Faculty Bibliography

BACKGROUND: Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. METHODS AND RESULTS: Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 mug; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. CONCLUSIONS: Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.

Tongue strength is reduced in patients treated with chemoradiotherapy for oral/oropharyngeal cancer. Tongue strengthening protocols have resulted in improved lingual strength and swallowing in healthy individuals, as well as in patients following a neurological event. However, no studies have examined the efficacy of tongue strengthening exercises on tongue strength, swallowing, and quality of life (QOL; Head and Neck Cancer Inventory) in patients treated with chemoradiotherapy. A randomized clinical trial examined the effects of a tongue strengthening programme paired with traditional exercises vs. traditional exercises alone. Dependent variables included tongue strength, swallowing, and QOL in a group of patients with oral and oropharyngeal cancer treated with primary radiotherapy with or without chemotherapy. Differences with regard to tongue strength and oropharyngeal swallow efficiency (OPSE) were not observed within or between groups. QOL in the eating and speech domains improved following treatment in both groups. However, the experimental group demonstrated greater impairment in QOL in the social disruption domain following treatment, whereas the control group demonstrated a slight improvement in functioning. Tongue strengthening did not yield a statistically significant improvement in either tongue strength or swallowing measures in this patient cohort. Patient compliance and treatment timing may be factors underlying these outcomes.

Abstract Background: Lymphedema (LE) is a frequent complication following breast cancer treatment. While progress is being made in the identification of phenotypic risk factors for the development of LE, little information is available on the molecular characterization of LE. The purpose of this study was to determine if variations in pro- and anti-inflammatory cytokine genes were associated with LE following breast cancer treatment. Methods and Results: Breast cancer patients completed a number of self-report questionnaires. LE was evaluated using bioimpedance spectroscopy. Genotyping was done using a custom genotyping array. No differences were found between patients with (n=155) and without LE (n=387) for the majority of the demographic and clinical characteristics. Patients with LE had a significantly higher body mass index, more advanced disease, and a higher number of lymph nodes removed. Genetic associations were identified for three genes (i.e., interleukin (IL4) 4 (rs2227284), IL 10 (rs1518111), and nuclear kappa factor beta 2 (NFKB2 (rs1056890)) associated with inflammatory responses. Conclusions: These genetic associations suggest a role for a number of pro- and anti-inflammatory genes in the development of LE following breast cancer treatment.

BACKGROUND: Cancer pain severely limits function and significantly reduces quality of life. Subtypes of sensory neurons involved in cancer pain and proliferation are not clear. METHODS: We produced a cancer model by inoculating human oral squamous cell carcinoma (SCC) cells into the hind paw of athymic mice. We quantified mechanical and thermal nociception using the paw withdrawal assays. Neurotoxins isolectin B4-saporin (IB4-SAP), or capsaicin was injected intrathecally to selectively ablate IB4(+) neurons or TRPV1(+) neurons, respectively. JNJ-17203212, a TRPV1 antagonist, was also injected intrathecally. TRPV1 protein expression in the spinal cord was quantified with western blot. Paw volume was measured by a plethysmometer and was used as an index for tumor size. Ki-67 immunostaining in mouse paw sections was performed to evaluate cancer proliferation in situ. RESULTS: We showed that mice with SCC exhibited both mechanical and thermal hypersensitivity. Selective ablation of IB4(+) neurons by IB4-SAP decreased mechanical allodynia in mice with SCC. Selective ablation of TRPV1(+) neurons by intrathecal capsaicin injection, or TRPV1 antagonism by JNJ-17203212 in the IB4-SAP treated mice completely reversed SCC-induced thermal hyperalgesia, without affecting mechanical allodynia. Furthermore, TRPV1 protein expression was increased in the spinal cord of SCC mice compared to normal mice. Neither removal of IB4(+) or TRPV1(+) neurons affected SCC proliferation. CONCLUSIONS: We show in a mouse model that IB4(+) neurons play an important role in cancer-induced mechanical allodynia, while TRPV1 mediates cancer-induced thermal hyperalgesia. Characterization of the sensory fiber subtypes responsible for cancer pain could lead to the development of targeted therapeutics.

The global burden of cancer pain is enormous and opioids, despite their side effects, remain the primary therapeutic approach. The cause of cancer pain is unknown. Mechanisms driving cancer pain differ from those mechanisms responsible for inflammatory and neuropathic pain. The prevailing hypothesis put forward to explain cancer pain posits that cancers generate and secrete mediators which sensitize and activate primary afferent nociceptors in the cancer microenvironment. Moreover, cancers induce neurochemical reorganization of the spinal cord, which contributes to spontaneous activity and enhanced responsiveness. The purpose of this review, which covers clinical and preclinical studies, is to highlight those peripheral and central mechanisms responsible for cancer pain. The challenges facing neuroscientists and clinicians studying and ultimately treating cancer pain are discussed.

Modern cleft surgery requires four-dimensional and functional anatomic understanding of the cleft (and noncleft) lip, nose, and alveolus. Some techniques for nasolabial repair rely more on precise anatomic geometry, whereas others afford the surgeon a more flexible design. Consistent anthropometry enables accurate assessment and reporting of long-term outcomes; such reports are needed to guide perioperative care, delineate optimal repair principles, and resolve ongoing controversies.

We report a case of lipoblastoma of the hand in a 19-month-old female patient with a history of cleft palate. The incidence of lipoblastoma and cleft palate individually is extremely rare. To the best of our knowledge, only 1 other case of a patient with both cleft palate and lipoblastoma exists in the literature. Lipoblastoma is a rare benign neoplasm in adipose tissue almost exclusively found in children younger than 3 years. Cytogenetic testing has shown that lipoblastomas characteristically share a clonal chromosomal rearrangement affecting the long arm of chromosome 8. Furthermore, recent research has shown that the 8q chromosome is an important genetic risk factor for cleft palate development. We describe the second case linking cleft palate with this rare tumor and provide evidence for a potential genetic association.

BACKGROUND: Beauty lies in the eyes of the beholder, but influenced by the individual's geographic, ethnic, and demographic background and characteristics. In plastic surgery, objective measurements are used as a foundation for aesthetic evaluations. This study assumes interdependence between variables such as country of residence, sex, age, occupation, and aesthetic perception. METHODS: Computerized images of a model's face were generated with the ability to alter nasal characteristics and the projection of the lips and chin. A survey containing these modifiable images was sent to more than 13,000 plastic surgeons and laypeople in 50 different countries, who were able to virtually create a face that they felt to be the aesthetically "ideal" and most pleasing. Demographic information about the interviewees was obtained. RESULTS: Values of various aesthetic parameters of the nose were described along with their relationship to geography, demography, and occupation of the respondents. Interregional and ethnic comparison revealed that variables of country of residence, ethnicity, occupation (general public vs surgeon), and sex correlate along a 3-way dimension with the ideal projection of the lips and the chin. Significant interaction effects were found between variables of country of residence or ethnicity with occupation and sex of the respondents. CONCLUSIONS: What are considered the "ideal" aesthetics of the face are highly dependent on the individual's cultural and ethnic background and cannot simply and solely be defined by numeric values and divine proportions. As confirmed with this study, ethnic, demographic, and occupational factors impact peoples' perception of beauty significantly.