MAP3K11 facilitates autophagy activity and is correlated with malignancy of oral squamous cell carcinoma.

Autophagy-related 4B (ATG4B) is a protease required for core machinery of autophagy. Phosphorylation of ATG4B promotes autophagy and is correlated with poor outcome of cancer. However, little is known about the upstream kinases for ATG4B phosphorylation and their association with clinical outcomes of cancer patients. Through siRNA library screening, MAP3K11 was identified as a potential kinase that phosphorylates ATG4B and increases its proteolytic activity. Ablation of MAP3K11 attenuated pS383/392-ATG4B protein levels and autophagic flux in oral cancer cells. Moreover, loss of MAP3K11 inhibited oral cancer cell growth, migration/invasion, and synergized starvation-reduced cell viability. MAP3K11 knock-out cancer cells also showed growth inhibition in vivo. Furthermore, the protein level of MAP3K11 was higher in tumor tissues than that in adjacent normal tissues in patients with oral squamous cell carcinoma (OSCC), comprising 179 buccal mucosa squamous cell carcinoma (BMSCC) and 249 tongue squamous cell carcinoma (TSCC). MAP3K11 protein levels were positively correlated with ATG4B and pS383/392-ATG4B levels in patients with OSCC, particularly in TSCC. In addition, high coexpression of MAP3K11 and ATG4B was associated with poor disease-specific survival in BMSCC and TSCC, while high coexpression of MAP3K11 and pS383/392-ATG4B was associated with unfavorable disease-free survival in BMSCC and TSCC. Taken together, our results indicated that MAP3K11 stimulated activity of ATG4B and autophagy, which may confer to malignancy of cancer cells. The expression of MAP3K11 and ATG4B was further associated with poor survival of OSCC, suggesting MAP3K11 could serve as a theranostic target of patients with OSCC.

Identifying Circulating MicroRNA in Kawasaki Disease by Next-Generation Sequencing Approach.

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs; therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes >2 and <0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-ß, epithelial-mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p < 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.

Effect of EGFR on SQSTM1 Expression in Malignancy and Tumor Progression of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types of cancer. However, the association of EGFR and SQSTM1 in OSCC is still unknown. Our results show that the expression levels of SQSTM1 and EGFR proteins are higher in tumor tissues than in the corresponding tumor-adjacent (CTAN) tissues of OSCC patients. The expression levels of SQSTM1 were positively associated with the EGFR expression level. High co-expression of SQSTM1 and EGFR is associated with poor prognosis in OSCC patients. Moreover, SQSTM1 expression is decreased in EGFR-knockdown cells. Cell growth and invasion/migration are also decreased in cells with single/combined knockdowns of EGFR and SQSTM1 or in SQSTM1-knockdown cells without EGFR kinase inhibitor Lapatinib treatment compared to that in scrambled cells. However, cell growth and invasion/metastasis were not significantly different between the scrambled cells and SQSTM1-knockdown cells in the presence of Lapatinib. This study is the first to indicate the biological roles and clinical significance of SQSTM1 regulation by EGFR in OSCC.

Prognostic role of RECK in pathological outcome-dependent buccal mucosa squamous cell carcinoma.

BACKGROUND: Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features. MATERIALS AND METHODS: The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models. RESULTS: The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer. CONCLUSION: The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.

Guanylate-binding protein 6 is a novel biomarker for tumorigenesis and prognosis in tongue squamous cell carcinoma.

OBJECTIVES: Guanylate-binding protein 6 (GBP6) is a member of the guanylate-binding protein family, and its role in cancer has not yet been reported. We aimed to investigate the clinical significance of GBP6 in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Next-generation sequencing was applied for analyzing differential gene expression profiling between corresponding tumor adjacent normal (CTAN) and tumor tissue from two paired OSCC patients. Real-time PCRs (RT-PCRs) were used to investigate the gene expression level of GBP6 of CTAN and tumor tissue samples from 14 TSCC patients. Immunohistochemistry was used to investigate the protein expression level of GBP6 in tumor tissues and paired CTAN tissues from 488 OSCC patients, including 183 buccal mucosa squamous cell carcinoma (BMSCC), 245 tongue squamous cell carcinoma (TSCC), and 60 lip squamous cell carcinoma (LSCC) patients. RESULTS: Compared with CTAN tissues of OSCC patients, GBP6 is identified as a downregulated gene using the NGS platform, which was confirmed in 14 OSCC patients by RT-PCR. Moreover, protein expression level of GBP6 in tumor tissues was lower than that in CTAN tissues and the low GBP6 expression was correlated with poor cell differentiation/lymph node metastasis in TSCC patients. In addition, TSCC patients with low expression levels of GBP6 had poor disease-specific survival rate. CONCLUSION: The low expression of GBP6 was associated with tumorigenesis and poor prognosis in OSCC patients, especially in TSCC patients. CLINICAL RELEVANCE: GBP6 may serve as a novel favorable diagnostic and prognostic biomarker in TSCC patients.

Differential clinical significance of COL5A1 and COL5A2 in tongue squamous cell carcinoma.

BACKGROUND: Type V collagen (COL5), in the functional heterotrimer [α1(V)2 α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. MATERIALS AND METHODS: The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate. RESULTS: Expression level of COL5A1 was significantly increased in tumor tissues (P < 0.001) compared to that in corresponding adjacent normal tissues. High expression level of COL5A1 was associated with advanced pathological stage (III, IV, P = 0.015) and lymph node metastasis (P = 0.005) of TSCC patients. High expression level of COL5A1 was also correlated with poor disease-specific survival (DSS, P = 0.001) and disease-free survival (DFS, P = 0.003) in TSCC patients. However, high expression level of COL5A2 was correlated with better DFS in TSCC patients (P = 0.043). Moreover, co-expression level of high (COL5A1)2 /low (COL5A2) heterotrimer was correlated with worse DSS (P = 0.004) and DFS (P = 0.004). CONCLUSION: COL5A1 is an unfavorable factor for tumorigenesis, clinicopathological outcomes, and prognosis, whereas COL5A2 is only a favorable factor for prognosis in TSCC. The co-expression of high (COL5A1)2/low (COL5A2) heterotrimer is a more potential unfavorable factor for prognosis in TSCC.

Knowledge, Attitude and Practice Survey of Prescribing Opioids for Chronic Noncancer Pain in Taiwan-Comparison of Pain and Non-Pain Physicians.

BACKGROUND: Prescribing opioids for chronic noncancer pain (CNCP) has been strictly regulated in Taiwan. This study was undertaken to survey pain and non-pain related physicians' knowledge, attitudes, and practices regarding prescribing opioids for CNCP. METHODS: A questionnaire survey was conducted in this comparison study. All 66 physicians who were treating officially registered CNCP outpatients were visited and completed anonymous questionnaires. The other physicians (anesthesiologists, oncologists, and non-pain physicians) were surveyed by a mailed questionnaire. RESULTS: A total of 266 (75%) questionnaires were received from 355 board-certified physicians. More CNCP physicians (81.8%) and anesthesiologists (69.7%) had received prior CNCP-related training courses than had oncologists (21.2%) and non-pain physicians (10.3%). Varied proportions of physicians by type were unfamiliar with the Taiwan opioid regulations (16.7-86.8%) and would accordingly skip or reduce dosage of opioid prescriptions (27.3-73.5%). In addition, non-pain physicians had a significantly lower knowledge level, more negative attitudes, and greater hesitation about prescribing opioids compared to the pain-related physicians (P < 0.001). CNCP physicians who had received CNCP-related training courses had a higher knowledge score than did those not receiving training (P = 0.002). Overall, the leading barriers for prescribing opioids were inadequate knowledge of pain management (76%), physician reluctance (73%), and family reluctance (78%). CONCLUSION: There are substantial knowledge gaps, negative attitudes, and hesitation toward prescribing long-term opioids for CNCP patients by physicians in Taiwan, suggesting that efforts are needed to improve postgraduate education regarding adequate opioid management for CNCP.

Isocitrate dehydrogenase 1-snail axis dysfunction significantly correlates with breast cancer prognosis and regulates cell invasion ability.

BACKGROUND: The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown. METHODS: In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion. RESULTS: The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08-2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer. CONCLUSION: Our findings revealed that a IDH1low/Snailhigh molecular signature could serve as an independent biomarker for poor prognosis in breast cancer.

miR-105/93-3p promotes chemoresistance and circulating miR-105/93-3p acts as a diagnostic biomarker for triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20-30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. METHODS: The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student's t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. RESULTS: miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/ß-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. CONCLUSIONS: miR-105/93-3p activates Wnt/ß-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC.

Antioxidant enzymes in oral verrucous carcinoma.

BACKGROUND: Verrucous carcinoma is a non-metastasizing variant of welldifferentiated squamous cell carcinoma, which has been associated with reactive oxygen species generated by betel quid chewing. Salivary antioxidant systems have been suggested to play a protective role in reducing the oxidative damage. Herein, we investigated the difference of the enzymatic antioxidant system expressions in oral verrucous carcinoma and oral squamous cell carcinoma. METHODS: The enzymatic antioxidant system expressions, including manganese superoxide dismutase, glutathione peroxidase, and catalase were evaluated by immunohistochemistry in a series of 202 surgically resected oral squamous cell carcinoma and 20 oral verrucous carcinoma specimens, using tissue microarray slides. RESULTS: The immuno-staining intensities of superoxide dismutase and glutathione peroxidase were strongest in the oral squamous cell carcinoma group than in verrucous carcinoma. The catalase expression showed no difference between different pathological groups. CONCLUSIONS: The different degrees of superoxide dismutase and glutathione expressions in verrucous carcinoma and squamous cell carcinoma may be helpful for pathologists to differentiate these two entities, especially between oral verrucous carcinoma and well differentiated oral squamous cell carcinoma.

Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study.

BACKGROUND/PURPOSE: Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids. METHODS: An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. RESULTS: For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ∼50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. CONCLUSION: This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.

Platelet Endothelial Cell Adhesion Molecule-1 Gene Polymorphisms are Associated with Coronary Artery Lesions in the Chronic Stage of Kawasaki Disease.

BACKGROUND: Kawasaki disease is the most common cause of pediatric acquired heart disease. The role of platelet endothelial cell adhesion molecule-1 in the inflammatory process has been documented. To date, no report has investigated the relationship between coronary artery lesions of Kawasaki disease and platelet endothelial cell adhesion molecule-1 polymorphisms. METHODS: A total of 114 Kawasaki disease children with coronary artery lesions and 185 Kawasaki disease children without coronary artery lesions were recruited in this study. The TaqMan assay was conducted to identify the genotype in this case-control study. RESULTS: In three single nucleotide polymorphisms (Leu125Val, Ser563Asn, and Arg670Gly) of platelet endothelial cell adhesion molecule-1, we found that the Leu-Ser-Arg haplotype was associated with a significantly increased risk for coronary artery lesions in the chronic stage (odds ratio 3.05, 95% confidence interval 1.06-8.80, p = 0.039), but not for coronary artery lesions in the acute stage. Analysis based on the diplotypes of platelet endothelial cell adhesion molecule-1 also showed that Kawasaki disease with one or two alleles of Leu-Ser-Arg had a significantly increased risk of chronic coronary artery lesions (odds ratio 3.38, 95% confidence interval 1.11-10.28, p = 0.032) and had increased platelet counts after Kawasaki disease was diagnosed, as compared to those with other diplotypes. CONCLUSIONS: The haplotype of platelet endothelial cell adhesion molecule-1 Leu-Ser-Arg might be associated with the increased platelet counts and the following risk of chronic coronary artery lesions in a dominant manner in Kawasaki disease.

Global DNA hypomethylation is associated with the development and poor prognosis of tongue squamous cell carcinoma.

BACKGROUNDS: Oral cancer is the 4th leading cause of cancer death for males and the top cancer in young adult males in Taiwan. Tongue squamous cell carcinoma (TSCC) is a common oral cancer and generally associated with poor prognosis. Global DNA hypomethylation at the 5 position of cytosine (5mC) is a well-known epigenetic feature of cancer. Therefore, the purpose of this study was to investigate the relationship of the global 5mC content with the tumorigenesis and prognosis of patients with TSCC. METHODS: The levels of global 5mC were evaluated by immunohistochemistry using tissue microarray slides of 248 surgically resected TSCC and 202 corresponding tumor adjacent normal (TAN) tissues. RESULTS: We found that the level of 5mC in TSCC (P < 0.001) was significantly decreased as compared to TAN. Among TSCC tissues, decreased levels of 5mC were associated with female gender (P = 0.036). In addition, the global hypomethylation was associated with the poor disease-specific survival in TSCC patients (adjusted hazard ratio: 1.55, P = 0.043), especially for patients in older age group (> 50 years, P = 0.013), with moderate or poor cell differentiation (P = 0.044), early stage of disease (I-II, P = 0.046), small tumor size (T1-T2, P = 0.005), without lymph node involvement (P = 0.041), and ever received postoperative radiotherapy (P = 0.009). CONCLUSIONS: Global hypomethylation was an independent biomarker for the development and poor prognosis of TSCC.

Association of OCT4, SOX2, and NANOG expression with oral squamous cell carcinoma progression.

BACKGROUND: OCT4, SOX2, and NANOG are major transcription factors related to stem cell self-renewal and differentiation. The aim of this study was to examine the association of OCT4, SOX2, and NANOG expression levels with the development and prognosis of patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Expression levels of OCT4, SOX2, and NANOG were evaluated by immunohistochemistry with tissue microarray slides of 436 OSCC, 362 corresponding tumor-adjacent normal (CTAN) tissues, and 71 normal uvula epithelium tissues. The clinicopathologic and follow-up data of the OSCC patients were recorded. RESULTS: OCT4 expression was significantly higher in normal and CTAN tissues than in tumor tissue (both P < 0.001). SOX2 expression in CTAN tissue was significantly higher than that in normal (P = 0.021) and tumor tissues (P < 0.001). However, NANOG expression was significantly higher in CTAN (P = 0.014) and tumor tissues (P = 0.009) than in normal tissue. Higher OCT4 and SOX2 expressions were associated with earlier AJCC stage (P = 0.002 and P < 0.001), small tumor size (P = 0.017 and P = 0.001), and the absence of lymph node metastasis (P = 0.015 and P = 0.025). Higher levels of SOX2 expression were associated with better disease-specific survival (P = 0.002) even after adjustment for clinicopathologic factors. DISCUSSION: OCT4 and SOX2 are biomarkers of tumorigenesis and early stage OSCC. SOX2 is an independent prognostic factor for OSCC.

Reduction of global 5-hydroxymethylcytosine is a poor prognostic factor in breast cancer patients, especially for an ER/PR-negative subtype.

DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

A survey of dermatological diseases among older male adults of a Veterans Home in Southern Taiwan.

BACKGROUNDS: The dermatologic diseases of the dependent elderly require special attention. METHODS: This screening and treatment service of dermatological diseases was conducted in a Veterans Home in Southern Taiwan. RESULTS: A total of 337 male residents were screened with mean age 83 years (range 46-99). 271 (80.4 %) residents were in dependent status. Their skin diseases were recorded and the distribution pattern was compared with those in the other studies. Comparing by Chi-square test, scabies, bacterial infection, chronic ulcers, pruritus, and brown spots on the legs were present significantly in certain major systemic diseases, respectively. Higher prevalence of certain skin diseases was related to the severity of disability or major systemic diseases of the residents. Actinic keratosis and non-melanoma skin cancers were early detected and managed. CONCLUSIONS: The distribution patterns of skin diseases in a Veterans Home were unique. It provides the evidences on appropriate management and key nursing points for dependent elderly.

Hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis.

OBJECTIVES: Among enterovirus 71 infections, brainstem encephalitis progressing abruptly to cardiac dysfunction and pulmonary edema causes rapid death within several hours. However, no currently known early indicators and treatments can monitor or prevent the unexpectedly fulminant course. We investigate the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the abrupt progression to cardiac dysfunction and pulmonary edema by using an animal model. DESIGN: Treatment study. SETTING: Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We microinjected 6-hydroxydopamine or vitamin C into nucleus tractus solitarii of the rat and evaluated the cardiopulmonary changes after treatment with ganglionic blocker. MEASUREMENTS AND MAIN RESULTS: The time course of changes in the heart and lungs of rats with brainstem lesions were investigated. Rats were administered 6-hydroxydopamine to induce brainstem lesions, causing acute hypertension in 10 minutes and acute elevations of catecholamines accompanied by acute cardiac dysfunction and increased strong expressions of connexin 43 gap junction protein in heart and lung specimens by immunohistochemical staining within 3 hours. Severe pulmonary hemorrhagic edema was produced within 6 hours, and the rats expired rapidly within 7 hours. After hexamethonium treatment, it was found that the acute hypertension induced by 6-hydroxydopamine lesions was immediately reversed and the acute high rise of catecholamine serum level was significantly attenuated within 3 hours, accompanied by preserved cardiac output and decreased expressions of connexin 43 in the heart and lungs. No pulmonary edema occurred and the rats survived for more than 14 hours. CONCLUSIONS: Early hexamethonium treatment attenuates acute excessive release of catecholamines to prevent cardiac dysfunction and pulmonary edema for increasing survival rate.

Analysis of factors correlated with the development of pseudophakic retinal detachment--a long-term study in a single medical center.

BACKGROUND: To analyze the possible factors correlated with the development of retinal detachment (RD) after cataract extraction and intraocular lens (IOL) implantation in a single medical center. METHODS: We performed a retrospective chart review of patients receiving cataract extraction and posterior chamber IOL implantation from January 2000 to June 2010 at one medical center. We analyzed demographic characteristics, medical history, axial length (AL), operation method, intraoperative and postoperative complications, Nd-YAG posterior capsulotomy and records for RD. RESULTS: The 9,184 patients analyzed included 6,464 males and 2,720 females, mean age 71.8 ± 9.1 years. The cumulative 7-year RD rate was 0.84 %. Young age, long axial length and intraoperative complications were significantly associated with the risk of pseudophakic RD. Although not a statistically significant factor for the whole group, Nd-YAG posterior capsulotomy represented a significant risk in those with high myopia stratified by axial length. In moderate myopic group, both intra-operative complication and Nd-YAG posterior capsulotomy showed more tendencies to increase risk of RD, but only intra-operative complication had significant difference. CONCLUSIONS: Young age, myopia and intra-operative complications were significant risk factors for the development of RD after cataract extraction and IOL implantation. Post-operative Nd-YAG posterior capsulotomy led to more risk for pseudophakic RD in myopic eyes, especially high myopia. The risk of pseudophakic RD should be considered before deciding to perform cataract extraction and the following capsulotomy in myopic eyes, particularly those for refractive indication in young patients.

Carboxyl-terminal modulator protein facilitates tumor metastasis in triple-negative breast cancer.

Currently, the survival rate for breast cancer is more than 90%, but once the cancer cells metastasize to distal organs, the survival rate is dramatically reduced, to less than 30%. Triple-negative breast cancer accounts for 15-20% of all breast cancers. Triple-negative breast cancer (TNBC) is associated with poor prognostic and diagnostic outcomes due to the limiting therapeutic strategies, relative to non-TNBC breast cancers. Therefore, the development of targeted therapy for TNBC metastasis remains an urgent issue. In this study, high Carboxyl-terminal modulator protein (CTMP) is significantly associated with recurrence and disease-free survival rate in TNBC patients. Overexpression of CTMP promotes migration and invasion abilities in BT549 cells. Down-regulating of CTMP expression inhibits migration and invasion abilities in MDA-MB-231 cells. In vivo inoculation of high-CTMP cells enhances distant metastasis in mice. The metastasis incidence rate is decreased in mice injected with CTMP-downregulating MDA-MB-231 cells. Gene expression microarray analysis indicates the Akt-dependent pathway is significantly enhanced in CTMP overexpressing cells compared to the parental cells. Blocking Akt activation via Akt inhibitor treatment or co-expression of the dominant-negative form of Akt proteins successfully abolishes the CTMP mediating invasion in TNBC cells. Our findings suggest that CTMP is a potential diagnostic marker for recurrence and poor disease-free survival in TNBC patients. CTMP promotes TNBC metastasis via the Akt-activation-dependent pathway.

The activation of EP300 by F11R leads to EMT and acts as a prognostic factor in triple-negative breast cancers.

Cancer progression is influenced by junctional adhesion molecule (JAM) family members. The relationship between JAM family members and different types of cancer was examined using The Cancer Genome Atlas dataset. mRNA levels of the F11R (F11 receptor) in tumours were inversely correlated to the expression of JAM-2 and JAM-3. This relationship was unique to breast cancer (BCa) and was associated with poor prognosis (p = 0.024, hazard ratio = 1.44 [1.05-1.99]). A 50-gene molecular signature (prediction analysis of microarray 50) was used to subtype BCa. F11R mRNA expression significantly increased in human epidermal growth factor receptor 2 (HER2)-enriched (p = 0.0035) and basal-like BCa tumours (p = 0.0005). We evaluated F11R protein levels in two different compositions of BCa subtype patient tissue array cohorts to determine the relationship between BCa subtype and prognosis. Immunohistochemistry staining revealed that a high F11R protein level was associated with poor overall survival (p < 0.001; Taipei Medical University [TMU] cohort, p < 0.001; Kaohsiung Veterans General Hospital [KVGH] cohort) or disease-free survival (p < 0.001 [TMU cohort], p = 0.034 [KVGH cohort]) in patients with BCa. Comparison of F11R levels in different subtypes revealed the association of poor prognosis with high levels of F11R among luminal (p < 0.001 [TMU cohort], p = 0.027 [KVGH cohort]), HER2 positive (p = 0.018 [TMU cohort], p = 0.037 [KVGH cohort]), and triple-negative (p = 0.013 [TMU cohort], p = 0.037 [KVGH cohort]) BCa. F11R-based RNA microarray analysis and Ingenuity Pathway Analysis were successful in profiling the detailed gene ontology of triple-negative BCa cells regulated by F11R. The EP300 transcription factor was highly correlated with F11R in BCa (R = 0.51, p < 0.001). By analysing these F11R-affected molecules with the L1000CDs datasets, we were able to predict some repurposing drugs for potential application in F11R-positive BCa treatment.