Faculty Bibliography

Vitiligo is an acquired condition that affects about 1% of the world's population and is defined by macular depigmentation of the skin that develops following melanocyte death. Vitiligo has a significant impact on both the physical and mental health of patients. While autoimmune-mediated destruction of melanocytes ultimately leads to depigmentation, the mechanisms that promote vitiligo onset remain poorly defined. We have been investigating the hypothesis that melanocytes from individuals genetically prone to develop vitiligo are less efficient in protecting against cellular traumas such as chemical exposure, which triggers an immune response against them. We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with the topical agent monobenzone (monobenzyl ether of hydroquinone or MBEH). Three key stress response pathways were activated by MBEH exposure: the unfolded protein stress response (UPR), the NRF2-regulated antioxidant response and the nuclear factor-kappa B (NFkappaB) pathway. We established a key role for the UPR and NRF2 pathways in determining melanocyte viability and demonstrated disruption of their activity in melanocytes from individuals who developed vitiligo (VMs). We further showed that the NFkappaB pathway contributes to an increase in expression of IL6 and IL8 following NM exposure to MBEH and that expression of these chemokines is higher in VMs compared to NMs. These chemokines can promote an autoimmune response. We have now used transcriptome analysis to identify additional stress response pathways that are dysfunctional in vitiligo. Our data suggest that multiple signaling pathways that protect cells against trauma and facilitate a return to homeostasis are disrupted in VMs and may cause these cells to be targeted by the immune system

Melanoma, the most lethal form of skin cancer, is rarely curable at its advanced stages. The early events of this disease, during which treatment would be beneficial, remain poorly elucidated. Melanocyte stem cells (McSCs) residing in the hair follicle niche have been proposed to be a cell-of-origin for melanoma. To understand the cellular and molecular mechanisms regulating the initiation and progression of McSC derived melanoma, we have established a novel c-Kit- CreER-driven melanoma mouse model that enabled us to \target McSCs and trace their oncogenic behaviors. Using this model, we showed that oncogenic McSCs first expand in the niche and then migrate to the epidermis to form epidermal melanoma that later invade into the underlying dermis and undergo metastasis. Furthermore, Wnt and Endothelin signals, secreted by epithelial niche cells during hair anagen onset promoted the malignant transformation of McSCs to melanoma. Finally, transcriptional profiling revealed a strong resemblance between murine McSC-derived melanoma and human melanoma in heterogeneity and gene signatures. These results suggest that follicular McSCs can be an origin of melanoma and that follicular niche can control McSC oncogenic transformation. The similarities of McSC derived melanoma with human melanoma in epidermal to dermal progression, heterogeneity and gene expression suggest the potential utilization of this mouse model as a pre-clinical model for human melanoma

The aim of this study was to carry out a case control study comparing the HPV genome in patients with oral cavity squamous cell carcinoma (OC-SCC) to normal patients using metagenomic shotgun sequencing. We recruited 50 OC-SCC cases which were then matched with a control patient by age, gender, race, smoking status and alcohol status. DNA was extracted from oral wash samples from all patients and whole genome shotgun sequencing performed. The raw sequence data was cleaned, reads aligned with the human genome (GRCH38), nonhuman reads identified and then HPV genotypes identified using HPViewer. In the 50 patients with OC-SCC, the most common subsite was tongue in 26 (52%). All patients were treated with primary resection and neck dissection. All but 2 tumors were negative on p16 immunohistochemistry. There were no statistically significant differences between the cases and controls in terms of gender, age, race/ethnicity, alcohol drinking, and cigarette smoking. There was no statistically significant difference between the cancer samples and control samples in the nonhuman DNA reads (medians 4,228,072 vs. 5,719,715, P value = 0.324). HPV was detected in 5 cases (10%) of OC-SCC (genotypes 10, 16, 98) but only 1 tumor sample (genotype 16) yielded a high number of reads to suggest a role in the etiology of OC-SCC. HPV was detected in 4 control patients (genotypes 16, 22, 76, 200) but all had only 1-2 HPV reads per human genome. Genotypes of HPV are rarely found in patients with oral cancer.

Cancer is a major public health problem and the second leading cause of death worldwide. The burden of cancer continues to grow and is projected to double by 2040. This situation calls for coordinated action and emphasizes the need to join efforts on worldwide initiatives, including World Cancer Research Day (WCRD), which aims to create and consolidate a yearly momentum to raise awareness and commitment for research on cancer. Cancer research is a key driver of advances in prevention and therapeutic strategies that will benefit tomorrow's cancer patients. In 2016, 10 international organizations partnered to launch the WCRD initiative. Five years later, a total of 89 organizations and more than half a million people have joined this global movement that helps raise awareness of the importance of cancer research, demonstrating that a collaborative research culture is essential to address current challenges and create opportunities to accelerate impactful cancer research for a better future.

Objective: To investigate the effectiveness of the nose ring drain (NRD) technique combined with Ilizarov circular external fixation in treatment of Gustilo IIIA Pilon fracture.
Method(s): Between March 2017 and December 2019, 17 patients with Gustilo IIIA Pilon fractures were admitted and treated with NRD technique combined with Ilizarov circular external fixation. Among them, there were 11 males and 6 females; the age ranged from 24 to 63 years, with an average of 38.2 years. There were 3 cases of traffic accident injury, 13 cases of falling injury, and 1 case of penetrating injury. There were 13 cases of emergency admittance and 4 cases of wound infection after surgical treatment. Furthermore, there were 2 cases of fibula fractures and 3 cases of lateral malleolus fractures.
Result(s): All patients were followed up 8-12 months, with an average of 9.9 months. All wounds healed by first intention, and 4 patients with preoperative infection had no recurrence during the follow-up. The external fixator was removed after fracture healing in 17 patients at 3-7 months after operation (mean, 4.5 months). At last follow-up, the pain score of the ankle joint Kofoe score was 40-50, with an average of 44; the functional score was 17-27, with an average of 25; the mobility score was 8-18, with an average of 14; and the effectiveness was rated as excellent in 8 cases, good in 7 cases, and poor in 1 case.
Conclusion(s): For Gustilo IIIA Pilon fractures, the NRD technique combined with Ilizarov circular external fixation has advantages of good fracture fixation and drainage effects, which greatly reduces the complications of traditional treatment options and the number of operations

A novel variant of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis on wild-type human codon optimized Spike to introduce the D614G variant. Using multiple human cell lines, including human lung epithelial cells, we found that the lentiviral particles pseudotyped with Spike D614G are more effective at transducing cells than ones pseudotyped with wild-type Spike. The increased transduction with Spike D614G ranged from 1.3 to 2.4-fold in Caco-2 and Calu-3 cells expressing endogenous ACE2, and 1.5 to 7.7-fold in A549^ACE2 and Huh7.5^ACE2 overexpressing ACE2. Furthermore, trans-complementation of SARS-CoV-2 virus with Spike D614G showed an increased infectivity of human cells. Although there is minimal difference in ACE2 receptor binding between the D614 and G614 Spike variants, we show that the G614 variant is more resistant to proteolytic cleavage in human cells, suggesting a possible mechanism for the increased transduction.

SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL_28-A. An in vitro luciferase assay revealed that XL_28-A has no transcriptional activity. XL_28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL_28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.