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23132960_3

The role of SIRT6 , also a histone deacetylase , in regulating inflammation in endothelial cells is not known .

23132960_4

The aim of this study was to determine the effect of SIRT6 knockdown on inflammatory markers in human umbilical vein endothelial cells ( HUVECs ) in the presence of lipopolysaccharide ( LPS ) .

23132960_5

LPS decreased expression of SIRT6 in HUVECs .

23132960_6

Knockdown of SIRT6 increased the expression of proinflammatory cytokines ( IL-1β , IL-6 , IL-8 ) , COX-prostaglandin system , ECM remodelling enzymes ( MMP-2 , MMP-9 and PAI-1 ) , the adhesion molecule ICAM-1 , and proangiogenic growth factors VEGF and FGF-2 ; cell migration ; cell adhesion to leukocytes .

23132960_7

Loss of SIRT6 increased the expression of NF-κB , whereas overexpression of SIRT6 was associated with decreased NF-κB transcriptional activity .

23132960_8

Taken together , these results demonstrate that the loss of SIRT6 in endothelial cells is associated with upregulation of genes involved in inflammation , vascular remodelling , and angiogenesis .

23132960_9

SIRT6 may be a potential pharmacological target for inflammatory vascular diseases .

22753494_0

MicroRNAs ( miRNAs ) are small noncoding RNAs , 19-24 nucleotides in length , that regulate gene expression and are expressed aberrantly in most types of cancer .

22753494_1

MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers .

22753494_2

It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs .

22753494_3

Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism , by binding as ligands to receptors of the Toll-like receptor ( TLR ) family , murine TLR7 and human TLR8 , in immune cells , triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis .

22753494_4

Thus , by acting as paracrine agonists of TLRs , secreted miRNAs are key regulators of the tumor microenvironment .

22753494_5

This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread , thus representing a possible target for cancer treatment .

23435856_0

The aim of the present study was to isolate endothelial cells from tooth buds ( unerupted deciduous teeth ) of miniature swine .

23435856_1

Mandibular molar tooth buds harvested from swine fetuses at fetal days90-110 were cultured in growth medium supplemented with 15% fetal bovine serum in 100-mm culture dishes until the primary cells outgrown from the tooth buds reached confluence .

23435856_2

A morphologically defined set of pavement-shaped primary cells were picked up manually with filter paper containing trypsin/ethylenediamine tetraacetic acid solution and transferred to a separate dish .

23435856_3

A characterization of the cellular characteristics and a functional analysis of the cultured cells at passages 3 to 5 were performed using immunofluorescence , a reverse transcriptase polymerase chain reaction assay , a tube formation assay , and transmission electron microscopy .

23435856_4

The isolated cells grew in a pavement arrangement and showed the characteristics of contact inhibition upon reaching confluence .

23435856_5

The population doubling time was at passage 3 .

23435856_6

As shown by immunocytostaining and western blotting with specific antibodies , the cells produced the endothelial marker proteins such as vascular endothelial cadherin , von Willebrand factor , and vascular endothelial growth factor receptor-2 .

23435856_7

Observation with time-lapse images showed that small groups of cells aggregated and adhered to each other to form tube-like structures .

23435856_8

Moreover , as revealed through transmission electron microscopy , these adherent cells had formed junctional complexes .

23435856_9

These endothelial cells from the tooth buds of miniature swine are available as cell lines for studies on tube formation and use in regenerative medical science .

21921941_0

Glioma tumors are refractory to conventional treatment .

21921941_1

Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans .

21921941_2

In this study , we introduce oxidative stress-energy depletion ( OSED ) therapy as a new suggested treatment for glioblastoma .

21921941_3

OSED utilizes D-amino acid oxidase ( DAO ) , which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide ( H2O2 ) .

21921941_4

OSED combines DAO with 3-bromopyruvate ( 3BP ) , a hexokinase II ( HK II ) inhibitor that interferes with Warburg effect , a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis .

21921941_5

Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action .

21921941_6

C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation , clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes .

21921941_7

DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley ( SD ) rats , especially after combination with 3BP .

21921941_8

OSED treatment was safe and tolerable in SD rats .

21921941_9

OSED therapy may be a promising therapeutic modality for glioma .

12659514_0

Solar ultraviolet radiation is considered to be injurious rather than necessary for most organisms living on the earth .

12659514_1

It is reported that the risk of skin cancer in humans increases by the depletion of the ozone layer .

12659514_2

We have examined the genotoxicity of solar ultraviolet , especially the longer wavelength light , using Drosophila .

12659514_3

Recently , we have demonstrated that light of wavelength up to 340 nm is mutagenic on Drosophila larvae .

12659514_4

Using an excision repair-deficient Drosophila strain ( mus201 ) , we have obtained results suggesting that the lesion caused in larvae by the 320 nm-light irradiation may be similar to the damage induced by irradiation at 310 nm , and that light of 330 and 340 nm may induce damage different from that induced by 310 and 320 nm-light .

12659514_5

To examine the difference in DNA damage induced by light of a particular wavelength , we performed monochromatic irradiation on larvae of two Drosophila strains ; one excision repair-deficient ( mei-9 ) and another postreplication repair-deficient ( mei-41). 310 and 320 nm-light was more mutagenic in the mei-9 strain than in mei-41 , whereas 330 and 340 nm-light was more mutagenic in mei-41 than in mei-9 .

12659514_6

It is demonstrated that the mei-41 gene is a homologue of the human atm gene which is responsible for a cell cycle checkpoint .

12659514_7

This result suggests that 310-320 nm-light induces DNA damage that is subject to nucleotide excision repair ( NER ) and that 330-360 nm-light causes damage to be recognized by the cell cycle checkpoint but it is not repairable by NER .

12386826_0

Genetic immunotherapy with tumor antigen gene-modified dendritic cells ( DC ) generates robust immunity , although antitumor protection is not complete in all models .

12386826_1

Previous experience in a model in which C57BL/6 mice immunized with DC transduced with adenoviral vectors expressing MART-1 demonstrated a 20-40% complete protection to a tumor challenge with B16 melanoma cells .

12386826_2

Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in na�ve mice .

12386826_3

In the present study , we wished to determine if the supraphysiological production of the Th1-skewing cytokine interleukin-12 ( IL-12 ) could enhance immune activation and antitumor protection in this model .

12386826_4

In a series of experiments immunizing mice with DC cotransduced with MART-1 and IL-12 , antitumor protection and antigen-specific splenocyte cytotoxicity and interferon gamma production inversely correlated with the amount of IL-12 produced by DC .

12386826_5

This adverse effect of IL-12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC , nor the production of nitric oxide leading to down-regulation of the immune response - the two mechanisms previously recognized to explain immune-suppressive effects of IL-12-based vaccine therapy .

12386826_6

In conclusion , in this animal model , IL-12 production by gene-modified DC leads to a cytokine-induced dose-dependent inhibition of antigen-specific antitumor protection .

20101074_0

Recently , the use of gold nanoparticles as potential tumor selective radiosensitizers has been proposed as a breakthrough in radiotherapy .

20101074_1

Experiments in living cells and in vivo have demonstrated the efficiency of the metal nanoparticles when combined with low energy x-ray radiations ( below conventional 1 MeV Linac radiation ) .

20101074_2

Further studies on DNA have been performed in order to better understand the fundamental processes of sensitization and to further improve the method .

20101074_3

In this work , we propose a new strategy based on the combination of platinum nanoparticles with irradiation by fast ions effectively used in hadron therapy .

20101074_4

It is observed in particular that nanoparticles enhance strongly lethal damage in DNA , with an efficiency factor close to 2 for double strand breaks .

20101074_5

In order to disentangle the effect of the nano-design architecture , a comparison with the effects of dispersed metal atoms at the same concentration has been performed .

20101074_6

It is thus shown that the sensitization in nanoparticles is enhanced due to auto-amplified electronic cascades inside the nanoparticles , which reinforces the energy deposition in the close vicinity of the metal .

20101074_7

Finally , the combination of fast ion radiation ( hadron therapy ) with platinum nanoparticles should strongly improve cancer therapy protocols .

21058195_0

Over the past two decades , bioactive natural compounds have been shown to be a plausible adjunct to the treatment of breast cancer , the second leading cause of cancer death among American women .

21058195_1

This study was designed to investigate the effects of ursolic acid ( UA ) , a pentacyclic triterpene found in many foods and herbs , in a model of postmenopausal breast cancer .

21058195_2

Ovariectomized C57BL/6 mice ( n = 40 ) were randomized to receive control diet ( AIN-93G ) or diet supplemented with UA at 1 of 3 doses ( wt/wt ) : 0.05% , 0.10% , or 0.25% ( ≈54 , 106 , or 266 mg/kg body weight/day , respectively ) .

21058195_3

After 3 wk , syngeneic MMTV-Wnt-1 mammary tumor cells were injected in the mammary fat pad , and mice continued on their respective diets for 5 more wk .

21058195_4

All UA doses decreased tumor cell proliferation , as assessed by Ki67 immunostaining ; nevertheless , UA at 0.10% was most effective in inhibiting tumor take and decreasing tumor final tumor size .

21058195_5

Modulation of Akt/mTOR signaling and induction of apoptosis appeared to mediate these effects on tumor growth .

21058195_6

UA potently disrupted cell cycle progression and induced necrosis in a clonal MMTV-Wnt-1 mammary tumor cell line in vitro .

21058195_7

This study supports the potential of UA as an antitumorigenic agent .

23054118_0

BACKGROUND : The immune system has been shown to play an important role in gastrointestinal stromal tumor ( GIST ) .

23054118_1

The neutrophil-to-lymphocyte ratio ( NLR ) in blood is an easily assessable parameter of systemic inflammatory response .

23054118_2

The aim of this study was to determine whether the NLR is prognostic in GIST .

23054118_3

METHODS : A total of 339 previously untreated patients with primary , localized GIST operated at our institution between 1995 and 2010 were identified from a prospectively collected sarcoma database .

23054118_4

NLR was assessed preoperatively .

23054118_5

Patients who received adjuvant imatinib treatment were excluded from the analysis ( n=64 ) .

23054118_6

Cox regression models were calculated and correlation analyses were performed .

23054118_7

RESULTS : On univariate analysis , NLR was associated with recurrence-free survival ( RFS ) ( P=0.003 , hazard ratio 3.3 , 95% confidence interval 1.5-7.4 ) .

23054118_8

Patients with a low NLR had a 1- and 5-year RFS of 98 and 91% , compared with 89 and 76% in those with a high NLR .

23054118_9

The median RFS was not reached .

23054118_10

Positive correlations were found between NLR and mitotic rate ( Pearson correlation coefficient [ r]=0.15 , P=0.03 ) , and NLR and tumor size ( r=0.36 , P=0.0001 ) .

23054118_11

RFS in patients with a GIST>5cm with low NLR was significantly longer compared to patients with high NLR ( P=0.002 ) .

23054118_12

Flow cytometry analysis of freshly obtained GISTs revealed that neutrophils constituted a minimal percentage of intratumoral immune cells .

23054118_13

CONCLUSIONS : NLR is a surrogate for high-risk tumor features .

23054118_14

Elevated blood NLR appears to represent systemic inflammation in patients with high-risk GIST .

20016540_0

A fully intact immune system would be expected to hinder the efficacy of oncolytic virotherapy by inhibiting viral replication .

20016540_1

Simultaneously , however , it may also enhance antitumor therapy through initiation of proinflammatory , antiviral cytokine responses at the tumor site .

20016540_2

The aim of this study was to investigate the role of a fully intact immune system on the antitumor efficacy of an oncolytic virus .

20016540_3

In this respect , injection of oncolytic vesicular stomatitis virus ( VSV ) into subcutaneous B16ova melanomas in C57Bl/6 mice leads to tumor regression , but it is not associated with viral replicative burst in the tumor .

20016540_4

In contrast , intratumoral delivery of VSV induces an acute proinflammatory reaction , which quickly resolves concomitantly with virus clearance .

20016540_5

Consistent with the hypothesis that therapy may not be dependent on the ability of VSV to undergo progressive rounds of replication , a single-cycle VSV is equally effective as a fully replication-competent VSV , whereas inactivated viruses do not generate therapy .

20016540_6

Even though therapy is dependent on host CD8+ and natural killer cells , these effects are not associated with interferon-gamma-dependent responses against either the virus or tumor .

20016540_7

There is , however , a strong correlation between viral gene expression , induction of proinflammatory reaction in the tumor and in vivo therapy .

20016540_8

Overall , our results suggest that acute innate antiviral immune response , which rapidly clears VSV from B16ova tumors , is associated with the therapy observed in this model .

20016540_9

Therefore , the antiviral immune response to an oncolytic virus mediates an intricate balance between safety , restriction of oncolysis and , potentially , significant immune-mediated antitumor therapy .

22969849_0

Liver cancer ranks as the fifth most prevalent malignancy of all cancers worldwide .

22969849_1

According to the principles of traditional Chinese medicine , liver Yin deficiency is a common clinical syndrome of liver cancer , and tonifying liver Yin is a common treatment method for liver cancer .

22969849_2

However , no hepatocarcinoma-specific liver Yin tonifying formula has yet been established .

22969849_3

In the present study , we established a liver cancer-specific combination of herbs , which we term liver Yin tonifying formula ( LYTF ) .

22969849_4

We found that LYTF inhibits the proliferation of Bel-7402 cells in a dose- and time-dependent manner .

22969849_5

LYTF induces apoptosis in Bel-7402 cells , which is accompanied by activation of caspases-8 , -9 and -3 .

22969849_6

Pan-caspase blocking completely abrogates LYTF-induced apoptosis and partially abrogates LYTF-induced proliferation inhibition .

22969849_7

LYTF also induces cell senescence , as indicated by a large and flattened morphology , senescence-activated β-galactosidase-positive staining and G0/G1 cell cycle arrest , accompanied by the up-regulation of p16 and p21 and the down-regulation of retinoblastoma protein phosphorylation .

22969849_8

These findings suggest that LYTF is effective in inhibiting the growth and survival of hepatocarcinoma cells through the induction of apoptosis and cell senescence .

22969849_9

Our study also provides insight into traditional Chinese medicine methods used for the treatment of liver cancer .

22313602_0

We have recently proposed a new model of cancer metabolism to explain the role of aerobic glycolysis and L-lactate production in fueling tumor growth and metastasis .