Inhibition of Polyinosinic-Polycytidylic Acid-Induced Acute Pulmonary Inflammation and NF-κB Activation in Mice by a Banana Plant Extract.

NF-κB activation is pivotal for the excess inflammation causing the critical condition and mortality of respiratory viral infection patients. This study was aimed to evaluate the effect of a banana plant extract (BPE) on suppressing NF-κB activity and acute lung inflammatory responses in mice induced by a synthetic double-stranded RNA viral mimetic, polyinosinic-polycytidylic acid (poly (I:C)). The inflammatory responses were analyzed by immunohistochemistry and HE stains and ELISA. The NF-κB activities were detected by immunohistochemistry in vivo and immunofluorescence and Western blot in vitro. Results showed that BPE significantly decreased influx of immune cells (neutrophils, lymphocytes, and total WBC), markedly suppressed the elevation of pro-inflammatory cytokines and chemokines (IL-6, RANTES, IFN-γ, MCP-1, keratinocyte-derived chemokine, and IL-17), and restored the diminished anti-inflammatory IL-10 in the bronchoalveolar lavage fluid (BALF) of poly (I:C)-stimulated mice. Accordingly, HE staining revealed that BPE treatment alleviated poly (I:C)-induced inflammatory cell infiltration and histopathologic changes in mice lungs. Moreover, immunohistochemical analysis showed that BPE reduced the pulmonary IL-6, CD11b (macrophage marker), and nuclear NF-κB p65 staining intensities, whilst restored that of IL-10 in poly (I:C)-stimulated mice. In vitro, BPE antagonized poly(I:C)-induced elevation of IL-6, nitric oxide, reactive oxygen species, NF-κB p65 signaling, and transient activation of p38 MAPK in human lung epithelial-like A549 cells. Taken together, BPE ameliorated viral mimic poly(I:C)-induced acute pulmonary inflammation in mice, evidenced by reduced inflammatory cell infiltration and regulation of both pro- and anti-inflammatory cytokines. The mechanism of action might closely associate with NF-κB signaling inhibition.

Managing the transition in cervical screening methods for Taiwan: Policy recommendations and perspectives.

Since government-provided annual cervical cytology testing for all Taiwanese women aged 30 years or older became available in 1995, both cervical cancer incidence and death have decreased significantly. However, with the 2018 introduction of the national immunization program for human papillomavirus (HPV) vaccination in all schoolgirls aged 13-15 years old, the positive predictive value of cytology testing is expected to decrease with rising vaccination rates, and therefore a transition to more sensitive HPV-based testing may be needed. This position paper, derived from discussions by a panel of experts in cervical cancer screening, provides short-, medium-, and long-term policy recommendations to manage the transition between cervical screening methods for Taiwan. The recommendations include concrete suggestions regarding testing procedures, standards, accreditation, monitoring, promotion, and implementation. It is hoped that comprehensive preparation and management of this transition will enable Taiwan to repeat the previous successes of the cervical cytology testing program.

The power of heteronemin in cancers.

Heteronemin (Haimian jing) is a sesterterpenoid-type natural marine product that is isolated from sponges and has anticancer properties. It inhibits cancer cell proliferation via different mechanisms, such as reactive oxygen species (ROS) production, cell cycle arrest, apoptosis as well as proliferative gene changes in various types of cancers. Recently, the novel structure and bioactivity evaluation of heteronemin has received extensive attention. Hormones control physiological activities regularly, however, they may also affect several abnormalities such as cancer. L-Thyroxine (T4), steroid hormones, and epidermal growth factor (EGF) up-regulate the accumulation of checkpoint programmed death-ligand 1 (PD-L1) and promote inflammation in cancer cells. Heteronemin suppresses PD-L1 expression and reduces the PD-L1-induced proliferative effect. In the current review, we evaluated research and evidence regarding the antitumor effects of heteronemin and the antagonizing effects of non-peptide hormones and growth factors on heteronemin-induced anti-cancer properties and utilized computational molecular modeling to explain how these ligands interacted with the integrin αvß3 receptors. On the other hand, thyroid hormone deaminated analogue, tetraiodothyroacetic acid (tetrac), modulates signal pathways and inhibits cancer growth and metastasis. The combination of heteronemin and tetrac derivatives has been demonstrated to compensate for anti-proliferation in cancer cells under different circumstances. Overall, this review outlines the potential of heteronemin in managing different types of cancers that may lead to its clinical development as an anticancer agent.

Heteronemin and Tetrac Induce Anti-Proliferation by Blocking EGFR-Mediated Signaling in Colorectal Cancer Cells.

Overexpressed EGFR and mutant K-Ras play vital roles in therapeutic resistance in colorectal cancer patients. To search for an effective therapeutic protocol is an urgent task. A secondary metabolite in the sponge Hippospongia sp., Heteronemin, has been shown to induce anti-proliferation in several types of cancers. A thyroxine-deaminated analogue, tetrac, binds to integrin αvß3 to induce anti-proliferation in different cancers. Heteronemin- and in combination with tetrac-induced antiproliferative effects were evaluated. Tetrac enhanced heteronemin-induced anti-proliferation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC). Heteronemin and tetrac arrested cell cycle in different phases. Combined treatment increased the cell accumulation in sub-G1 and S phases. The combined treatment also induced the inactivation of EGFR signaling and downregulated the phosphorylated ERK1/2 protein in both cell lines. Heteronemin and the combination showed the downregulation of the phosphorylated and total PI3K protein in HT-29 cells (KRAS WT CRC). Results by NanoString technology and RT-qPCR revealed that heteronemin and combined treatment suppressed the expression of EGFR and downstream genes in HCT-116 cells (KRAS MT CRC). Heteronemin or combined treatment downregulated genes associated with cancer progression and decreased cell motility. Heteronemin or the combined treatment suppressed PD-L1 expression in both cancer cell lines. However, only tetrac and the combined treatment inhibited PD-L1 protein accumulation in HT-29 cells (KRAS WT CRC) and HCT-116 cells (KRAS MT CRC), respectively. In summary, heteronemin induced anti-proliferation in colorectal cancer cells by blocking the EGFR-dependent signal transduction pathway. The combined treatment further enhanced the anti-proliferative effect via PD-L1 suppression. It can be an alternative strategy to suppress mutant KRAS resistance for anti-EGFR therapy.

Toxicologic Concerns with Current Medical Nanoparticles.

Nanotechnology is one of the scientific advances in technology. Nanoparticles (NPs) are small materials ranging from 1 to 100 nm. When the shape of the supplied nanoparticles changes, the physiological response of the cells can be very different. Several characteristics of NPs such as the composition, surface chemistry, surface charge, and shape are also important parameters affecting the toxicity of nanomaterials. This review covered specific topics that address the effects of NPs on nanomedicine. Furthermore, mechanisms of different types of nanomaterial-induced cytotoxicities were described. The distributions of different NPs in organs and their adverse effects were also emphasized. This review provides insight into the scientific community interested in nano(bio)technology, nanomedicine, and nanotoxicology. The content may also be of interest to a broad range of scientists.

Role of thyroid hormone-integrin αvß3-signal and therapeutic strategies in colorectal cancers.

Thyroid hormone analogues-particularly, L-thyroxine (T4) has been shown to be relevant to the functions of a variety of cancers. Integrin αvß3 is a plasma membrane structural protein linked to signal transduction pathways that are critical to cancer cell proliferation and metastasis. Thyroid hormones, T4 and to a less extend T3 bind cell surface integrin αvß3, to stimulate the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway to stimulate cancer cell growth. Thyroid hormone analogues also engage in crosstalk with the epidermal growth factor receptor (EGFR)-Ras pathway. EGFR signal generation and, downstream, transduction of Ras/Raf pathway signals contribute importantly to tumor cell progression. Mutated Ras oncogenes contribute to chemoresistance in colorectal carcinoma (CRC); chemoresistance may depend in part on the activity of ERK1/2 pathway. In this review, we evaluate the contribution of thyroxine interacting with integrin αvß3 and crosstalking with EGFR/Ras signaling pathway non-genomically in CRC proliferation. Tetraiodothyroacetic acid (tetrac), the deaminated analogue of T4, and its nano-derivative, NDAT, have anticancer functions, with effectiveness against CRC and other tumors. In Ras-mutant CRC cells, tetrac derivatives may overcome chemoresistance to other drugs via actions initiated at integrin αvß3 and involving, downstream, the EGFR-Ras signaling pathways.

Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells.

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated ß-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.

Combined Treatment of Heteronemin and Tetrac Induces Antiproliferation in Oral Cancer Cells.

BACKGROUND: Heteronemin, a marine sesterterpenoid-type natural product, possesses an antiproliferative effect in cancer cells. In addition, heteronemin has been shown to inhibit p53 expression. Our laboratory has demonstrated that the thyroid hormone deaminated analogue, tetrac, activates p53 and induces antiproliferation in colorectal cancer. However, such drug mechanisms are still to be studied in oral cancer cells. METHODS: We investigated the antiproliferative effects by Cell Counting Kit-8 and flow cytometry. The signal transduction pathway was measured by Western blotting analyses. Quantitative PCR was used to evaluate gene expression regulated by heteronemin, 3,3',5,5'-tetraiodothyroacetic acid (tetrac), or their combined treatment in oral cancer cells. RESULTS: Heteronemin inhibited not only expression of proliferative genes and Homo Sapiens Thrombospondin 1 (THBS-1) but also cell proliferation in both OEC-M1 and SCC-25 cells. Remarkably, heteronemin increased TGF-ß1 expression in SCC-25 cells. Tetrac suppressed expression of THBS-1 but not p53 expression in both cancer cell lines. Furthermore, the synergistic effect of tetrac and heteronemin inhibited ERK1/2 activation and heteronemin also blocked STAT3 signaling. Combined treatment increased p53 protein and p53 activation accumulation although heteronemin inhibited p53 expression in both cancer cell lines. The combined treatment induced antiproliferation synergistically more than a single agent. CONCLUSIONS: Both heteronemin and tetrac inhibited ERK1/2 activation and increased p53 phosphorylation. They also inhibited THBS-1 expression. Moreover, tetrac suppressed TGF-ß expression combined with heteronemin to further enhance antiproliferation and anti-metastasis in oral cancer cells.

Integrin αvß3 in the Mediating Effects of Dihydrotestosterone and Resveratrol on Breast Cancer Cell Proliferation.

Hormones and their receptors play an important role in the development and progression of breast cancer. Hormones regulate the proliferation of breast cancer cells through binding between estrogen or progestins and steroid receptors that may reside in the cytoplasm or be transcriptionally activated as steroid-protein nuclear receptor complexes. However, receptors for nonpeptide hormones also exist in the plasma membrane. Via those receptors, hormones are able to stimulate breast cancer cell proliferation when activated. Integrins are heterodimeric structural proteins of the plasma membrane. Their primary functions are to interact with extracellular matrix proteins and growth factors. Recently, integrin αvß3 has been identified as a receptor for nonpeptide hormones, such as thyroid hormone and dihydrotestosterone (DHT). DHT promotes the proliferation of human breast cancer cells through binding to integrin αvß3. A receptor for resveratrol, a polyphenol stilbene, also exists on this integrin in breast cancer cells, mediating the anti-proliferative, pro-apoptotic action of the compound in these cells. Unrelated activities of DHT and resveratrol that originate at integrin depend upon downstream stimulation of mitogen-activated protein kinase (MAPK, ERK1/2) activity, suggesting the existence of distinct, function-specific pools of ERK1/2 within the cell. This review will discuss the features of these receptors in breast cancer cells, in turn suggesting clinical applications that are based on the interactions of resveratrol/DHT with integrin αvß3 and other androgen receptors.

Epigenetic Modification and Differentiation Induction of Malignant Glioma Cells by Oligo-Fucoidan.

Malignant glioma (MG) is a poor prognostic brain tumor with inevitable recurrence after multimodality treatment. Searching for more effective treatment is urgently needed. Differentiation induction via epigenetic modification has been proposed as a potential anticancer strategy. Natural products are known as fruitful sources of epigenetic modifiers with wide safety margins. We thus explored the effects of oligo-fucoidan (OF) from brown seaweed on this notion in MG cells including Grade III U87MG cells and Grade IV glioblastoma multiforme (GBM)8401 cells and compared to the immortalized astrocyte SVGp12 cells. The results showed that OF markedly suppress the proliferation of MG cells and only slightly affected that of SVGp12 cells. OF inhibited the protein expressions of DNA methyltransferases 1, 3A and 3B (DNMT1, 3A and 3B) accompanied with obvious mRNA induction of differentiation markers (MBP, OLIG2, S100ß, GFAP, NeuN and MAP2) both in U87MG and GBM8401 cells. Accordingly, the methylation of p21, a DNMT3B target gene, was decreased by OF. In combination with the clinical DNMT inhibitor decitabine, OF could synergize the growth inhibition and MBP induction in U87MG cells. Appropriated clinical trials are warranted to evaluate this potential complementary approach for MG therapy after confirmation of the effects in vivo.

Heteronemin Induces Anti-Proliferation in Cholangiocarcinoma Cells via Inhibiting TGF-ß Pathway.

A marine sesterterpenoid-type natural product, heteronemin, retains anticancer effects. In the current study, we investigate the antitumor mechanism of heteronemin in cholangiocarcinoma cells and further explore its molecular targets. Initially, heteronemin exhibited potent cytotoxic effects against cholangiocarcinoma HuccT1 and SSP-25 cells. In vitro, heteronemin altered the abilities of cell adhesion and cell migration in HuccT1 and SSP-25 cell lines. It repressed messenger ribonucleic acid (mRNA) expression levels of transforming growth factor (TGF)-ß, mothers against decapentaplegic homolog (SMAD) and Myc, whose protein products play important roles in regulating cell growth, angiogenesis, and metastasis. In addition, heteronemin altered several signaling pathways. The results indicate that heteronemin was able to modulate cell adhesion, the expression of extracellular matrix (ECM) receptors, the TGF-ß pathway, cell motility, the membrane integration, metastasis response, matrix metalloproteinase (MMP) remodeling, the regulation of metabolism, sprouting angiogenesis, transcription factors, and vasculogenesis in cholangiocarcinoma cell lines. The results also suggest that it activated multiple signal transduction pathways to induce an anti-proliferation effect and anti-metastasis in cholangiocarcinoma. In conclusion, heteronemin may be used as a potential medicine for anticancer therapy.

Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction.

BACKGROUND: Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. METHODS: By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. RESULTS: The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. CONCLUSIONS: Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs.

A phase I clinical study of immunotherapy for advanced colorectal cancers using carcinoembryonic antigen-pulsed dendritic cells mixed with tetanus toxoid and subsequent IL-2 treatment.

BACKGROUND: To better evaluate and improve the efficacy of dendritic cell (DC)-based cancer immunotherapy, we conducted a clinical study of patients with advanced colorectal cancer using carcinoembryonic antigen (CEA)-pulsed DCs mixed with tetanus toxoid and subsequent interleukin-2 treatment. The tetanus toxoid in the vaccine preparation serves as an adjuvant and provides a non-tumor specific immune response to enhance vaccine efficacy. The aims of this study were to (1) evaluate the toxicity of this treatment, (2) observe the clinical responses of vaccinated patients, and (3) investigate the immune responses of patients against CEA before and after treatment. METHODS: Twelve patients were recruited and treated in this phase I clinical study. These patients all had metastatic colorectal cancer and failed standard chemotherapy. We first subcutaneously immunized patients with metastatic colorectal cancer with 1 × 10(6) CEA-pulsed DCs mixed with tetanus toxoid as an adjuvant. Patients received 3 successive injections with 1 × 10(6) CEA-pulsed DCs alone. Low-dose interleukin-2 was administered subcutaneously following the final DC vaccination to boost the growth of T cells. Patients were evaluated for adverse event and clinical status. Blood samples collected before, during, and after treatment were analyzed for T cell proliferation responses against CEA. RESULTS: No severe treatment-related side effects or toxicity was observed in patients who received the regular 4 DC vaccine injections. Two patients had stable disease and 10 patients showed disease progression. A statistically significant increase in proliferation against CEA by T cells collected after vaccination was observed in 2 of 9 patients. CONCLUSIONS: The results of this study indicate that it is feasible and safe to treat colorectal cancer patients using this protocol. An increase in the anti-CEA immune response and a clinical benefit was observed in a small fraction of patients. This treatment protocol should be further evaluated in additional colorectal cancer patients with modifications to enhance T cell responses. TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT00154713 ), September 8, 2005.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-glucoside Isolated from Polygoni Multiflori Ameliorates the Development of Periodontitis.

Periodontitis, a chronic infection by periodontopathic bacteria, induces uncontrolled inflammation, which leads to periodontal tissue destruction. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygoni Multiflori, reportedly has anti-inflammatory properties. In this study, we investigated the mechanisms of THSG on the Porphyromonas gingivalis-induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. Human gingival fibroblast cells were treated with lipopolysaccharide (LPS) extracted from P. gingivalis in the presence of resveratrol or THSG to analyze the expression of TNF-α, IL-1ß, and IL-6 genes. Increased AMP-activated protein kinase (AMPK) activation and SirT1 expression were induced by THSG. Treatment of THSG decreased the expression of LPS-induced inflammatory cytokines, enhanced AMPK activation, and increased the expression of SirT1. In addition, it suppressed the activation of NF-κB when cells were stimulated with P. gingivalis LPS. The anti-inflammatory effect of THSG and P. Multiflori crude extracts was reproduced in ligature-induced periodontitis animal modeling. In conclusion, THSG inhibited the inflammatory responses of P. gingivalis-stimulated human gingival fibroblasts and ameliorated ligature-induced periodontitis in animal model.

Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR-Mutated Elderly Pulmonary Adenocarcinoma Patients.

BACKGROUND: Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown. MATERIALS AND METHODS: We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected. RESULTS: In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were ≥70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients. CONCLUSION: Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients. IMPLICATIONS FOR PRACTICE: The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR-TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy.

Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells.

Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC). Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3'-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1), a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-ß receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin) and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9), by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-ß signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.

PURPOSE: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease. METHODS: We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family. RESULTS: We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells. CONCLUSION: Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.

Reciprocal relationship of Tn/NF-κB and sTn as an indicator of the prognosis of oral squamous cell carcinoma.

AIMS: In order to determine whether the expression of tumour-associated carbohydrate antigens (Tn/sTn) and a representative inflammation marker, nuclear factor-κB (NF-κB), is associated with the invasiveness of oral squamous cell carcinoma (OSCC), this study has attempted to investigate the correlation of the aforementioned markers with the well-established invasive pattern grading score (IPGS) and clinicopathological parameters. METHODS AND RESULTS: Specimens from 143 OSCC patients with classified clinicopathological parameters and IPGS were stained immunohistochemically using anti-Tn, sTn and NF-κB antibodies. Our results showed that the expression of both Tn and NF-κB was correlated positively with staging (P = 0.036; P = 0.015), recurrence (P < 0.001; P < 0.001) and distant metastasis (P = 0.005; P = 0.009), as well as with IPGS, while the expression of sTn was correlated inversely. In addition, poor survival was associated with overexpression of Tn and NF-κB but not with expression of sTn. CONCLUSIONS: Our results indicate that a reciprocal relationship between Tn and sTn expression may serve as a reliable indicator for OSCC prognostic evaluation. In addition, expression of Tn rather than sTn may play an important role in deeply invasive OSCC via regulation of NF-κB signalling.

Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol.

Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells. Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase-dependent signal transduction pathway and change in mitochondrial potential are also involved in ceramide-induced apoptosis.