Gwo-Shing Chen

Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center

BACKGROUND Previous reports regarding the rates at which various internal tumors metastasize to the skin have been limited and have only included the Caucasian population. Moreover, the mechanisms that predispose certain internal malignancies to metastasize to the skin have rarely been discussed in the scientific literature. OBJECTIVES We determined the frequencies with which various internal malignancies metastasize to the skin in patients from a Taiwanese medical center. We also evaluated whether expressions of chemokine receptors CCR10 and CXCR4 by tumor cells correlate with cutaneous metastatic ability. METHODS Clinical records from Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, during 20 years (1986-2006) were reviewed and cases of biopsy-proven primary internal malignancies and cutaneous metastases were identified. Immunohistochemical staining with antibodies to CCR10 and CXCR4 was performed on a selected number of internal malignancies with and without skin metastases. RESULTS From 12,146 patients with internal malignancies, we found 124 cases (1.02%) with cutaneous metastases. The highest rates of skin metastases were found to occur from carcinoma of the breast, followed by the lung, oral mucosa, colon and rectum, stomach, and esophagus. However, the rate of cutaneous metastasis from breast cancer was much lower compared with previous studies involving Caucasians. In general, adenocarcinomas gave rise to cutaneous metastases at a higher frequency compared with other histologic subtypes. In addition, the expressions of CCR10 and CXCR4 by tumor cells did not correlate well with the presence or absence of skin metastases. LIMITATION This study is retrospective in nature. CONCLUSIONS Different internal malignancies metastasize to the skin with different frequencies, and the rates at which different malignancies metastasize to cutaneous sites differ between the Taiwanese and Caucasian populations. The mechanisms responsible for the cutaneous metastatic ability of certain malignancies likely involve factors other than chemokine receptors CCR10 and CXCR4, because their expressions by tumor cells are neither necessary nor sufficient for the formation of skin metastases.

High-glucose Environment Enhanced Oxidative Stress and Increased Interleukin-8 Secretion From Keratinocytes: New Insights Into Impaired Diabetic Wound Healing

Impaired wound healing frequently occurs in patients with diabetes. Interleukin (IL)-8 production by keratinocyte is responsible for recruiting neutrophils during healing. Intense inflammation is associated with diabetic wounds, while reduction of neutrophil infiltration is associated with enhanced healing. We hypothesized that increased neutrophil recruitment by keratinocytes may contribute to the delayed healing of diabetic wounds. Using cultured human keratinocytes and a diabetic rat model, the current study shows that a high-glucose environment enhanced IL-8 production via epidermal growth factor receptor (EGFR)–extracellular signal–regulated kinase (ERK) pathway in a reactive oxygen species (ROS)-dependent manner in keratinocytes. In addition, diabetic rat skin showed enhanced EGFR, ERK, and IL-8 expression compared with control rats. The dermal neutrophil infiltration of the wound, as represented by expression of myeloperoxidase level, was also significantly higher in diabetic rats. Treating diabetic rats with dapsone, an agent known to inhibit neutrophil function, was associated with improved healing. In conclusion, IL-8 production and neutrophil infiltration are increased in a high-glucose environment due to elevated ROS level and contributed to impaired wound healing in diabetic skin. Targeting these dysfunctions may present novel therapeutic approaches.

Aberrant Cell Proliferation by Enhanced Mitochondrial Biogenesis via mtTFA in Arsenical Skin Cancers

Arsenic-induced Bowens disease (As-BD), a cutaneous carcinoma in situ, is thought to arise from gene mutation and uncontrolled proliferation. However, how mitochondria regulate the arsenic-induced cell proliferation remains unclear. The aim of this study was to clarify whether arsenic interfered with mitochondrial biogenesis and function, leading to aberrant cell proliferation in As-BD. Skin biopsy samples from patients with As-BD and controls were stained for cytochrome c oxidase (Complex IV), measured for mitochondrial DNA (mtDNA) copy number and the expression levels of mitochondrial biogenesis-related genes, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (mtTFA). The results showed that expression of cytochrome c oxidase, mtTFA, NRF-1, and PGC-1α was increased in As-BD compared with in healthy subjects. Treatment of primary keratinocytes with arsenic at concentrations lower than 1.0 μmol/L induced cell proliferation, along with enhanced mitochondrial biogenesis. Furthermore, we observed that the mitochondrial oxygen consumption rate and intracellular ATP level were increased in arsenic-treated keratinocytes. Blocking of mitochondrial function by oligomycin A (Complex V inhibitor) or knockdown of mtTFA by RNA interference abrogated arsenic-induced cell proliferation without affecting cyclin D1 expression. We concluded that mtTFA up-regulation, augmented mitochondrial biogenesis, and enhanced mitochondrial functions may contribute to arsenic-induced cell proliferation. Targeting mitochondrial biogenesis may help treat arsenical cancers at the stage of cell proliferation.

Peripheral Vascular Diseases Resulting from Chronic Arsenical Poisoning

Drinking water contaminated by arsenic remains a major public health problem. Long‐term arsenic exposure has been found to be associated with peripheral vascular diseases in a variety of studies. Reports of vascular effects of arsenic in drinking water, which span almost 100 years, have been published in Taiwan, Chile, Mexico, and China. This paper reviewed the association of peripheral vascular diseases resulting from arsenic exposure to drinking water from the clinical and pathological points of view. An endemic peripheral vascular disorder called “blackfoot disease” has been noticed in a limited area in Taiwan. This disease results in gangrene in the extremities. It has been associated with the ingestion of high concentrations of arsenic‐tainted artesian well water. Epidemiological studies confirmed a dose‐response relationship between long‐term arsenic exposure and the occurrence of blackfoot disease. Whereas arsenic has induced various clinical manifestations of vascular effects in Chile, Mexico and China, they do not compare in magnitude or severity to the blackfoot disease found in Taiwan. The pathogenesis of vascular effects induced by arsenic is still controversial. The possible mechanisms include endothelial cell destruction, arsenic‐associated atherogenesis, carotene and zinc deficiency, and/or some immunological mechanism. Microcirculatory assessments revealed that deficits of capillary blood flow and permeability exist in clinically normal skin of patients with chronic arsenical poisoning. The vascular effects of chronic arsenic poisoning may involve cardiovascular and cerebrovascular systems as well. In view of the increasing public health problems caused by arsenic exposure, vascular effects should be included in the future study of health effects of arsenic.

Defective IL-2 receptor expression in lymphocytes of patients with arsenic-induced Bowen’s disease

Abstract The immune function of peripheral mononuclear cells (MNC) in patients with endemic arsenic-induced Bowen’s disease (BD) was investigated. Many cytokines and immune-related factors were determined in the present study. Interleukin-1β and TNF-α production was used as an indicator of monocyte/macrophage function. Il-2 and sIL-2R production was used as an indicator of lymphocyte activation. The release of sCD4 and sCD8 was used as an indicator of activation of respective T-cell subpopulations. Production of IFN-γ and IL-2 reflected the cellular effector function of helper T-cells type 1. In vivo cell-mediated immunity was also assessed by estimation of the percentage of T-cells in peripheral blood MNC and the nonspecific delayed-type hypersensitivity (DTH) response to 2,4-dinitrochlorobenzene (DNCB). Both assays revealed depressed cell-mediated immunity in BD. Compared with healthy controls, spontaneous and PHA-induced IFN-γ and TNF-α production was significantly decreased in BD whereas spontaneous release of IL-2, sCD4 and sCD8 was significantly increased. Although PHA stimulation increased IL-2 release, the expression of IL-2R α and β chains and the release of sIL-2R were not proportionately increased in BD. In addition, IL-2-mediated [ 3 H]-thymidine incorporation by MNC in patients with BD was significantly decreased. These findings suggest that the defective cell-mediated immune function in BD is due to impairment of membrane IL-2R expression in lymphocytes after stimulation.

Hand eczema among University Hospital nursing staff: identification of high-risk sector and impact on quality of life.

Background:  Hand eczema is a commonly encountered occupational disease and has a negative impact on life quality.

Arthritis as an important determinant for psoriatic patients to develop severe vascular events in Taiwan: a nation-wide study.

Background  Psoriasis is an important systemic inflammatory disease that often leads to severe vascular diseases. This study was launched to determine if joint involvement affects incidence of vascular comorbidities in psoriatic patients. In addition, potential vasculo‐protective effects of methotrexate in psoriatic patients were also evaluated.

Enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP‐1 and Akt pathway in keloids

Please cite this paper as: Enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP‐1 and Akt pathway in keloids. Experimental Dermatology 2010; 19: e142–e150.

Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes

Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human β-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections.

Low-Energy Helium-Neon Laser Therapy Induces Repigmentation and Improves the Abnormalities of Cutaneous Microcirculation in Segmental-Type Vitiligo Lesions

Segmental vitiligo (SV) is a special form of vitiligo occurring in a dermatomal distribution, and an abnormality involving the sympathetic nerves supplying the affected dermatome is known to underlie this disorder. Previously, we have shown that SV is associated with an abnormal increase in cutaneous blood flow and adrenoceptor responses in the affected areas. Since SV is resistant to conventional forms of therapy, its management represents a challenge for dermatologists. Low energy helium‐neon lasers (He‐Ne laser, wavelength 632.8nm) have been employed as a therapeutic instrument in many clinical situations, including vitiligo management and repair of nerve injury. The purpose of this study was to evaluate the effectiveness and safety of He‐Ne lasers in treating SV, and determine their effects on the repair of sympathetic nerve dysfunction. Forty patients with stable‐stage SV on the head and/or neck were enrolled in this study. He‐Ne laser irradiation was administered locally at 3.0J/cm2 with point stimulation once or twice weekly. Cutaneous microcirculatory assessments in six SV patients were performed using a laser Doppler flowmeter. The sympathetic adrenoceptor response of cutaneous microcirculation was determined by measuring cutaneous blood flow before, during and after iontophoresis with sympathomimetic drugs (phenylephrine, clonidine and propranolol). All measurements of microcirculation obtained at SV lesions were simultaneously compared with contralateral normal skin, both before and after He‐Ne laser treatment. After an average of 17 treatment sessions, initial repigmentation was noticed in the majority of patients. Marked repigmentation (> 50%) was observed in 60% of patients with successive treatments. Cutaneous blood flow was significantly higher at SV lesions compared with contralateral skin, but this was normalized after He‐Ne laser treatment. In addition, the abnormal decrease in cutaneous blood flow in response to clonidine was improved by He‐Ne laser therapy. Our study showed that He‐Ne laser therapy is an effective treatment for SV by normalizing dysfunctions of cutaneous blood flow and adrenoceptor responses in SV patients. Thus, the beneficial effects of He‐Ne laser therapy may be mediated in part by a reparative effect on sympathetic nerve dysfunction.