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Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normal--tumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase--Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer. [ABSTRACT FROM AUTHOR]

Background: High Snail expression is known as a poor prognostic factor in breast cancer. However, its prognostic impact for breast cancer with different molecular subtypes is still controversial. Methods: Snail expression was examined by immunohistochemistry in tissue microarray slides of 85 corresponding tumor-adjacent normal (CTAN) and 247 breast invasive ductal carcinoma (IDC) tissues. Multivariable Cox regression analysis was used to assess the impact of Snail expression on survival rate by different molecular subtypes of breast IDC patients. Results: The level of Snail expression in IDC tumor tissues was significantly higher than that in CTAN tissues. Moreover, high Snail expression had direct impacts on poor disease specific survival (DSS) and disease-free survival (DFS) in breast IDC patients with human epidermal growth factor receptor 2 (HER2)-positive and human epidermal growth factor receptor (EGFR)-positive statuses as well as the HER2 intrinsic subtype. Additionally, breast IDC patients with a combination of three prognostic factors, including high Snail expression and HER2-positive and EGFR-positive statuses, had much poor DSS and DFS with a statistically significant linear trend. Conclusion: High Snail expression could predict a poor prognosis for breast IDC patients with HER2/EGFR-positive subtypes. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are more than 200 nucleotides in length and lack transcriptional ability. The biological function of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. The aim of this study was to identify the dysfunction of lncRNA in OSCC. Results: We analyzed the transcriptome profiles of human OSCC tissues and paired adjacent normal tissues from two patients through a next-generation sequencing approach. A total of 14 lncRNAs were upregulated (fold change ≥3) and 13 were downregulated (fold change ≤ -3) in OSCC tissues compared with the adjacent normal tissues. SOX21- AS1 was subjected to further analysis, revealing that the expression levels of SOX21-AS1 significantly decreased in OSCC compared with the adjacent normal tissue. The promoter activity of SOX21-AS1 was obviously suppressed by in vitro methylation. The DNA methylation status of the SOX21-AS1 promoter was analyzed using combined bisulfite restriction analysis, revealing that the aberrant promoter hypermethylation of SOX21-AS1 was observed frequently in OSCC tissues. The effects of SOX21-AS1 on cell proliferation and invasion were examined through transient transfection. Our data showed that SOX21-AS1 could significantly suppress oral cancer cell growth and invasion. Furthermore, the low expression level of SOX21-AS1 was significantly correlated with an advanced stage (P =0.047), large tumor size (P = 0.033), and poor disease-specific survival in OSCC patients (P = 0.002). Conclusions: SOX21-AS1 was identified as susceptible dysfunction correlated with promoter hypermethylation in OSCC. Low SOX21-AS1 expression may be an adverse prognostic biomarker for OSCC. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRs) are a class of small endogenous non-coding RNAs of ~21-24 nucleotides in length. Previous studies have indicated that miR-196b has either an oncogenic or tumor-suppressive function in various types of cancer. However, the biological role of miR-196b in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, the expression levels of miR-196b were examined in oral cancer tissues and corresponding adjacent normal tissues from 69 OSCC patients using stem-loop reverse transcription-quantitative polymerase chain reaction. The results indicated that miR-196b was significantly overexpressed in OSCC tissues compared with the corresponding adjacent normal tissue samples (64 of 69, 92.7%, P<0.001). Analysis of the methylation status of the miR-196b gene indicated more frequent hypomethylation of the CpG islands located upstream of the miR-196b gene in the OSCC tissues than in the adjacent normal tissues (32 of 69, 46.3%), and the methylation status of miR-196b correlated inversely with its expression levels. Furthermore, the unmethylated status of the miR-196b promoter correlated with poor disease-specific survival in OSCC patients (P=0.035). Functional analysis revealed that ectopic miR-196b expression promoted oral cancer cell migration and invasion abilities, and that silencing of miR-196b could abrogate in vitro migration and invasion of oral cancer cells. Collectively, the present findings indicate that the epigenetic regulation of miR-196b expression plays a crucial role in modulating cell migration and invasion during OSCC progression, and thus may serve as a potential prognosis marker or therapeutic target for OSCC. [ABSTRACT FROM AUTHOR]

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1a (CK1a), a suppressor of pro-metastatic TCF4/b-catenin signaling. Inversely, CK1a is upregulated upon NIFK knockdown. The silencing of CK1a expression in NIFK-silenced cells restores TCF4/b-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1a) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1a repression, which activates TCF4/b-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation. [ABSTRACT FROM AUTHOR]

Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor--initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFα expression and activation of its downstream p38--MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFα--p38--MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET--TNFα--p38--MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy. [ABSTRACT FROM AUTHOR]

The article discusses the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the sudden progression to cardiac dysfunction and pulmonary edema by using an animal model. The researchers microinjected 6-hydroxydopamine or vitamin C into nucleus tractus solitarii of the Sprague-Dawley rat. Results showed early hexamethonium treatment reduces acute excessive release of catecholamines to prevent cardiac dysfunction and pulmonary edema to increase survival rate.

Background: MicroRNAs (miRNAs) are short noncoding RNAs (approximately 22 nucleotides in length) that play important roles in breast cancer progression by downregulating gene expression. The detailed mechanisms and biological functions of miRNA molecules in breast carcinogenesis have yet to be fully elucidated. This study used bioinformatics and experimental approaches to conduct detailed analysis of the dysregulated miRNAs, arm selection preferences, 3' end modifications, and position shifts in isoforms of miRNAs (isomiRs) in breast cancer. Methods: Next-generation sequencing (NGS) data on breast cancer was obtained from the NCBI Sequence Read Archive (SRA). The miRNA expression profiles and isomiRs in normal breast and breast tumor tissues were determined by mapping the clean reads back to human miRNAs. Differences in miRNA expression and pre-miRNA 5p/3p arm usage between normal and breast tumor tissues were further investigated using stem-loop reverse transcription and real-time polymerase chain reaction. Results: The analysis identified and confirmed the aberrant expression of 22 miRNAs in breast cancer. Results from pathway enrichment analysis further indicated that the aberrantly expressed miRNAs play important roles in breast carcinogenesis by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Data also indicated that the position shifts in isomiRs and 3' end modifications were consistent in breast tumor and adjacent normal tissues, and that 5p/3p arm usage of some miRNAs displayed significant preferences in breast cancer. Conclusions: Expression pattern and arm selection of miRNAs are significantly varied in breast cancers through analyzing NGS data and experimental approach. These miRNA candidates have high potential to play critical roles in the progression of breast cancer and could potentially provide as targets for future therapy. [ABSTRACT FROM AUTHOR]

Given the need for tools for early and accurate diagnosis, prediction of disease progression, and monitoring efficacy of therapeutic agents for AD, the study of cerebrospinal fluid (CSF) biomarkers has become a rapidly growing field of research. Several studies have reported conflicting data regarding the relationships between CSF biomarkers and dementia severity. In this study, we have focused on the identification of CSF biomarkers and their correlations with the impairment of different cognitive domains measured using the Cognitive Abilities Screening Instrument (CASI). Patients with AD (n=28), non-AD dementia (n=16), other neurological disorders (OND, n=14), and healthy controls (HC, n=21) were enrolled. Our results revealed significantly higher CSF total tau (t-tau) and lower amyloid-β_{42} levels in AD patients compared with those in HC and OND groups. Moreover, our data show that CSF t-tau levels, but not Aβ_{42} levels, have an inverse correlation with the score of short-term memory in CASI for patients with AD (Spearman: r=-0.444; p=0.018). This data might indicate that the higher CSF t-tau level is associated with more NFT pathology and more severe impairment of short-term memory in AD patients. [ABSTRACT FROM AUTHOR]

A case-control study was conducted to investigate the association between the consumption of local common foods that are rich in vitamin A and the risk of lung cancer in Taiwan. A total of 301 incident lung cancer cases, 602 hospital controls, and 602 neighborhood controls were recruited. The consumption of 13 food items and vitamin supplements was estimated by use of a food frequency questionnaire. The conditional logistic regression models were used to estimate the adjusted odds ratios (AOR) and 95% confidence intervals (CI) for lung cancer risk with each control group as reference by adjustment of covariates. A reduced risk for lung cancer was found to be associated with increased intakes of vitamin A, α-carotene, and β-carotene from 13 food items. More servings of vegetables (AOR for the highest versus the lowest quartile = 0.67-0.70, 95% CI = 0.42-1.08, plinear trend = 0.04), garland chrysanthemum (AOR for the highest versus the lowest tertile = 0.58-0.74, 95% CI = 0.37-1.14, plinear trend ≤ 0.04) and sweet potato leaves (AOR for the highest versus the lowest tertile = 0.43-0.65, 95% CI = 0.28-0.96, plinear trend ≤ 0.03) were associated with the reduced risk for lung cancer. In conclusion, higher consumption of vitamin A-rich vegetables, especially garland chrysanthemum and sweet potato leaves might provide potential protection from lung cancer. [ABSTRACT FROM AUTHOR]

The host genetic factors that determine the clinical outcomes forHelicobacter pylori-infected individuals remain unclear.To elucidate the relations amonginterleukin-1locus polymorphisms, andH. pyloriinfection in the development of duodenal ulcers.In a case–control study involving 168 control subjects and 147 patients with duodenal ulcer, biallelic polymorphisms of twointerleukin-1loci,IL-1B–511 andIL-1B+3954, as well as the penta-allelic variable number of tandem repeats ofinterleukin-1receptor antagonistIL-1RN, were genotyped, and theH. pyloristates of controls and patients were examined.Helicobacter pyloriinfection, male gender and the carriage ofIL-1RN*2 independently increased the risk of duodenal ulcer with odds ratios of 6.4 (95% confidence interval, 3.7–11.0), 1.9 (95% confidence interval, 1.1–3.4) and 2.7 (95% confidence interval, 1.1–6.8), respectively. Statistical analysis revealed an interaction betweenIL-1RN*2 andH. pyloriinfection with the duodenal ulcer risk conferred by theH. pyloriinfection substantially increased (odds ratios, 22.6; 95% confidence interval, 5.9–86.5) by the carriage ofIL-1RN*2. In addition, a synergistic interaction betweenIL-1RN*2 and blood group O existed. The combined risk ofH. pyloriinfection, the carriage ofIL-1RN*2 and blood group O for duodenal ulcer was 27.5 (95% confidence interval, 3.1–243.6).This work is the first to verifyIL-1RN*2 as an independent factor that governs the development of duodenal ulcers. Our data indicate thatH. pyloriinfection andIL-1RN*2 synergistically determine susceptibility to duodenal ulcer. The blood group phenotype is possibly a crucial determinant for the outcome of the impact of aninterleukin-1locus polymorphism onH. pylori-infected individuals. [ABSTRACT FROM AUTHOR]