The accumulation of viral RNA depends on many host cellular factors. The hexagonal peroxisome (Hex1) protein is a fungal protein that is highly expressed when the DK21 strain of Fusarium graminearum virus 1 (FgV1) infects its host, and Hex1 affects the accumulation of FgV1 RNA. The Hex1 protein is the major constituent of the Woronin body (WB), which is a peroxisome-derived electron-dense core organelle that seals the septal pore in response to hyphal wounding. To clarify the role of Hex1 and the WB in the relationship between FgV1 and Fusarium graminearum, we generated targeted gene deletion and overexpression mutants. Although neither HEX1 gene deletion nor overexpression substantially affected vegetative growth, both changes reduced the production of asexual spores and reduced virulence on wheat spikelets in the absence of FgV1 infection. However, the vegetative growth of deletion and overexpression mutants was increased and decreased, respectively, upon FgV1 infection compared to that of an FgV1-infected wild-type isolate. Viral RNA accumulation was significantly decreased in deletion mutants but was significantly increased in overexpression mutants compared to the viral RNA accumulation in the virus-infected wild-type control. Overall, these data indicate that the HEX1 gene plays a direct role in the asexual reproduction and virulence of F. graminearum and facilitates viral RNA accumulation in the FgV1-infected host fungus.
In cancer patients undergoing radiation therapy, the beneficial effects of radiation can extend beyond direct cytotoxicity to tumor cells. Delivery of localized radiation to tumors often leads to systemic responses at distant sites, a phenomenon known as the abscopal effect which has been attributed to the induction and enhancement of the endogenous anti-tumor innate and adaptive immune response. The mechanisms surrounding the abscopal effect are diverse and include trafficking of lymphocytes into the tumor microenvironment, enhanced tumor recognition and killing via up-regulation of tumor antigens and antigen presenting machinery and, induction of positive immunomodulatory pathways. Here, we discuss potential mechanisms of radiation-induced enhancement of the anti-tumor response through its effect on the host immune system and explore potential combinational immune-based strategies such as adoptive cellular therapy using ex vivo expanded NK and T cells as a means of delivering a potent effector population in the context of radiation-enhanced anti-tumor immune environment.
radiation; abscopal effect; cell therapy; trafficking; recognition
We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) γ-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.
AKR/J mice; DNA repair genes; low-dose-rate radiation; thymic lymphoma
The tumour-suppressor gene CDKN1A (encoding p21Waf/Cip1) is thought to be epigenetically repressed in cancer cells. FBI-1 (ZBTB7A) is a proto-oncogenic transcription factor repressing the alternative reading frame and p21WAF/CDKN1A genes of the p53 pathway. FBI-1 interacts directly with MBD3 (methyl-CpG–binding domain protein 3) in the nucleus. We demonstrated that FBI-1 binds both non-methylated and methylated DNA and that MBD3 is recruited to the CDKN1A promoter through its interaction with FBI-1, where it enhances transcriptional repression by FBI-1. FBI-1 also interacts with the co-repressors nuclear receptor corepressor (NCoR), silencing mediator for retinoid and thyroid receptors (SMRT) and BCL-6 corepressor (BCoR) to repress transcription. MBD3 regulates a molecular interaction between the co-repressor and FBI-1. MBD3 decreases the interaction between FBI-1 and NCoR/SMRT but increases the interaction between FBI-1 and BCoR. Because MBD3 is a subunit of the Mi-2 autoantigen (Mi-2)/nucleosome remodelling and histone deacetylase (NuRD)-HDAC complex, FBI-1 recruits the Mi-2/NuRD-HDAC complex via MBD3. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs and HP1. MBD3 and BCoR play a significant role in the recruitment of the Mi-2/NuRD-HDAC complex– and the NuRD complex–associated proteins, DNMTs and HP. By recruiting DNMTs and HP1, Mi-2/NuRD-HDAC complex appears to play key roles in epigenetic repression of CDKN1A by DNA methylation.
Supratentorial hemangioblastomas (HBs) are rare, and pituitary stalk HBs are extremely uncommon; therefore, pituitary stalk evaluation is often overlooked. Herein, we report the development of pituitary stalk HB over a 20-year period and the importance of regular long-term follow up for patients
Cerebellar hemangioblastoma; von Hippel-Lindau disease; Pituitary stalk dissemination; Natural course
This study is aimed to determine significant physiological parameters of brain and heart under meditative state, both in each activities and their dynamic correlations. Electrophysiological changes in response to meditation were explored in 12 healthy volunteers who completed 8 weeks of a basic training course in autogenic meditation. Heart coherence, representing the degree of ordering in oscillation of heart rhythm intervals, increased significantly during meditation. Relative EEG alpha power and alpha lagged coherence also increased. A significant slowing of parietal peak alpha frequency was observed. Parietal peak alpha power increased with increasing heart coherence during meditation, but no such relationship was observed during baseline. Average alpha lagged coherence also increased with increasing heart coherence during meditation, but weak opposite relationship was observed at baseline. Relative alpha power increased with increasing heart coherence during both meditation and baseline periods. Heart coherence can be a cardiac marker for the meditative state and also may be a general marker for the meditative state since heart coherence is strongly correlated with EEG alpha activities. It is expected that increasing heart coherence and the accompanying EEG alpha activations, heart brain synchronicity, would help recover physiological synchrony following a period of homeostatic depletion.
EEG; HRV; heart coherence; meditation; lagged coherence; heart brain synchronicity
The possible beneficial effects of chronic low-dose irradiation (LDR) and its mechanism of action in a variety of pathophysiological processes such as cancer are a subject of intense investigation. While animal studies involving long-term exposure to LDR have yielded encouraging results, the influence of LDR at the cellular level has been less well defined. We reasoned that since natural killer (NK) cells constitute an early responder to exogenous stress, NK cells may reveal sentinel alterations in function upon exposure to LDR. When purified NK cells received LDR at 4.2 mGy/h for a total of 0.2 Gy in vitro, no significant difference in cell viability was observed. Likewise, no functional changes were detected in LDR-exposed NK cells, demonstrating that LDR alone was insufficient to generate changes at the cellular level. Nonetheless, significant augmentation of cytotoxic, but not proliferative, function was detected when NK cells were stimulated with low-dose IL-2 prior to irradiation. This enhancement of NK cytotoxicity was not due to alterations in NK-activating receptors, NK1.1, NKG2D, CD69 and 2B4, or changes in the rate of early or late apoptosis. Therefore, LDR, in the presence of suboptimal cytokine levels, can facilitate anti-tumor cytotoxicity of NK cells without influencing cellular proliferation or apoptosis. Whether these results translate to in vivo consequences remains to be seen; however, our data provide initial evidence that exposure to LDR can lead to subtle immune-enhancing effects on NK cells and may explain, in part, the functional basis underlying, diverse beneficial effects seen in the animals chronically exposed to LDR.
Low-dose radiation; natural killer cells; natural cytotoxicity; innate immunity
The purpose of this study was to investigate effect of nutrition education at worksite program in male workers. The subjects were 75 male workers who had received nutrition education by a clinical dietitian for 4 months. The anthropometric data, blood pressure and biochemical blood indices were measured before and after nutrition education. Dietary habits and lifestyle were investigated by self-administered questionnaires. Nutrients intake was determined by 24-hour dietary recall method. The results showed significant decreases in body mass index (p < 0.05), fasting blood sugar (p < 0.01), total cholesterol (p < 0.05), and LDL-cholesterol (p < 0.05) after nutrition education. The correlation analyses among anthropometric and clinical parameters after nutrition education indicated that there was a significantly positive correlations between blood pressure and weight, r-GTP. A significantly positive correlations was observed between fasting blood sugar and triglycerides. A significantly positive correlations was observed between triglycerides and body mass index, r-GTP, SGPT. A significantly positive correlations was observed between SGPT and weight, body mass index. A significantly negative correlations was observed between HDL-cholesterol and weight. It could be concluded that nutrition education might be effective tool to improve anthropometric measures and clinical parameters in male workers. Continuing and systematic nutritional management programs should be developed and implemented for male workers at the worksites to maintain optimal health status.
Body mass index; Blood lipids; Blood pressure; Blood glucose; Liver function tests; Nutrition eduction
Fusarium graminearum virus 1 strain-DK21 (FgV1-DK21) is a mycovirus that confers hypovirulence to F. graminearum, which is the primary phytopathogenic fungus that causes Fusarium head blight (FHB) disease in many cereals. Understanding the interaction between mycoviruses and plant pathogenic fungi is necessary for preventing damage caused by F. graminearum. Therefore, we investigated important cellular regulatory processes in a host containing FgV1-DK21 as compared to an uninfected parent using a transcriptional approach.
Using a 3′-tiling microarray covering all known F. graminearum genes, we carried out genome-wide expression analyses of F. graminearum at two different time points. At the early point of growth of an infected strain as compared to an uninfected strain, genes associated with protein synthesis, including ribosome assembly, nucleolus, and ribosomal RNA processing, were significantly up-regulated. In addition, genes required for transcription and signal transduction, including fungal-specific transcription factors and cAMP signaling, respectively, were actively up-regulated. In contrast, genes involved in various metabolic pathways, particularly in producing carboxylic acids, aromatic amino acids, nitrogen compounds, and polyamines, showed dramatic down-regulation at the early time point. Moreover, genes associated with transport systems localizing to transmembranes were down-regulated at both time points.
This is the first report of global change in the prominent cellular pathways in the Fusarium host containing FgV1-DK21. The significant increase in transcripts for transcription and translation machinery in fungal host cells seems to be related to virus replication. In addition, significant down-regulation of genes required for metabolism and transporting systems in a fungal host containing the virus appears to be related to the host defense mechanism and fungal virulence. Taken together, our data aid in the understanding of how FgV1-DK21 regulates the transcriptional reprogramming of F. graminearum.
We report magnetic resonance image (MRI) and magnetic resonance spectroscopy (MRS) findings in a patient of cerebral fat embolism (CFE) occurred in a 26-year-old woman after an autologous fat injection into the face. After initial neurologic symptom onset, MRI and MRS data were obtained two times to investigate repeated CFE. We obtained the MRS data in the two different time intervals and two different echo times to compare the lesions with normal brain parenchyma. The results of MRS data showed that a decrease in N-acetyl-aspartate, an increase in lactate and a very high early peak of free lipids between 0.9 and 1.4 ppm were obtained at the acute infarcted lesion as compared with normal brain parenchyma. In addition, these findings were more clearly detected on short echo time spectrum rather than long spectrum. A close relationship between the clinical manifestations and MRI and MRS findings of the brain can helpful to distinguish CFE with other conditions and to evaluate the cause materials of infarctions rather than conventional MRI or diffusion-weighted imaging.
Cerebral fat embolism; Single-voxel MR spectroscopy; Point-resolved spectroscopy (PRESS); Autologous fat injection
We conducted a pilot study to evaluate the effects of pelvic radiotherapy on biologic markers of oxidative stress and plasma endotoxin levels, and to assess the relationship between the changes of such factors and radiotherapy-related complications.
Twelve gynecologic cancer patients who were treated via pelvic radiotherapy with or without concurrent chemotherapy were enrolled in this study. Biologic markers of oxidative stress, such as glutathione (GSH) and oxidized glutathione (GSSG), as well as endotoxin levels, were measured weekly during treatment. Subjective symptoms were assessed using the Korean version of the EORTC QLQ-C30 at the baseline and on the 5th week of radiotherapy.
No changes were noted in the level of GSH in whole blood, but the GSH/GSSG ratio was reduced dramatically after the initiation of radiotherapy. The mean plasma endotoxin for all patients tended to increase and persisted during radiotherapy, and the number of patients who evidenced clinically significant endotoxin levels (defined as >0.005 EU/mL) also increased. Nausea/vomiting and diarrhea were significantly changed (p=0.019 and p<0.001, respectively). A significant relationship was noted to exist between the changes in the endotoxin level and nausea/vomiting (p=0.001). However, such symptoms did not correlate with the changes of oxidative stress markers.
Pelvic radiotherapy oxidized the GSH redox system and increased plasma endotoxin. Further investigations containing interventional and longitudinal studies will be required to assess the effects of the changes in oxidative stress markers and endotoxin on radiotherapy-related adverse events.
Adverse effects; Endotoxins; Oxidative stress; Radiotherapy
Rhinocerebral mucormycosis is an acute fulminant opportunistic fungal infection usually seen in diabetic or immunocompromised patients. The fungi that cause mucormycosis inoculate the nasal mucosa and may spread to the paranasal sinuses, orbit, and brain. Our patient initially presented with mild ethmoid sinusitis. At that time, brain MRI and contrast-enhanced MR angiography were grossly normal. However, aggravation of sinusitis with extension to the right orbit and anterior cranial fossa rapidly developed within two months. Moreover, an occlusion of the right internal carotid artery was combined. We report a case of a pathologically-proven rhino-orbital-cerebral mucormycosis with serial follow-up imaging for over one year.
Mucormycosis; Carotid artery, Internal; Fungal sinusitis
Ultraviolet (UV) radiation is the primary environmental risk factor in the development of nonmelanoma skin cancer, and UVB in particular promotes tumor growth through various signaling pathways. Kaempferol, a flavonoid with anti-inflammatory and anti-oxidative properties, has been studied as a chemopreventive agent; however, little is known regarding its effects on UVB-induced photo-carcinogenesis. Here, we examined the effect of kaempferol on UVB-induced skin inflammation. We found that kaempferol suppressed UVB-induced cyclooxygenase-2 (COX-2) protein expression in mouse skin epidermal JB6 P+ cells and attenuated the UVB-induced transcriptional activities of cox-2 and activator protein-1 (AP-1). Kaempferol attenuated the UVB-induced phosphorylation of several mitogen-activated protein kinases (MAPKs), including ERKs, p38, and JNKs, but had no effect on the phosphorylation of the upstream MAPK regulator Src. However, in vitro and ex vivo kinase assays demonstrated that kaempferol suppressed Src kinase activity. Furthermore, in vivo data from mouse skin support the idea that kaempferol suppresses UVB-induced COX-2 expression by blocking Src kinase activity. A pull-down assay revealed that kaempferol competes with ATP for direct binding to Src. Docking data suggest that kaempferol docks easily into the ATP-binding site of Src, which is located between the N and C lobes of the kinase domain. Taken together, these results suggest that kaempferol is a potent chemopreventive agent against skin cancer through its inhibitory interaction with Src.
flavonoid; photo-carcinogenesis; skin cancer
Protein arginine methylation is important for a variety of cellular processes including transcriptional regulation, mRNA splicing, DNA repair, nuclear/cytoplasmic shuttling and various signal transduction pathways. However, the role of arginine methylation in protein biosynthesis and the extracellular signals that control arginine methylation are not fully understood. Basic fibroblast growth factor (bFGF) has been identified as a potent stimulator of myofibroblast dedifferentiation into fibroblasts. We demonstrated that symmetric arginine dimethylation of eukaryotic elongation factor 2 (eEF2) is induced by bFGF without the change in the expression level of eEF2 in mouse embryo fibroblast NIH3T3 cells. The eEF2 methylation is preceded by ras-raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2)-p21Cip/WAF1 activation, and suppressed by the mitogen-activated protein kinase (MAPK) inhibitor PD98059 and p21Cip/WAF1 short interfering RNA (siRNA). We determined that protein arginine methyltransferase 7 (PRMT7) is responsible for the methylation, and that PRMT5 acts as a coordinator. Collectively, we demonstrated that eEF2, a key factor involved in protein translational elongation is symmetrically arginine-methylated in a reversible manner, being regulated by bFGF through MAPK signaling pathway.
cyclin-dependent kinase inhibitor p21; fibroblast growth factor 2; mitogen-activated protein kinases; N,N-dimethylarginine; peptide elongation factor 2; protein-arginine N-methyltransfe
There is increasing concern regarding the use of fungicides to control plant diseases, whereby interest has increased in the biological control of phytopathogenic fungi by the application of hypovirulent mycoviruses as a possible alternative to fungicides. Transmission of hypovirulence-associated double-stranded RNA (dsRNA) viruses between mycelia, however, is prevented by the vegetative incompatibility barrier that often exists between different species or strains of filamentous fungi. We determined whether protoplast fusion could be used to transmit FgV1-DK21 virus, which is associated with hypovirulence on F. boothii (formerly F. graminearum strain DK21), to F. graminearum, F. asiaticum, F. oxysporum f. sp. lycopersici, and Cryphonectria parasitica. Relative to virus-free strains, the FgV1-DK21 recipient strains had reduced growth rates, altered pigmentation, and reduced virulence. These results indicate that protoplast fusion can be used to introduce FgV1-DK21 dsRNA into other Fusarium species and into C. parasitica and that FgV1-DK21 can be used as a hypovirulence factor and thus as a biological control agent.
Arsenite is a well-known human carcinogen that especially targets skin. The tumor progression locus 2 (Tpl2) gene encodes a serine/threonine protein kinase that is overexpressed in various cancer cells. However, the relevance of Tpl2 in arsenite-induced carcinogenesis and the underlying mechanisms remain to be explored. We demonstrate that arsenite increased Tpl2 kinase activity and its phosphorylation in mouse epidermal JB6 P+ cells in a dose- and time-dependent manner. Exposure to arsenite resulted in a marked induction of cyclooxygenase (COX)-2 and prostaglandin (PG)E2, important mediators of inflammation and tumor promotion. Treatment with a Tpl2 kinase inhibitor (TKI) or Tpl2 short hairpin RNA (shRNA) suppressed COX-2 expression and PGE2 production induced by arsenite treatment, suggesting that Tpl2 is critical in arsenite-induced carcinogenesis. We also found that arsenite-induced phosphorylation of extracellular signal-regulated kinases (ERKs) or c-Jun NH2-terminal kinases (JNKs) was markedly suppressed by TKI or Tpl2 shRNA. Inhibition of arsenite-induced ERKs or JNKs signaling using a pharmacological inhibitor of ERKs or JNKs substantially blocked COX-2 expression. Furthermore, inhibition of Tpl2 reduced the arsenite-induced promoter activity of nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1), indicating that NF-κB and AP-1 are downstream transducers of arsenite-triggered Tpl2. Our results demonstrated that Tpl2 plays a key role in arsenite-induced COX-2 expression and PGE2 production and further elucidated the role of Tpl2 in arsenite signals that activate ERKs/JNKs and NF-κB/AP-1 in JB6 P+ cells.
tumor progression locus 2 (Tpl2); arsenite; cyclooxygenase (COX)-2; prostaglandin (PG)E2
The aim of this study was to compare the surgical outcomes of laparoscopic surgery and conventional laparotomy for endometrial cancer.
A total of 104 consecutive patients were non-randomly assigned to either laparoscopic surgery or laparotomy. All patients underwent comprehensive surgical staging procedures including total hysterectomy, bilateral salpingo-oophorectomy, and pelvic/para-aortic lymphadenectomy. The safety, morbidity, and survival rates of the two groups were compared, and the data was retrospectively analyzed.
Thirty-four patients received laparoscopic surgery and 70 underwent laparotomy. Operation time for the laparoscopic procedure was 227.0±28.8 minutes, which showed significant difference from the 208.1±46.4 minutes (p=0.032) of the laparotomy group. The estimated blood loss of patients undergoing laparoscopic surgery was 230.3±92.4 mL. This was significantly less than that of the laparotomy group (301.9±156.3 mL, p=0.015). The laparoscopic group had an average of 20.8 pelvic and 9.1 para-aortic nodes retrieved, as compared to 17.2 pelvic and 8.5 para-aortic nodes retrieved in the laparotomy group. There was no significant difference (p=0.062, p=0.554). The mean hospitalization duration was significantly greater in the laparotomy group than the laparoscopic group (23.3 and 16.4 days, p<0.001). The incidence of postoperative complications was 15.7% and 11.8% in the laparotomy and laparoscopic groups respectively. No statistically significant difference was found between the two groups in the survival rate.
Laparoscopic surgical staging operation is a safe and effective therapeutic procedure for management of endometrial cancer with an acceptable morbidity compared to the laparotomic approach, and is characterized by far less blood loss and shorter postoperative hospitalization.
Endometrial cancer; Laparoscopic surgical staging; Laparotomy
Recent data suggest that pretreatment HPV (Human papillomavirus) viral load is useful to predict the severity of intraepithelial lesions of the uterine cervix and formulate a treatment plan. However, the relationship between initial HPV viral load and prognosis of cervical cancer patients has not yet been clearly defined. The objective of this study was to determine whether HPV viral load has prognostic significance in patients with early stage cervical carcinoma treated by surgery.
A retrospective review of all patients with early stage cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy at our institution from August 2003 to December 2007 was conducted. Patients were included only if they had pretreatment Hybrid Capture II test for HPV DNA detection.
We identified 34 patients who met the inclusion criteria. Two groups were identified: patients who had low HPV viral load (≤100 RLU) versus those who had high viral load (>100 RLU). There were no differences in age, FIGO stage, histology, pathologic risk factors - tumor size, deep stromal invasion, lymph-vascular space invasion, parametrial extensions, vaginal margin involvement, and lymph node metastasis - and adjuvant CCRT. There was no significant difference of disease-free survival regard to pretreatment HPV viral load (p=0.7756).
In our study, survival was not significantly different between early stage cervical cancer patients who had low and high pretreatment HPV viral load. It seems that pretreatment HPV viral load may not be of help to predict disease prognosis.
HPV load; Cervical cancer; Prognosis
Natural killer (NK) cells are critical in the immune response to tumor cells, virally infected cells, and bone marrow allografts. 2B4 (CD244) is expressed on all NK cells and the ligand for 2B4, CD48, is expressed on hematopoietic cells. Cross-linking 2B4 on NK cells with anti-2B4 monoclonal antibody leads to NK cell activation in vitro. Therefore, 2B4 is considered to be an activating receptor. Surprisingly, we have found, using antibody-blocking and 2B4-deficient NK cells, that NK lysis of CD48+ tumor and allogeneic targets is inhibited by 2B4 ligation. Interferon γ production by NK cells is also inhibited. Using a peritoneal tumor clearance assay, it was found that 2B4−/− mice have increased clearance of CD48+ tumor cells in vivo. Retroviral transduction of 2B4 was sufficient to restore inhibition in 2B4−/− primary NK cells. It was found that although mature NK cells express SH2D1A, in vitro–derived NK cells do not. However, both populations are inhibited by 2B4 ligation. This indicates that 2B4 inhibitory signaling occurs regardless of the presence of SH2D1A. These findings reveal a novel role for 2B4 as a non–major histocompatibility complex binding negative regulator of NK cells.
CD48; CD150; tumor; IFN-γ; innate immunity