Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micrometastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action.

The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-κB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.

Arsenic-induced Bowen's 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-1␣ (PGC-1␣), 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-1␣ was increased in As-BD compared with in healthy subjects. Treatment of primary keratinocytes with arsenic at concentrations lower than 1.0 mol/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.

Pain and itch are closely related sensations, yet qualitatively quite distinct. Despite recent advances in brain imaging techniques, identifying the differences between pain and itch signals in the brain cortex is difficult due to continuous temporal and spatial changes in the signals. The high spatial resolution of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has substantially advanced research of pain and itch, but these are uncomfortable because of expensiveness, importability and the limited operation in the shielded room. Here, we used near infrared spectroscopy (NIRS), which has more conventional usability. NIRS can be used to visualize dynamic changes in oxygenated hemoglobin and deoxyhemoglobin concentrations in the capillary networks near activated neural circuits in real-time as well as fMRI. We observed distinct activation patterns in the frontal cortex for acute pain and histamine-induced itch. The prefrontal cortex exhibited a pain-related and itch-related activation pattern of blood flow in each subject. Although it looked as though that activation pattern for pain and itching was different in each subject, further cross correlation analysis of NIRS signals between each channels showed an overall agreement with regard to prefrontal area involvement. As a result, pain-related and itch-related blood flow responses (delayed responses in prefrontal area) were found to be clearly different between pain (τ = +18.7 sec) and itch (τ = +0.63 sec) stimulation. This is the first pilot study to demonstrate the temporal and spatial separation of a pain-induced blood flow and an itch-induced blood flow in human cortex during information processing.

Acne is a common disease in adolescence with female preponderance. It could cause poor self-esteem and social phobia. Previous studies based on questionnaires from several thousands of adolescents showed that acne is associated with major depression and suicide. However, the gender- and age-specific risk of depression and suicide in patients with acne remain largely unknown. Using a database from the National Health Insurance, which included 98% of the population of Taiwan in 2006, we identified patients of acne, major depression, and suicide based on ICD-9-CM codes. Totally 47111 patients with acne were identified (16568 males and 30543 females) from 1 million subjects. The youths of 7–12 years had the highest prevalence of acne (14.39%). Major depression was more common in those with acne (0.77%) than controls (0.56% , P < 0.0001) regardless of gender. Multiple logistic regression showed an increased risk of major depression in women without acne (OR = 1.85, 95% CI 1.75–1.96). The risk is additive in women with acne (OR = 2.78, 95% CI 2.43–3.17). Similar additive risk of suicide was noticed in women with acne. In conclusion, acne and gender, independently and jointly, are associated with major depression and suicide. Special medical support should be warranted in females with acne for the risk of major depression and suicide.

Expression of the chemokine receptor CXCR4 by tumor cells promotes metastasis, possibly by activating prosurvival signals that render cancer cells resistant to immune attack. Inhibition of CXCR4 with a peptide antagonist, T22, blocks metastatic implantation of CXCR4-transduced B16 (CXCR4-luc-B16) melanoma cells in lung, but not the outgrowth of established metastases, raising the question of how T22 can best be used in a clinical setting. Herein, whereas the treatment of CXCR4-luc-B16 cells in vitro with the CXCR4 ligand CXCL12 did not reduce killing induced by cisplatin or cyclophosphamide, CXCL12 markedly reduced Fasdependent killing by gp100-specific (pmel-1) CD8 + T cells. T22 pretreatment restored sensitivity of CXCR4-luc-B16 cells to pmel-1 killing, even in the presence of CXCL12. Two immune-augmenting regimens were used in combination with T22 to treat experimental lung metastases. First, low-dose cyclophosphamide treatment (100 mg/kg) on day 5 in combination with T22 (days 4 -7) yielded a f70% reduction of B16 metastatic tumor burden in the lungs compared with cyclophosphamide treatment alone (P < 0.001). Furthermore, whereas anti -CTL antigen 4 (CTLA4) monoclonal antibody (mAb; or T22 treatment) alone had little effect on established B16 metastases, pretreatment with T22 (in combination with anti-CTLA4 mAb) resulted in a 50% reduction in lung tumor burden (P = 0.02). Thus, in vitro, CXCR4 antagonism with T22 renders B16 cells susceptible to killing by antigen-specific T cells. In vivo, T22 synergizes with cyclophosphamide or anti-CTLA4 mAb in the treatment of established lung metastases, suggesting a novel strategy for augmenting the efficacy of immunotherapy. [Mol Cancer Ther 2006;5(10):2592 -9]

Skin cancer is among the 10 most common cancers. Recent research revealed the superiority of artificial intelligence (AI) over dermatologists to diagnose skin cancer from predesignated and cropped images. However, there remain several uncertainties for AI in diagnosing skin cancers, including lack of testing for consistency, lack of pathological proof or ambiguous comparisons. Hence, to develop a reliable, feasible and user‐friendly platform to facilitate the automatic diagnostic algorithm is important. The aim of this study was to build a light‐weight skin cancer classification model based on deep learning methods for aiding first‐line medical care. The developed model can be deployed on cloud platforms as well as mobile devices for remote diagnostic applications. We reviewed the medical records and clinical images of patients who received a histological diagnosis of basal cell carcinoma, squamous cell carcinoma, melanoma, seborrheic keratosis and melanocytic nevus in 2006–2017 in the Department of Dermatology in Kaohsiung Chang Gung Memorial Hospital (KCGMH). We used the deep learning models to identify skin cancers and benign skin tumors in the manner of binary classification and multi‐class classification in the KCGMH and HAM10000 datasets to construct a skin cancer classification model. The accuracy reached 89.5% for the binary classifications (benign vs malignant) in the KCGMH dataset; the accuracy was 85.8% in the HAM10000 dataset in seven‐class classification and 72.1% in the KCGMH dataset in five‐class classification. Our results demonstrate that our skin cancer classification model based on deep learning methods is a highly promising aid for the clinical diagnosis and early identification of skin cancers and benign tumors.

Hyperpigmentation, hyperkeratoses, and Bowen's disease are hallmarks of chronic arsenic exposure. The association between arsenic-induced skin lesions and subsequent internal cancers is examined by using a community-based prospective study. The cohort was enrolled from an arseniasis-endemic area in southwestern Taiwan, where 2,447 residents participated in skin examinations during the late 1980s. The number of participants diagnosed with hyperpigmentation was 673; with hyperkeratosis, 243; and with skin cancer (Bowen's disease or non-melanoma skin cancer), 378. Newly diagnosed internal cancers were ascertained through linkage with National Cancer Registry profiles. Cox regression was performed to estimate hazard ratios with 95% confidence intervals for potential risk predictors. Compared with participants without skin lesions, patients affected with skin cancers had a significantly increased risk of lung cancer (hazard ratio = 4.64, 95% confidence interval: 2.92, 7.38) and urothelial carcinoma (hazard ratio = 2.02, 95% confidence interval: 1.23, 3.30) after adjustment for potential confounders and cumulative arsenic exposure. Hyperkeratosis is significantly associated with an increased lung cancer risk (hazard ratio = 2.76, 95% confidence interval: 1.35, 5.67). A significant interactive effect on lung cancer risk between hyperkeratosis and cigarette smoking was identified, which suggests that patients with hyperkeratosis who have been exposed to arsenic should cease smoking.