IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway.

BACKGROUND: Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated. METHODS: Tumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan-Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry. RESULTS: Clinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin-a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes-reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin. CONCLUSIONS: The current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.

DNA Repair Protein Rad51 Induces Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma via a p38/Akt-Dependent Pathway.

BACKGROUND: Rad51 is a protein which plays a vital role in DNA double-strand break repair and maintenance of telomeres. However, the underlying mechanism for its action in esophageal squamous cell carcinoma (ESCC) remains unclear. PATIENTS AND METHODS: Eighty-seven patients with ESCC were enrolled in this study. Expression of Rad51 in ESCC was determined by immunohistochemistry and correlated with clinicopathological variables by Chi square test. The role of Rad51 in patient survival was determined by Kaplan-Meier estimates. The effects of Rad51 knockdown and overexpression on esophageal cancer growth, migration, and invasion were examined using TE8, CE81T, and KYSE70 cells. The mechanisms involved were also analyzed. Nude mice models were used for assessment of tumor growth. RESULTS: Rad51 staining was predominantly observed in ESCC patients. ESCC patients with high Rad51 expression had significantly decreased survival (P < 0.001) combined with increased tumor size (P = 0.034) and lymph node metastasis (P = 0.039). Rad51 overexpression promoted, while its knockdown attenuated, esophageal cancer cell viability through cell cycle entry and migration/invasion via epithelial-mesenchymal transition. Moreover, Rad51 overexpression increased colony formation in vitro and tumor growth in vivo. In addition, high Rad51 expression increased cancer progression through the p38/Akt/Snail signaling pathway. CONCLUSIONS: This study indicates a new biological role for Rad51 in ESCC progression. Rad51 may serve as a potential prognostic biomarker and therapeutic target for ESCC patients.

Epidemiology of Depression in Patients with Psoriasis: A Nationwide Population-based Cross-sectional Study.

The epidemiology of depression in patients with psoriasis has not been well defined in the Asian population. This study evaluated the epidemiological features of, and risk factors for, depression among patients with psoriasis in Taiwan. A nationwide population-based cross-sectional study was undertaken using the National Health Insurance Research Database. This study included 17,086 patients with psoriasis and 1,607,242 patients from the general population. The prevalence of depression in patients with psoriasis was 11.52%, while the prevalence of depression in the general population was 7.73% (prevalence ratio 1.49, 95% confidence interval 1.43-1.55). Multivariable analysis showed that, in patients with psoriasis, risk factors associated with depression were: age 20-50 years, female sex, low income, and major comorbid diseases, including liver cirrhosis, renal disease, cardiovascular disease and cerebrovascular disease. Therefore, the prevalence of depression is higher in patients with psoriasis, particularly in young and middle-aged women with low income and major comorbidities.

Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury.

Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-ß, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.

CYT-Rx20 Inhibits Cervical Cancer Cell Growth and Migration Through Oxidative Stress-Induced DNA Damage, Cell Apoptosis, and Epithelial-to-Mesenchymal Transition Inhibition.

OBJECTIVE: The ß-nitrostyrene family has been reported to possess anticancer properties. However, the anticancer activity of ß-nitrostyrenes on cervical cancer cells and the underlying mechanisms involved remain unexplored. In this study, a ß-nitrostyrene derivative CYT-Rx20 (3'-hydroxy-4'-methoxy-ß-methyl-ß-nitrostyrene) was synthesized, and its anticancer activity on cervical cancer cells and the mechanisms involved were investigated. METHODS: The effect of CYT-Rx20 on human cervical cancer cell growth was evaluated using cell viability assay. Reactive oxygen species (ROS) generation and annexin V staining were detected by flow cytometry. The protein expression levels of cleaved caspase-3, cleaved caspase-9, cleaved poly (ADPribose) polymerase, γH2AX, ß-catenin, Vimentin, and Twist were measured by Western blotting. DNA double-strand breaks were determined by γ-H2AX foci formation and neutral comet assay. Migration assay was used to determine cancer cell migration. Nude mice xenograft was used to investigate the antitumor effects of CYT-Rx20 in vivo. RESULTS: CYT-Rx20 induced cytotoxicity in cervical cancer cells by promoting cell apoptosis via ROS generation and DNA damage. CYT-Rx20-induced cell apoptosis, ROS generation, and DNA damage were reversed by thiol antioxidants. In addition, CYT-Rx20 inhibited cervical cancer cell migration by regulating the expression of epithelial-to-mesenchymal transition markers. In nude mice, CYT-Rx20 inhibited cervical tumor growth accompanied by increased expression of DNA damage marker γH2AX and decreased expression of mesenchymal markers ß-catenin and Twist. CONCLUSIONS: CYT-Rx20 inhibits cervical cancer cells in vitro and in vivo and has the potential to be further developed into an anti-cervical cancer drug clinically.

Tungsten lamp and chronic actinic dermatitis.

Chronic actinic dermatitis is often associated with sensitivity to UV light. It is not well recognised that chronic actinic dermatitis may be exacerbated by light in the visible spectrum. We describe an unusual case of chronic actinic dermatitis exacerbated by a tungsten lamp, which emits light in the visible spectrum.

Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment.

Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment.

Immunosuppressive medication use and risk of herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE): A nationwide case-control study.

BACKGROUND: The association between immunosuppressive medication use and herpes zoster (HZ) in patients with systemic lupus erythematosus (SLE) has not been clearly defined. OBJECTIVE: We evaluated the risk of HZ in patients with SLE treated with different immunosuppressants. METHODS: A nationwide population-based case-control study was conducted using the Taiwanese National Health Insurance Research Database. Cases (1555 patients with SLE who developed HZ) and controls (3049 age- and sex-matched patients with SLE but without HZ) were analyzed for use of various immunosuppressive medications in the preceding 3-month period, and dose-response relationships were determined. Logistic regression was performed to estimate the adjusted odds ratio for HZ development. RESULTS: Medications associated with greater HZ risk in patients with SLE included oral corticosteroids, intravenous methylprednisolone, hydroxychloroquine, oral cyclophosphamide, intravenous cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. Combination immunosuppressive therapy was common in patients with SLE and was associated with greatly increased HZ risk. For oral corticosteroids and hydroxychloroquine, the risk of HZ was strongly dependent on the medication dose. LIMITATIONS: This study is retrospective in nature. CONCLUSION: Recent immunosuppressive medication use is associated with increased HZ risk in patients with SLE, particularly those receiving high-dose oral corticosteroids and multiagent immunosuppressive therapy.

Nasal-type extranodal natural killer/T-cell lymphoma presenting as a solitary non-healing lower leg ulcer.

Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is an aggressive form of non-Hodgkin's lymphoma with a poor prognosis. Primary cutaneous lesions of ENTCL usually present as nodules or infiltrative plaques. The presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare and may be easily misdiagnosed. In this report, we describe an unusual case of ENTCL with a diagnostically challenging clinical presentation as a solitary non-healing leg ulcer in an elderly woman.

Dermal desmoplastic fibroblastoma presenting as a large sacral mass.

Desmoplastic fibroblastoma (collagenous fibroma) is a rare and recently recognised benign tumour. Most desmoplastic fibroblastomas arise in the subcutaneous tissue or skeletal muscle. Involvement of the dermis is extremely rare. We describe an unusual case of dermal desmoplastic fibroblastoma presenting as a large sacral mass in a 16-year-old male. An awareness of this entity is necessary to avoid confusion with other benign and malignant soft tissue neoplasms.

CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation.

The chemokine receptor CXCR7 has been demonstrated to be involved in the development of certain cancers, but its role in cutaneous squamous cell carcinoma (SCC) has not been previously investigated. We seek to determine whether CXCR7 is expressed in human cutaneous SCC skin lesions and SCC cell lines. In addition, we evaluate whether CXCR7 plays a role in SCC cell proliferation, survival and migration and which signalling pathways are involved. Using quantitative RT-PCR to analyse the mRNA expression of 19 different chemokine receptors, we found that CXCR7 was much more highly expressed compared to other chemokine receptors in cutaneous SCC cell lines (HSC-1 and HSC-5). On immunohistochemical staining, CXCR7 was found to be expressed in 70% (28 of 40) of human cutaneous SCC tissue specimens, and its expression correlated with tumor depth >4 mm and cancer stage ≥II. CXCR7 but not CXCR4 protein was expressed on the surface of HSC-1 and HSC-5 cells by flow cytometry. Activation of the CXCR7 receptor by CXCL12 promoted survival of HSC-1 and HSC-5 cells through the ERK pathway, but had no significant effect on cell proliferation or migration. In summary, our findings indicate that CXCR7 is frequently expressed in cutaneous SCC skin lesions and its expression correlates with tumor depth and cancer stage. CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway. These findings provide new insights into the significance of CXCR7 in the pathophysiology of SCC.

Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation.

BACKGROUND: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive. METHODS: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE. RESULTS: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters. CONCLUSION: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

Lymphopaenia, anti-Ro/anti-RNP autoantibodies, renal involvement and cyclophosphamide use correlate with increased risk of herpes zoster in patients with systemic lupus erythematosus.

Herpes zoster occurs with increased frequency in patients with systemic lupus erythematosus (SLE). The aim of this study was to identify and evaluate clinical and laboratory risk factors associated with development of herpes zoster in patients with SLE. A retrospective case-control study was performed in a population of patients with SLE. Patients were identified as cases if their first episode of herpes zoster occurred after diagnosis of SLE. Patients with SLE who never developed herpes zoster were enrolled as controls. Medical charts and laboratory data for both cases and control patients were comprehensively reviewed. A total of 65 cases and 105 controls were included. Risk factors associated with the development of herpes zoster in patients with SLE were found to be lymphopaenia, anti-Ro antibodies, anti-RNP antibodies, neuropsychiatric manifestations, renal involvement and cyclophosphamide use. Therefore, the presence of certain disease manifestations in patients with SLE represents risk factors for the development of herpes zoster.

Fumarate hydratase inhibits non-small cell lung cancer metastasis via inactivation of AMPK and upregulation of DAB2.

Lung cancer is one of the leading causes of cancer mortality worldwide. As it is often first diagnosed only when cancer metastasis has already occurred, the development of effective biomarkers for the risk prediction of cancer metastasis, followed by stringent monitoring and the early treatment of high-risk patients, is essential for improving patient survival. Cancer cells exhibit alterations in metabolic pathways that enable them to maintain rapid growth and proliferation, which are quite different from the metabolic pathways of normal cells. Fumarate hydratase (FH, fumarase) is a well-known tricarboxylic acid cycle enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. The current study sought to investigate the relationship between FH expression levels and the outcome of patients with lung cancer. FH was knocked down in lung cancer cells using shRNA or overexpressed using a vector, and the effect on migration ability was assessed. Furthermore, the role of AMP-activated protein kinase (AMPK) phosphorylation and disabled homolog 2 in the underlying mechanism was investigated using an AMPK inhibitor approach. The results showed that in lung cancer tissues, low FH expression was associated with lymph node metastasis, tumor histology and recurrence. In addition, patients with low FH expression exhibited a poor overall survival in comparison with patients having high FH expression. When FH was overexpressed in lung cancer cells, cell migration was reduced with no effect on cell proliferation. Furthermore, the level of phosphorylated (p-)AMPK, an energy sensor molecule, was upregulated when FH was knocked down in lung cancer cells, and the inhibition of p-AMPK led to an increase in the expression of disabled homolog 2, a tumor suppressor protein. These findings suggest that FH may serve as an effective biomarker for predicting the prognosis of lung cancer and as a therapeutic mediator.

The impact of the synergistic effect of SO2 and PM2.5/PM10 on obstructive lung disease in subtropical Taiwan.

Background: Chronic Obstructive lung diseases (COPD) are complex conditions influenced by various environmental, lifestyle, and genetic factors. Ambient air pollution has been identified as a potential risk factor, causing 4.2 million deaths worldwide in 2016, accounting for 25% of all COPD-related deaths and 26% of all respiratory infection-related deaths. This study aims to evaluate the associations among chronic lung diseases, air pollution, and meteorological factors. Methods: This cross-sectional study obtained data from the Taiwan Biobank and Taiwan Air Quality Monitoring Database. We defined obstructive lung disease as patients with FEV1/FVC < 70%. Descriptive analysis between spirometry groups was performed using one-way ANOVA and the chi-square or Fisher's exact test. A generalized additive model (GAM) was used to evaluate the relationship between SO2 and PM2.5/PM10 through equations and splines fitting. Results: A total of 2,635 participants were enrolled. Regarding environmental factors, higher temperature, higher relative humidity, and lower rainfall were risk factors for obstructive lung disease. SO2 was positively correlated with PM10 and PM2.5, with correlation coefficients of 0.53 (p < 0.0001) and 0.52 (p < 0.0001), respectively. Additionally, SO2 modified the relative risk of obstructive impairment for both PM10 [ß coefficient (ß) = 0.01, p = 0.0052] and PM2.5 (ß = 0.01, p = 0.0155). Further analysis per standard deviation (per SD) increase revealed that SO2 also modified the relationship for both PM10 (ß = 0.11, p = 0.0052) and PM2.5 (ß = 0.09, p = 0.0155). Our GAM analysis showed a quadratic pattern for SO2 (per SD) and PM10 (per SD) in model 1, and a quadratic pattern for SO2 (per SD) in model 2. Moreover, our findings confirmed synergistic effects among temperature, SO2 and PM2.5/PM10, as demonstrated by the significant associations of bivariate (SO2 vs. PM10, SO2 vs. PM2.5) thin-plate smoothing splines in models 1 and 2 with obstructive impairment (p < 0.0001). Conclusion: Our study showed high temperature, humidity, and low rainfall increased the risk of obstructive lung disease. Synergistic effects were observed among temperature, SO2, and PM2.5/PM10. The impact of air pollutants on obstructive lung disease should consider these interactions.