Computer-Aided Discovery of Small Molecule Inhibitors of Thymocyte Selection-Associated High Mobility Group Box Protein (TOX) as Potential Therapeutics for Cutaneous T-Cell Lymphomas.

Cutaneous T-cell lymphomas (CTCL) are the most common primary lymphomas of the skin. We have previously identified thymocyte selection-associated high mobility group (HMG) box protein (TOX) as a promising drug target in CTCL; however, there are currently no small molecules able to directly inhibit TOX. We aimed to address this unmet opportunity by developing anti-TOX therapeutics with the use of computer-aided drug discovery methods. The available NMR-resolved structure of the TOX protein was used to model its DNA-binding HMG-box domain. To investigate the druggability of the corresponding protein-DNA interface on TOX, we performed a pilot virtual screening of 200,000 small molecules using in silico docking and identified 'hot spots' for drug-binding on the HMG-box domain. We then performed a large-scale virtual screening of 7.6 million drug-like compounds that were available from the ZINC15 database. As a result, a total of 140 top candidate compounds were selected for subsequent in vitro validation. Of those, 18 small molecules have been characterized as selective TOX inhibitors.

Evidence of an oncogenic role of aberrant TOX activation in cutaneous T-cell lymphoma.

TOX is a nuclear factor essential for the development of CD4(+) T cells in the thymus. It is normally expressed in low amounts in mature CD4(+) T cells of the skin and the peripheral blood. We have recently discovered that the transcript levels of TOX were significantly increased in mycosis fungoides, the most common type of cutaneous T-cell lymphoma (CTCL), as compared to normal skin or benign inflammatory dermatoses. However, its involvement in advanced CTCL and its biological effects on CTCL pathogenesis have not been explored. In this study, we demonstrate that TOX expression is also enhanced significantly in primary CD4(+)CD7(-) cells from patients with Sézary syndrome, a leukemic variant of CTCL, and that high TOX transcript levels correlate with increased disease-specific mortality. Stable knockdown of TOX in CTCL cells promoted apoptosis and reduced cell cycle progression, leading to less cell viability and colony-forming ability in vitro and to reduced tumor growth in vivo. Furthermore, TOX knockdown significantly increased 2 cyclin-dependent kinase (CDK) inhibitors, CDKN1B and CDKN1C. Lastly, blocking CDKN1B and CDKN1C reversed growth inhibition of TOX knockdown. Collectively, these findings provide strong evidence that aberrant TOX activation is a critical oncogenic event for CTCL.

The prevalence of anxiety and depression in patients with or without hyperhidrosis (HH).

BACKGROUND: There are conflicting data about the correlation between hyperhidrosis (HH) and anxiety and depression. OBJECTIVE: We sought to determine the prevalence of anxiety and depression in patients with or without HH. METHODS: We examined 2017 consecutive dermatology outpatients from Vancouver, British Columbia, Canada, and Shanghai, China, using Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 scales for anxiety and depression assessments. Multivariable logistic regression analysis was performed to evaluate if the impact of HH on anxiety and depression is dependent on demographic factors and diagnoses of the patients' presenting skin conditions. RESULTS: The prevalence of anxiety and depression was 21.3% and 27.2% in patients with HH, respectively, and 7.5% and 9.7% in patients without HH, respectively (P value <.001 for both). There were positive correlations between HH severity and the prevalence of anxiety and depression. Multivariable analysis showed that HH-associated increase in anxiety and depression prevalence is independent of demographic factors and presenting skin conditions. LIMITATION: The data from the questionnaires relied on the accuracy of patients' self-reports. CONCLUSION: Both single variant and multivariable analyses showed a significant association between HH and the prevalence of anxiety and depression in a HH severity-dependent manner.

Deficiency of SATB1 expression in Sezary cells causes apoptosis resistance by regulating FasL/CD95L transcription.

Sézary syndrome (SS) is an aggressive subtype of cutaneous T-cell lymphoma that is characterized by circulating leukemic Sézary cells. The accumulation of these malignant cells has been shown to be the result of the resistance to apoptosis, in particular, activation-induced cell death. However, the mechanism of apoptosis resistance remains unknown. By characterizing the gene transcription profiles of purified CD4(+)CD7(-) Sézary cells from patients with SS and cultured Sézary cells, it was found that Sézary cells are deficient in the expression of special AT-rich region binding protein 1 (SATB1), a key regulator of T-cell development and maturation. Retrovirus-mediated gene transduction revealed that SATB1 restoration in cultured Sézary cells (Hut78) triggered spontaneous cell death and sensitized Hut78 cells to activation-induced cell death, with associated activation of caspase 8 and caspase 3. Furthermore, endogenous expression of FasL in Sézary cells was increased in transcriptional and translational levels on restoration of SATB1 expression in cultured Sézary cells. These results suggest that deficiency in SATB1 expression in Sézary cells plays an important role in SS pathogenesis by causing apoptosis resistance. Thus, restoration of SATB1 expression may represent a potential molecular targeted therapy for SS, which does not have a cure at present.

The association between retina thinning and hippocampal atrophy in Alzheimer's disease and mild cognitive impairment: a meta-analysis and systematic review.

Introduction: The retina is the "window" of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer's disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection. Methods: We systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher's Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method. Results: Of the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490-0.4377, I2 = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905-0.1510, I2 = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(-0.0447-0.3192), I2 = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference. Conclusion: The correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, CRD42022328088.

Effect of hearing aids on cognitive functions in middle-aged and older adults with hearing loss: A systematic review and meta-analysis.

Objective: The study aimed to examine the effects of hearing aids on cognitive function in middle-aged and older adults with hearing loss. Data sources and study selection: PubMed, Cochrane Library, and Embase were searched for studies published before 30 March 2022. Randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) were included in the search. Restriction was set on neither types, severity, or the time of onset of hearing impairment nor cognitive or psychiatric statuses. Data extraction and synthesis: Two independent reviewers extracted data and assessed the study quality of RCTs. Cognitive function outcomes were descriptively summarized and converted to standardized mean difference (SMD) in the meta-analysis. Meta-analysis was conducted in RCTs. Sub-group analyses were conducted by cognitive statuses, psychiatric disorders, and cognitive domains. Results: A total of 15 studies met the inclusion criteria, including five RCTs (n = 339) and 10 NRSIs (n = 507). Groups were classified as subjects without dementia or with normal global cognition, subjects with AD or dementia, and subjects with depressive symptoms. For subjects without dementia, improvements were found in global cognition, executive function, and episodic memory. For subjects with depressive symptoms, improvements were found in immediate memory, global cognition, and executive function. No improvement was found in subjects with AD or dementia. In total, four RCTs were included in the meta-analysis. For subjects without dementia (SMD = 0.11, 95% confidence interval [CI]: -0.15-0.37) and those with AD, no significant effect was found (SMD = -0.19, 95% CI: -0.65-0.28). For subjects without dementia, no significant effect was found in language (SMD = 0.14, 95% CI: -0.30-0.59) or general executive function (SMD = -0.04, 95% CI: -0.46-0.38). Further sub-group analysis found no significant effect in executive function (SMD = -0.27, 95% CI: -0.72-0.18) or processing speed (SMD = -0.02, 95% CI: -0.49-0.44). Conclusion: Hearing aids might improve cognitive performance in domains such as executive function in subjects without dementia. The effects on subjects with depressive symptoms remained unclear. No improvement was found in subjects with AD or dementia. Long-term RCTs and well-matched comparison-group studies with large sample sizes are warranted. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022349057.

Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells.

AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4(+)CD7(-) Sezary cells from patients with Sezary syndrome. Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1-mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1-suppressed CTCL cells. Fifteen up-regulated and 6 down-regulated genes were identified and confirmed by quantitative reverse transcription-polymerase chain reaction. Seven were further confirmed in a microarray analysis of CD4(+)CD7(-) Sezary cells from Sezary syndrome patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression, which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biologic response to its inhibitor, dasatinib, were observed in AHI-1-suppressed or -overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells.

The Correlation Between Olfactory Test and Hippocampal Volume in Alzheimer's Disease and Mild Cognitive Impairment Patients: A Meta-Analysis.

Background: Previous studies have reported that olfactory identification deficits may be the earliest clinical features of Alzheimer's disease (AD). However, the association between odor identification and hippocampal atrophy remains unclear. Objective: This meta-analysis quantified the correlation between odor identification test scores and hippocampal volume in AD. Method: A search of the PUBMED, EMBASE, and WEB OF SCIENCE databases was conducted from January 2003 to June 2020 on studies with reported correlation coefficients between olfactory identification score and hippocampal volume in patients with amnestic AD or mild cognitive impairment (MCI). The quality of the studies was assessed using the Newcastle-Ottawa quality assessment scale (NOS). Pooled r-values were combined and computed in R studio. Results: Seven of 627 original studies on AD/MCI using an olfactory identification test (n = 902) were included. A positive correlation was found between hippocampal volume and olfactory test scores (r = 0.3392, 95% CI: 0.2335-0.4370). Moderator analysis showed that AD and MCI patients were more profoundly correlated than normal controls (AD: r = 0.3959, 95% CI: 0.2605-0.5160; MCI: r = 0.3691, 95% CI: 0.1841-0.5288; NC: r = 0.1305, 95% CI: -0.0447-0.2980). Age difference and patient type were the main sources of heterogeneity in this analysis. Conclusion: The correlation appears to be more predominant in the cognitive disorder group (including MCI and AD) than in the non-cognitive disorder group. Age is an independent factor that affects the severity of the correlation during disease progression. The mildness of the correlation suggests that olfactory tests may be more accurate when combined with other non-invasive examinations for early detection. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202140088.

Vitiligo Skin Biomarkers Associated With Favorable Therapeutic Response.

Vitiligo is an acquired depigmentation skin disease caused by immune-mediated death of melanocytes. The most common treatment for vitiligo is narrow band ultraviolet B phototherapy, which often is combined with topical therapies such as tacrolimus. However, patients' responses to these treatments show large variations. To date, the mechanism for this heterogeneity is unknown, and there are no molecular indicators that can predict an individual patient's response to therapy. The goal of this study is to identify clinical parameters and gene expression biomarkers associated with vitiligo response to therapy. Six patients with segmental vitiligo and 30 patients with non-segmental vitiligo underwent transcriptome sequencing of lesional and nonlesional skin at baseline before receiving combined UBUVB and tacrolimus therapy for 6 month, and were separated into good response and bad response groups based on target lesion achieving > 10% repigmentation or not. Our study revealed that treatment-responsive vitiligo lesions had significantly shorter disease duration compared with non-responsive vitiligo lesions (2.5 years vs 11.5 years, p=0.046, t-Test), while showing no significant differences in the age, gender, ethnicity, vitiligo subtype, or disease severity. Transcriptomic analyses identified a panel of 68 genes separating the good response from bad response lesions including upregulation of immune active genes, such as CXCL10, FCRL3, and TCR, Further, compared with vitiligo lesions with long disease duration, the lesions with short duration also have much higher level of expression of immune-active genes, including some (such as FCRL3 and TCR genes) that are associated with favorable therapeutic response. In conclusion, our study has identified clinical parameters such as short disease duration and a panel of immune active and other gene expression biomarkers that are associated with favorable response to immune suppressive NBUVB + tacrolimus therapy. These markers may be useful clinically for individualized therapeutic management of vitiligo patients in the future.

Clinical Features and Therapeutic Effects of Anti-leucine-rich Glioma Inactivated 1 Encephalitis: A Systematic Review.

Background: Clinical presentations and treatment programs about anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis still remain incompletely understood. Objective: This study analyzed the clinical features and therapeutic effects of anti-LGI1 encephalitis. Methods: PubMed, EMBASE, and the Cochrane Library were searched to identify published English and Chinese articles until April 2021. Data were extracted, analyzed, and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 80 publications detailing 485 subjects matched our inclusion criteria. Short-term memory loss (75.22%), faciobrachial dystonic seizures (FBDS) (52.53%), other seizures excluding FBDS (68.48%), psychiatric symptoms (57.67%), and sleep disturbances (34.30%) were the most frequently described symptoms in anti-LGI1 encephalitis. Hyponatremia (54.90%) was the most common hematologic examination change. The risk of incidence rate of malignant tumors was higher than in healthy people. The positive rate of anti-LGI1 in serum (99.79%) was higher than CSF (77.38%). Steroids (93.02%), IVIG (87.50%), and combined use (96.67%) all had a high remission rate in the initial visit. A total of 35 of 215 cases relapsed, of which 6/35 (17.14%) did not use first-line treatment, and 21 (60.00%) did not maintain long-term treatment. Plasma exchange (PE) could be combined in severe patients, immunosuppressant could be used for refractory patients or for recurrence and using an anti-epileptic drug to control seizures may benefit cognition. Conclusions: Short-term memory loss, FBDS, psychiatric symptoms, and hyponatremia were key features in identifying anti-LGI1 encephalitis. Serum and CSF antibody tests should be considered in diagnosis criteria. Steroids with IVIG should be recommended, PE was combined for use in severe patients, immunosuppressant therapy might improve outcomes if recurrence or progression occurred, and control seizures might benefit cognition. The useful ways to reduce relapse rate were early identification, clear diagnosis, rapid treatment, and maintaining long-term treatment. The follow-up advice was suggested according to the research of paraneoplastic syndrome, and concern about tumors was vital as well.

Immunohistochemistry analysis reveals lysyl oxidase-like 3 as a novel prognostic marker for primary melanoma.

Lysyl oxidase-like 3 (LOXL3) is an extracellular enzyme involved in the synthesis of collagen and elastin, and it has been reported to promote melanoma cell proliferation and invasion in vitro. However, the expression level of LOXL3 at different stages of melanocytic lesions and the role of LOXL3 in melanoma pathogenesis remain unknown. Immunohistochemical staining of LOXL3 in a tissue microarray of 373 biopsies at different melanocytic stages was conducted. The correlation between LOXL3 expression and patient survival was examined using Kaplan-Meier survival analysis. Univariate and multivariate Cox regression analyses were conducted to study the hazard ratios. The tissue microarray study revealed that stronger expression of LOXL3 protein was found at more advanced melanocytic stages (P < 0.0001; χ2 test). Increased LOXL3 expression was associated with enhanced tumor thickness and mitosis. Survival analysis showed significantly worsened prognosis in primary melanoma patients when the LOXL3 expression level was higher (P = 0.043; log-rank test). Multivariate Cox regression analysis further showed that LOXL3 expression is a prognostic factor for primary melanoma patient survival (P = 0.04). LOXL3 expression is positively correlated with tumor progression and invasion, and its overexpression is associated with worse prognosis of primary melanoma patients. LOXL3 can serve as a prognostic marker to help identify primary melanoma patients at higher risks of death.

Whole-Exome Sequencing Reveals Frequent Mutations in Chromatin Remodeling Genes in Mammary and Extramammary Paget's Diseases.

Paget's disease (PD) is an intraepidermal adenocarcinoma of the skin at the breast (mammary PD) or urogenital locations (extramammary PD [EMPD]). At present, there is lack of clarity on PD's pathogenesis, the relationship between its subtypes, and its lineage link with the underlying invasive carcinomas. Here we describe that mammary PD and EMPD have similar mutational profiles, with the most frequent recurrent mutations occurring in the chromatin remodeling genes, such as KMT2C (MLL3, 39%) and ARID2 (22%), with additional recurrent somatic mutations detected in genes previously not known to be mutated in cancers, such as CDCC168 (34%), FSIP2 (29%), CASP8AP2 (29%), and BIRC6 (24%). In paired mammary PD and underlying breast carcinoma samples, distinct gene mutations were detected, indicating that they represent independent oncogenic events. Finally, multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. Our results reveal similar genomic landscapes between mammary PD and EMPD, including early aberrations in chromatin remodeling genes. In addition, mammary PD and underlying breast ductal carcinomas represent independent oncogenic events. These findings provide approaches for developing diagnostic tools and therapeutic interventions for PD.

Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease.

Paget's disease (PD) is an uncommon intraepithelial adenocarcinoma with unknown pathogenesis. There are two anatomic subtypes: mammary (MPD) and extramammary (EMPD). Little is known about their molecular characteristics. Our objective was to discover novel molecular markers for PD and its subtypes. In the discovery phase, we used transcriptome analyses to uncover the most differentially expressed genes and pathways in EMPD biopsies compared with normal skin. In the validation phase, we performed immunohistochemistry analyses on the most promising marker (FOXA1) and other markers selected from a literature review (GATA3, estrogen receptor [ER], and androgen receptor [AR]) on independent biopsies of MPD (n = 86), EMPD (n = 59), and normal skin (n = 21). Transcriptome analyses revealed 210 genes differentially expressed more than 10-fold between EMPD and normal skin. These genes are involved in mammary and sweat gland development (FOXA1) and immune regulation, as well as epidermal differentiation. Immunohistochemistry staining revealed that FOXA1 was positive in 88% of both MPD and EMPD, whereas GATA3 was positive in 67% of MPD and 77% of EMPD, and ER was positive in 9% of MPD and 19% of EMPD. Finally, AR was positive in 33% of PD and 54% of EMPD. Mammary Paget's disease and EMPD share dysregulation of the glandular developmental regulator gene FOXA1, suggesting similarity in cell-specific transcriptional regulation. Further, FOXA1 may be a useful molecular target for developing PD therapies.

Aberrant expression of collagen triple helix repeat containing 1 in human solid cancers.

PURPOSE: The collagen triple helix repeat containing 1 (CTHRC1) is a promigratory protein first found to be expressed during rat tissue repair process. Recent preliminary results revealed CTHRC(1) mRNA in melanoma and breast cancer. However, the full significance of CTHRC1 to human carcinogenesis remains unclear. This study is to further characterize the clinical and functional relevance of CTHRC1 in melanoma and other human solid cancers. EXPERIMENTAL DESIGN: First, semiquantitative immunohistochemistry analysis was done on 304 clinically annotated, paraffin-embedded biopsies representing different stages of melanoma progression. Then, short interfering RNA was used to inhibit expression of CTHRC1 protein for migration analysis on cultured melanoma cells. Finally, the CTHRC1 expression was surveyed in 310 samples representing 19 types of human solid cancers. RESULTS: In benign nevi and noninvasive melanoma biopsies, there was little CTHRC1 protein expression. In contrast, in invasive primary melanomas, there was a significant increase of CTHRC1 protein (P < 0.01, chi(2) test). There was a further increase of CTHRC1 protein in metastatic melanoma specimens compared with nonmetastatic lesions (P < 0.01, chi(2) test). In addition, inhibition of CTHRC1 expression resulted in decreased cell migration in vitro. Finally, transcription survey in 19 types of human solid cancers revealed aberrant CTHRC1 expression in 16 cancer types, especially cancers of the gastrointestinal tract, lung, breast, thyroid, ovarian, cervix, liver, and the pancreas. CONCLUSIONS: Aberrant expression of CTHRC1 is widely present in human solid cancers and seems to be associated with cancer tissue invasion and metastasis. It potentially plays important functional roles in cancer progression, perhaps by increasing cancer cell migration.

Aberrant expression of T-plastin in Sezary cells.

Mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SS), are the most common cutaneous T-cell lymphomas, with a combined incidence of 0.36 of 100,000 person-years. Although thought to be closely related to mature T-helper cells, the true nature of the cancer cells in MF/SS is unknown. In addition, there is no known specific marker for MF/SS cancer cells, which can result in difficulties in the diagnosis and treatment. To identify MF/SS-specific markers, Sezary cancer cells were analyzed with a global genomic screening tool, the modified representational difference analysis. It was discovered that unlike T-helper cells from healthy individuals or patients with nonmalignant dermatoses, Sezary cells from most patients with Sezary syndrome aberrantly expressed T-plastin mRNA and protein. This is the first time T-plastin protein, a cytoplasmic protein regulating actin assembly and cellular motility, has been detected in the hematopoietic cells. Therefore, T-plastin has the potential to be a Sezary cell-specific marker valuable for diagnostic and treatment of Sezary syndrome.

Hyperhidrosis Prevalence and Demographical Characteristics in Dermatology Outpatients in Shanghai and Vancouver.

BACKGROUND: There is a wide variation in the reported prevalence of primary hyperhidrosis in the literature. Further, it is unknown if primary hyperhidrosis is a lifelong condition, or if demographical factors influence hyperhidrosis prevalence. OBJECTIVES: This study aims to examine the prevalence of hyperhidrosis in multiple ethnic groups from two ethnically diverse cities and to determine if the prevalence of primary hyperhidrosis changes according to age, gender, ethnicity, body mass index, and geographical locations. METHODS: In total, 1010 consecutive subjects attending dermatology outpatient clinics in Shanghai Skin Disease Hospital and 1018 subjects in Skin Care Center of Vancouver General Hospital were invited to fill out a questionnaire on their presenting concerns, demographical information, and sweating symptoms. The subjects were then classified to have primary hyperhidrosis using the criteria of International Hyperhidrosis Society, late-onset hyperhidrosis, or no-hyperhidrosis. The prevalence of primary HH and late-onset HH was calculated for the entire study population and in subgroups stratified according to age of examination, sex, ethnicity, presenting diagnosis, body mass index, and specific study cities. Multivariate logistic regression analyses were performed to assess the impact of these factors on HH prevalence. RESULTS: The prevalence of primary hyperhidrosis is very similar in Shanghai and in Vancouver, at 14.5% and 12.3% respectively. In addition, 4.0% of subjects in Shanghai and 4.4% subjects in Vancouver suffer from late-onset HH. Primary HH has highest prevalence in those younger than 30 years of age, decreasing dramatically in later years. Caucasian subjects are at least 2.5 times more likely to develop axillary hyperhidrosis compared to Chinese subjects. Obesity does not have much influence on primary HH presentation, although it does increase significantly the development of late-onset HH. Finally, there is no major difference of hyperhidrosis between Chinese subjects in Shanghai and Vancouver. LIMITATIONS: The data were gathered according to patients' self-reports only and the sample size was relatively small in some groups after stratification for gender, ethnicity and age. CONCLUSION: Prevalence of primary HH and late-onset HH is similar in dermatology outpatients independent of geographical locations. However, certain specific HH subtypes can show great variations according to ethnicity, age, body mass index and sex.

Osteopontin expression correlates with melanoma invasion.

Melanoma is one of the most aggressive cancers affecting humans. Although early melanomas are curable with surgical excision, metastatic melanomas are associated with high mortality. The mechanism of melanoma development, progression, and metastasis is largely unknown. In order to uncover genes unique to melanoma cells, we used high-density DNA microarrays to examine the gene expression profiles of metastatic melanoma nodules using benign nevi as controls. Over 190 genes were significantly overexpressed in metastatic melanomas compared with normal nevi by at least 2-fold. One of the most abundantly expressed genes in metastatic melanoma nodules is osteopontin (OPN). Immunohistochemistry staining on tissue microarrays and individual skin biopsies representing different stages of melanoma progression revealed that OPN expression is first acquired at the step of melanoma tissue invasion. In addition, blocking of OPN expression by RNA interference reduced melanoma cell numbers in vitro. Our observations suggest that OPN may be acquired early in melanoma development and progression, and may enhance tumor cell growth in invasive melanoma.

Thymocyte selection-associated high mobility group box gene (TOX) is aberrantly over-expressed in mycosis fungoides and correlates with poor prognosis.

Mycosis fungoides (MF) often mimics the common chronic inflammatory skin diseases and is difficult to be diagnosed with certainty, partly because of the lack of well-characterized molecular markers. Previously, we discovered that TOX, a key T cell development regulator,was aberrantly over-expressed in early stage MF. In the current multi-center study involving two independent patient cohorts, we determined the prevalence of TOX over-expression in the full spectrum of MF skin biopsies, and tested if TOX expression levels correlated with long term clinical outcomes. We examined TOX expression levels in 113 MF biopsies. We found that the MF biopsies expressed higher TOX mRNA than the controls in both cohorts (17.9 fold in cohort 1, P = 0.002; 5.8 fold in cohort 2, P < 0.0001). In addition, thicker skin lesions such as plaques and tumors expressed even higher TOX levels than thinner patches. Further, TOX over-expression differentiated MF from the controls (area under the curve [AUC]=0.87, P < 0.0001). Finally, high TOX mRNA levels correlated with increased risks of disease progression (P = 0.003) and disease-specific mortality (P = 0.008). In conclusion, TOX may be a useful marker for improving MF diagnosis and prognostication.

CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo.

Vitiligo is an autoimmune disease of the skin that results in disfiguring white spots. There are no U.S. Food and Drug Administration-approved treatments for vitiligo, and most off-label treatments yield unsatisfactory results. Vitiligo patients have increased numbers of autoreactive, melanocyte-specific CD8(+) T cells in the skin and blood, which are directly responsible for melanocyte destruction. We report that gene expression in lesional skin from vitiligo patients revealed an interferon-γ (IFN-γ)-specific signature, including the chemokine CXCL10. CXCL10 was elevated in both vitiligo patient skin and serum, and CXCR3, its receptor, was expressed on pathogenic T cells. To address the function of CXCL10 in vitiligo, we used a mouse model of disease that also exhibited an IFN-γ-specific gene signature, expression of CXCL10 in the skin, and up-regulation of CXCR3 on antigen-specific T cells. Mice that received Cxcr3(-/-) T cells developed minimal depigmentation, as did mice lacking Cxcl10 or treated with CXCL10-neutralizing antibody. CXCL9 promoted autoreactive T cell global recruitment to the skin but not effector function, whereas CXCL10 was required for effector function and localization within the skin. Surprisingly, CXCL10 neutralization in mice with established, widespread depigmentation induces reversal of disease, evidenced by repigmentation. These data identify a critical role for CXCL10 in both the progression and maintenance of vitiligo and thereby support inhibiting CXCL10 as a targeted treatment strategy.