properties of living tissues have a significant impact on cell differentiation, but remain unexplored in the context of myelin formation and repair. In the PNS, the extracellular matrix (ECM) incorporates a basal lamina significantly denser than the loosely organized CNS matrix. Inhibition of non-muscle myosin II (NMII) enhances central but impairs peripheral myelination and NMII has been implicated in cellular responses to changes in the elasticity of the ECM. To directly evaluate whether mechanotransduction plays a role in glial cell differentiation, we cultured Schwann cells (SC) and oligodendrocytes (OL) on matrices of variable elastic modulus, mimicking either their native environment or conditions found in injured tissue. We found that a rigid, lesion-like matrix inhibited branching and differentiation of OL in NMII-dependent manner. By contrast, SC developed normally in both soft and stiffer matrices. Although SC differentiation was not significantly affected by changes in matrix stiffness alone, we found that expression of Krox-20 was potentiated on rigid matrices at high laminin concentration. These findings are relevant to the design of biomaterials to promote healing and regeneration in both CNS and PNS, via transplantation of glial progenitors or the implantation of tissue scaffolds.

BACKGROUND:Nipple reconstruction is the last stage in cosmetic reconstruction of the breast after mastectomy, but no method produces reliable and consistent aesthetic results. This study examined the use of the Biodesign Nipple Reconstruction Cylinder (NRC) during reconstruction of the nipple after mastectomy. METHODS:Patients with a history of breast cancer and mastectomy desiring nipple reconstruction were invited to participate. After obtaining consent, unilateral or bilateral nipple reconstruction was performed. Skin flaps were raised, the NRC was placed beneath the flaps as a stent, and the site was protected for up to 4 weeks with a nipple shield. Nipple projection was measured for 12 months after surgery. Patient satisfaction was measured and adverse events were recorded. Follow-up examinations were performed at 1 week, and then at 1, 3, 6, and 12 months after surgery. RESULTS:Eighty-two nipple reconstructions were performed in 50 patients. Related postoperative adverse events were minor, but reported in 8 reconstructions (9.8%) representing 7 patients (14.0%). Average projection at 6 and 12 months was 4.1 ± 1.6 mm and 3.8 ± 1.5 mm, respectively, compared with 10.5 ± 2.2 mm 1 week after surgery. Of patients completing the satisfaction questionnaire at 12 months, 70/75 (93.3%) of reconstructions were rated "pleased" or "very pleased" with the overall outcome. Overall, 45/46 (97.8%) patients would recommend nipple reconstruction to other women. CONCLUSIONS:The Biodesign NRC offers a safe alternative to nipple reconstruction, resulting in stable projection and a high level of patient satisfaction for 12 months after placement.

In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). Phosphorylated eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development. Our previous studies showed that the ISR is activated in medulloblastoma in both human patients and animal models, and that the decreased ISR via PERK heterozygous deficiency attenuates medulloblastoma formation in Patched1 heterozygous deficient (Ptch1+/-) mice by enhancing apoptosis of pre-malignant granule cell precursors (GCPs) during cell transformation. We showed here that GADD34 heterozygous mutation moderately enhanced the ISR and noticeably increased the incidence of medulloblastoma in adult Ptch1+/- mice. Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1+/- mice. Intriguingly, GADD34 homozygous mutation significantly enhanced pre-malignant GCP apoptosis in cerebellar hyperplastic lesions and reduced the lesion numbers in young Ptch1+/- mice. Nevertheless, neither GADD34 heterozygous mutation nor GADD34 homozygous mutation had a significant effect on medulloblastoma cells in adult Ptch1+/- mice. Collectively, these data imply the dual role of the ISR, promoting and inhibiting, in medulloblastoma tumorigenesis by regulating apoptosis of pre-malignant GCPs during the course of malignant transformation.

The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.

Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don't efficiently upregulate Skints or activate STAT3. Notably, when epidermal Stat3, Skints, or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.

Oral melanoacanthoma (MA) is a rare, benign pigmented lesion that presents as a painless, rapidly growing, brown-black macular lesion that commonly affects the buccal mucosa in areas that are subject to chronic trauma/irritation.1,2 MA is commonly seen in the third and fourth decades of life and primarily affects blacks with a strong female predilection.3,4 Histopathologically, the lesions exhibit proliferation of keratinocytes and dendritic melanocytes.5 This report includes two cases of oral melanoacanthoma and a review of the literature. Case 1: A 43-year-old black female presented with a slowly enlarging pigmented lesion on the right buccal mucosa. The patient did not recall any known trauma to the area or previous infection and reported that the lesion was painless but had a gradually increased in size. Oral examination revealed a 2.0 x 2.0 cm. brown macule on the right buccal mucosa. A punch biopsy was taken of the pigmented area. The tissue was placed in 10% formalin and submitted for microscopic examination. The tissue was stained with hematoxylin and eosin and exhibited acanthotic, stratified squamous epithelium with dendritic melanocytes dispersed throughout the epithelium consistent with a diagnosis of melanoacanthoma. Case 2: A-35 year-old black female presented with a rapidly growing pigmented lesion on the left buccal mucosa. Two years prior to presentation the patient had noted a brown lesion on the buccal mucosa adjacent to a fractured tooth. The lesion remained unchanged and asymptomatic for approximately two years. One week prior to presentation, the patient noted that the lesion was enlarging, but remained painless. Oral examination revealed a 1.5 x 1.5 cm. brown macule surrounded by erythema on the left buccal mucosa adjacent to a fractured tooth. A punch biopsy was taken that included both the pigmented and erythematous areas. The tissue was placed in 10% formalin and submitted for microscopic examination. The tissue was stained with hematoxylin and eosin and exhibited similar histopathologic features to the previous case. Immunohistochemical staining with S-100 and Melan-A dramatically demonstrated the dendritic melanocytes. Review of the literature revealed a total of 50 cases of oral melanoacanthoma. These lesions were reported in black females on the buccal mucosa with subsequent resolution. The cases here demonstrate similar clinical features and age at presentation to previously reported cases. The pathogenesis of oral MA remains unclear, however, most studies suggest this is a reactive process due to chronic irritation.2 Oral MA may regress following biopsy and no surgical intervention is required due to its selfresolving quality.5

Solitary fibrous tumors (SFTs) are a relatively rare group of mesenchymal neoplasms. Klemperer and Rabin first described a case in the pleura in 1931, but SFTs have also been reported in extrapleural sites, including the oral cavity. SFTs of the oral cavity most commonly affect the buccal mucosa and tongue of female patients in their sixth decade of life. To date, only seven cases of oral SFTs located in the palate (three soft palate, four hard palate) have been documented in the literature. We present a case of a solitary fibrous tumor of the hard palate with review of the literature. A 26-year-old female with a past medical history significant for tuberous sclerosis presented to NYU College of Dentistry reporting a several year history of a painless mass of the hard palate. The mass was biopsied, initially diagnosed as cellular angiofibroma, and referred to the Department of Oral & Maxillofacial Surgery at Bellevue Hospital Center for further management. Examination revealed a 3x3 cm exophytic lesion on the right hard palate extending past the midline. The mass was non-tender to palpation and the mucosa overlying the lesion was intact without evidence of ulceration or necrosis. A CTA of the lesion showed mild prominence of vasculature along the right lateral soft and hard palate, possibly demonstrating supply from the ascending palatine artery. Postoperative surgical histopathology demonstrated a well-circumscribed, non-encapsulated lesion composed of spindle cells with admixed background slit-and-staghorn vessels in a patternless pattern. Immunohistochemical staining was diffusely positive for CD34 and Bcl-2 while negative for SMA, CD31, AE1/AE3, CAM5.2, S-100, EMA and demonstrated low KI-67 immunolabeling. SFTs constitute a heterogeneous group of rare spindlecell tumors that include benign and malignant neoplasms. Their cell of origin remains uncertain since CD34-positive spindle cells are also found in other mesenchymal neoplasms, such as giant cell angiofibromas and hemangiopericytoma, and share similar microscopic, immunohistochemical and biologic features. SFTs are usually well-demarcated and partially encapsulated neoplasms. Microscopically, SFTs show a wide range of morphological characteristics from predominantly fibrous lesions containing alternating fibrous areas and hyalinized thick-walled vessels to more cellular fibrous neoplasms with a "patternless pattern" and thinwalled branching vessels. Immunohistochemically, SFTs usually demonstrate CD34 and CD99, and vimentin positivity with variable Bcl-2, EMA and SMA positivity and are usually negative for CD68, desmin, pan-cytokeratins, and S-100 protein immunoreactivity. Malignant SFTs tend to demonstrate nuclear atypia, hypercellularity, loss of margin integrity, high mitotic rate (>4 per 10 high power fields) and lose CD34 immunoreactivity while overexpressing S-100 and p53. Our patient's lesion demonstrated positivity for only CD34 and Bcl-2, which, along with its aforementioned histological characteristics, was more consistent with the diagnosis of benign SFT than for the original diagnosis of cellular angiofibroma. CT imaging typically demonstrates SFTs as well-circumscribed, hypervascular masses with varying degrees of enhancement, necrosis or cystic change, and may show occasional internal calcification. Our patient's lesion demonstrated mild prominence of vasculature associated with the lesion with no invasion into the adjacent hard palate, consistent with a benign tumor. Due to its rare entity, SFTs are seldom considered in the differential diagnosis for submucosal masses of the oral cavity. However, reports suggest that SFTs may possess malignant characteristics and, thus, should be considered when evaluating well-circumscribed, solid masses in the oral cavity

Poor glycemic control in patients with diabetes mellitus (DM) has long been considered a contraindication for dental implant therapy due to the increased risk of delayed healing, infection, and microvascular/macrovascular complications. Numerous animal and human studies have also suggested poor glycemic control as a contraindication to dental implant therapy. However, recent studies have assessed implant stability over the initial four to six months after implant placement in patients with Type II DM possessingHbA1C levels as high as 12% and reported high rates of implant survival regardless of the patients' level of glycemic control. Although these results are promising, the studies were of a short duration and primarily assessed implant-related outcomes prior to restoration of the implants. In contrast to these studies, the goal of our study was to assess the effects of elevated glycemic levels on post-loaded dental implant survival. We conducted a retrospective review of patients who completed dental implant therapy at a single institution from January 2013 through December 2015. Only patients who received stage I implant placement with delayed loading and documented HbA1C values obtained within 3-months pre- or postoperatively were included in our study. These values reflect the average level of glycemic control over 60-90 days, representing the critical time period for bone metabolism, healing and osseointegration. Additional inclusion criteria included a follow-up assessment of the restored dental implant at least 1-year postimplant placement and at least 6-months post-loading. We defined loading as implants restored with either a single- unit crown, multi-unit fixed partial denture, or a removable overdenture. We defined survival as an implant lacking any signs of clinical mobility or failure of the implant to osseointegrate, pain, infection, or periimplant radiolucency. Our study consisted a total of 42 male patients with 173 implants (83 maxillary, 90 mandibular). HbA1C levels ranged from 5.5 to 12.2%. At the time of implant placement, 27 patients (102 implants) in group 1 had no history of DM(and/or HbA1C<=5.9%), 10 patients (47 implants) in group 2 had well-controlled DM (HbA1C 6-8%) and 5 patients (24 implants) in group 3 had poorly-controlled DM (HbA1C >= 8.1%). There were a total of five implant failures (2.89%), with three implant failures (three patients) in group 1, two implant failures (one patient) in group 2, and zero implant failures in group 3. We found no statistically significant difference in the number of implant failures among the three groups (p = 0.42). We also found no statistically significant difference in the percentage of implant failures among the three groups (p = 0.34). Patients with poorly controlled DM are typically not considered appropriate candidates for dental implant therapy. However, recent studies demonstrate that the effects of hyperglycemia on implant therapy remain uncertain. Although further investigation of longer-termeffects of elevated HbA1C levels is warranted, the results of our study demonstrate favorable outcomes for post-loaded dental implant survival in patients with HbA1C levels as high as 12.2%. The clinical results of our study are consistent with those of previous studies, which reported similar rates of implant survival in patients with Type II DM and elevated HbA1C levels

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants that are utilized to treatmajor depressive disorders and anxiety disorders; SSRIs are the most widely used antidepressants worldwide.3 Past literature on SSRIs have documented that use of SSRIs reduce bone formation thus increasing the risk of bone fracture. Inhibiting the reuptake of 5-HTs results in increased osteoclast differentiation and inhibition of osteoblast proliferation, leading to an overall decrease in bone mass and bone mineral density. 1Recent studies have suggested that use of SSRIs is associated with increased risk of dental implant failure, although other studies involving bone loss and remodeling have reported conflicting results. In addition to SSRIs, proton- proton inhibitors and anti-epileptic drugs have also been implicated in impaired bone remodeling. We conducted a retrospective study on patients who completed dental implant therapy from December 2007 to January 2016 at a single institution. A total of 510 dental implants (167 implants placed in 29 patients using SSRIs) placed in 108 male patients were used to assess the risk associated with the use of SSRI. The data was analyzed with a multivariate analysis and linear regression model. Osseointegration is defined as a direct structural and functional connection between ordered living bone and the surface of a load-carrying implant, that is critical for implant stability.2 In order for implants to be considered successful, they must be fully osseointegrated with the bone and provide function. Implant failure is defined as presenting with one or more of the following: clinical signs of mobility, pain, infection, total loss of implant, radiographic bone loss and/or peri-apical pathology. The results of our study show that in patients taking an SSRI at the time of dental implant therapy, 10 implants failed and 157 were successful (5.99% failure rate), while in those who were not taking an SSRI, 20 implants failed and 323 were successful (5.83% failure rate). We found no association between SSRI and dental implant failure risk (RR = 1.03; 95% confidence interval, 0.4918-2.1443; p = 0.9436). A secondary outcome that was associated with increased failure rate was smoking habits (p = 0.03), which is in agreement with previous studies. Additionally, we did not find a dose-dependent risk of dental implant failure in patients who were taking a low-moderate vs. moderate- high dose of SSRIs (RR = 1.91, 95% confidence interval, 0.4201 -8.6981; p = 0.40) The study assessed the use of proton- pump inhibitors and anti-epileptic drugs in the above patients, demonstrating that there was no associated risk of implant failure (p =0.93; p = 0.84, respectively). Our results conclude that treatment with SSRIs is not associated with an increased failure rate of osseointegration of dental implants, which is not in agreement with previously reported studies. 4