Temporal Profiles of Symptom Scores After Palliative Radiotherapy for Bleeding Gastric Cancer With Adjustment for the Palliative Prognostic Index: An Exploratory Analysis of a Multicentre Prospective Observational Study (JROSG 17-3).

AIMS: Although palliative radiotherapy for gastric cancer may improve some symptoms, it may also have a negative impact due to its toxicity. We investigated whether symptoms improved after radiotherapy with adjustment for the Palliative Prognostic Index (PPI) considering that patients with limited survival tend to experience deterioration of symptoms. MATERIALS AND METHODS: This study was an exploratory analysis of the Japanese Radiation Oncology Study Group study (JROSG 17-3). We assessed six symptom scores (nausea, anorexia, fatigue, shortness of breath, pain at the irradiated area and distress) at registration and 2, 4 and 8 weeks thereafter. We tested whether symptoms linearly improved after adjusting for the baseline PPI. Shared parameter models were used to adjust for potential bias in missing data. RESULTS: The present study analysed all 55 patients enrolled in JROSG 17-3. With time from registration as the only explanatory variable in the model, a significant linear decrease was observed in shortness of breath, pain and distress (slopes, -0.26, -0.22 and -0.19, respectively). Given that the interaction terms (i.e. PPI × time) were not significantly associated with symptom scores in any of the six symptoms, only PPI was included as the main effect in the final multivariable models. After adjusting for the PPI, shortness of breath, pain and distress significantly improved (slope, -0.25, -0.19 and -0.17; P < 0.001, 0.002 and 0.047, respectively). An improvement in fatigue and distress was observed only in patients treated with a biologically effective dose ≤14.4 Gy. CONCLUSION: Shortness of breath, pain and distress improved after radiotherapy. Moreover, a higher PPI was significantly associated with higher symptom scores at all time points, including baseline. In contrast, PPI did not seem to influence the improvement of these symptoms. Regardless of the expected survival, patients receiving radiotherapy for gastric cancer can expect an improvement in shortness of breath, pain and distress over 8 weeks. Multiple-fraction radiotherapy might hamper the improvement in fatigue and distress by its toxicity or treatment burden.

Hypoxic volume evaluated by 18F-fluoromisonidazole positron emission tomography (FMISO-PET) may be a prognostic factor in patients with oral squamous cell carcinoma: preliminary analyses.

Tumour hypoxia can be detected by 18F-fluoromisonidazole positron emission tomography (FMISO-PET). Few studies have assessed the relationships of new PET parameters, including hypoxic volume (HV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG), with 5-year survival of patients treated surgically for oral squamous cell carcinoma (OSCC). This study evaluated the relationships between these PET parameters and 5-year survival in OSCC patients. Twenty-three patients (age 42-84 years; 15 male, eight female) with OSCC underwent FMISO- and 18F-fluoro-2-deoxyglucose (FDG)-PET computed tomography before surgery. All of them underwent radical surgery and were followed up for more than 5 years. The FDG-PET maximum standardized uptake value (SUVmax), HV, MTV, and TLG were measured. The ability of PET parameters to predict disease-free survival (DFS) and loco-regional recurrence (LR) was evaluated using receiver operating characteristic curve analysis. During the follow-up period, five of the 23 patients (22%) died and six (26%) experienced LR. Although FDG-PET SUVmax was not significantly associated with DFS or LR, HV correlated significantly with both DFS and LR. TLG, but not MTV, was significantly associated with DFS; however neither MTV nor TLG was related significantly to LR. In conclusion, tumour HV may predict outcomes in patients with OSCC.

The effects of exercise load during development on oxidative stress levels and antioxidant potential in adulthood.

The objective of this study was to elucidate the impact of physical activity during the growth period as well as on oxidative stress and antioxidative potential in adulthood. The experimental animals used were four-week old male Wistar rats, which were randomly divided into three groups. The exercise loads were as follows: control (CON), treadmill exercise (TE), and jumping exercise (JE). The exercise was performed at the same time of day, at a frequency of five days per week, for eight weeks. Derivatives of reactive oxygen metabolites (d-ROSs) and biological antioxidant potential (BAP) were measured during periods of rest prior to commencement of the experiment and after the experiment. Analysis was conducted using a Wilcoxon signed-rank test and Schaffer's multiple comparison procedure and the significance level was set at p < 0.05. The percent increase in d-ROM levels in the JE group, which experienced short-duration intense exercise loads, was higher than that in the TE group, which experienced moderately intense exercise loads. However, BAP, which is an index of antioxidant potential, markedly decreased in adulthood in the CON group, as compared to that in the developmental period, whereas the exercise groups showed no notable changes in BAP levels. Oxidative stress levels and antioxidant potential are affected differently in adulthood, depending on the intensity of sustained exercise loads experienced during development. Results suggested that in order to increase antioxidant potential, while taking oxidative stress production into account, moderately intense exercise loads are more desirable than highly intense exercise loads.

A change of osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP-5b) with the menstrual cycle.

Bone metabolism markers associated with 4 menstrual cycle phases were evaluated in 14 healthy young females without menstrual disorder. Menstrual cycle phases were confirmed with basal body temperature for 3 months, luteinizing hormone kits, and sexual hormone concentrations of serum. The bone metabolism markers used were osteocalcin (OC), which was measured by immunoradiometric assay (IRMA), and tartrate resistant acid phosphatase 5b (TRACP-5b), which was measured by enzyme immunometric assay (EIA). The highest values of OC and TRACP-5b were observed in the ovulation phase, and TRACP-5b increased significantly when compared with levels in the menstrual phase (p<0.05). Furthermore, the changes in sex-hormone secretion involved in OC and TRACP-5b showed specific patterns during the menstrual cycle. In other words, TRACP-5b levels are influenced by sex hormones produced during the menstrual period and are based on the bone-formation status. Therefore, it is presumed that the TRACP-5b levels during ovulation play a central role in bone formation and bone metabolism.

Functional dissociation between Kana and Kanji: agraphia following a thalamic hemorrhage.

We report the case of a 61-year-old woman with a left thalamic hemorrhage causing agraphia of Kanji (morphograms). Single-photon emission computed tomography (SPECT) showed a decrease in the blood flow in the left thalamus from the superior temporal convolution to the parietal lobe, as well as in the frontal lobe while computed tomography showed no remarkable lesions in the cortex. The agraphia in this case may be due to the thalamic lesion itself, but the SPECT findings strongly suggest that a secondary cortical lesion may be involved in producing the higher cognitive disorder.

A loss-of-function p.G191R variant in the anionic trypsinogen (PRSS2) gene in Japanese patients with pancreatic disorders.

OBJECTIVE: There is a concept that pancreatitis results from an imbalance of proteases and their inhibitors within the pancreatic parenchyma. It has been recently shown that a loss-of-function variant, c.571G>A (p.G191R), in the anionic trypsinogen (PRSS2) gene protects against chronic pancreatitis in European populations. Here we examined the association of the p.G191R variant with pancreatic disorders in Japan. METHODS: Genomic DNA was prepared from 378 healthy controls and 604 patients with pancreatic disorders (241 patients with chronic pancreatitis, 174 with acute pancreatitis, and 189 with pancreatic neoplasm). Mutational analysis of the PRSS2 gene was performed by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. RESULTS: The heterozygous p.G191R variant was found in three of 241 (1.2%) patients with chronic pancreatitis, in seven of 174 (4.0%) patients with acute pancreatitis, and in 12 of 189 (6.3%) patients with pancreatic neoplasm. The p.G191R variant was found in 25 (two were homozygous and 23 were heterozygous) of 378 (6.6%) healthy controls. The p.G191R frequency in patients with chronic pancreatitis was lower than that in healthy controls (p = 0.001; odds ratio (OR) 0.178; 95% confidence interval (CI) = 0.057 to 0.561). The p.G191R frequency was lower in patients with alcoholic (0.9%; p = 0.015; OR, 0.132; 95% CI, 0.022 to 0.779) and idiopathic (1.0%; p = 0.025; OR, 0.144; 95% CI, 0.025 to 0.851) chronic pancreatitis than that in healthy controls. There were no statistical differences in the p.G191R frequency between healthy controls and patients with acute pancreatitis or with pancreatic neoplasm. Patients with alcoholic acute pancreatitis (n = 59) had no variant carrier, and the p.G191R frequency was lower than that in healthy controls (p = 0.035). CONCLUSION: The p.G191R variant protected against alcoholic and idiopathic chronic pancreatitis as well as alcoholic acute pancreatitis in Japan.

Neurotrophic regulation of epidermal dedifferentiation during wound healing and limb regeneration in the axolotl (Ambystoma mexicanum).

Adult urodeles (salamanders) are unique in their ability to regenerate complex organs perfectly. The recently developed Accessory Limb Model (ALM) in the axolotl provides an opportunity to identify and characterize the essential signaling events that control the early steps in limb regeneration. The ALM demonstrates that limb regeneration progresses in a stepwise fashion that is dependent on signals from the wound epidermis, nerves and dermal fibroblasts from opposite sides of the limb. When all the signals are present, a limb is formed de novo. The ALM thus provides an opportunity to identify and characterize the signaling pathways that control blastema morphogenesis and limb regeneration. In the present study, we have utilized the ALM to identity the buttonhead-like zinc-finger transcription factor, Sp9, as being involved in the formation of the regeneration epithelium. Sp9 expression is induced in basal keratinocytes of the apical blastema epithelium in a pattern that is comparable to its expression in developing limb buds, and it thus is an important marker for dedifferentiation of the epidermis. Induction of Sp9 expression is nerve-dependent, and we have identified KGF as an endogenous nerve factor that induces expression of Sp9 in the regeneration epithelium.

Nationwide surveillance of IC anterior (or dorsal) wall aneurysm: with special reference to its dissecting nature.

Two hundred and twenty-one cases of IC dorsal aneurysm (ICDA) with subarachnoid hemorrhage (SAH) from 365 cases in the nationwide surveillance of ICDA (NSICDA) data bank were studied with special reference to the dissecting type. Dissection of the internal carotid artery (ICA) was confirmed in 50 out of 221 SAH cases. In 193 surgically treated cases, 40 were of the certified dissecting type. Including those with clinical features which strongly suggests the existence of dissecting changes in the ICA wall, 97 cases (55.6% of operated) were thought to be a dissecting type. Incidence of intraoperative bleeding is significantly higher and surgical outcome is significantly worse in the dissecting type than in the non-dissecting type. Treatment options for this peculiar and formidable aneurysm (An) are described.

Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML.

Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and an associated molecule, placenta growth factor (PlGF), are thought to be important for normal and malignant hematopoiesis. This study examined mRNA expression of VEGF, PlGF and receptors for these molecules in AML cells and identified the disease-specific patterns of expression. AML M3 having t(15;17) abnormality showed highest expression of VEGF and VEGF receptor type 1 (VEGFR1), suggesting the autocrine pathway of VEGF-VEGFR1. Then, t(8;21) AML demonstrated augmented expression of VEGF and VEGF receptor type 2 (VEGFR2), suggesting VEGF-VEGFR2 autocrine pathway. Then, addition of VEGFR2 kinase inhibitor in Kasumi-1, a t(8;21) AML cell line, resulted in marked inhibition of cell growth, although growth inhibitory effect of R2 kinase inhibitor to HL-60 was marginal. In addition, cell cycle analysis study showed S-phase cell population reduction by R2 kinase inhibitor in Kasumi-1, but not in HL-60. This observation is thought to be the rationale for novel molecular target therapy directed to angiogenic molecules.

Global transcriptome analysis of the responses of a fluoroquinolone-resistant Streptococcus pneumoniae mutant and its parent to ciprofloxacin.

Streptococcus pneumoniae M22 is a multidrug-resistant mutant selected after exposure of capsulated wild-type S. pneumoniae NCTC 7465 (strain M4) to ciprofloxacin. DNA microarray analysis comparing the gene expression profiles of strain M22 with those of strain M4 showed that strain M22 constitutively expressed 22 genes at levels higher than those observed in strain M4 under all conditions studied. These included the genes encoding the enzymes involved in branched-chain amino acid biosynthesis and two genes (patA and patB) with sequences suggestive of ABC transporter proteins. Expression of the patA and patB genes was induced by ciprofloxacin in both strains, but in strain M4 it only reached the levels observed in strain M22 after long incubation with high concentrations of ciprofloxacin. The altered expression profile observed with strain M22 suggested that the mutation or mutations acquired during resistance selection bring the cell into a state in which the expression of critical genes is preemptively altered to correct for the potential effects of ciprofloxacin on gene expression in the parent strain.

Management of severe subarachnoid hemorrhage; significance of assessment of both neurological and systemic insults at acute stage.

In order to elucidate mutual interrelationship between neurological and systemic dysfunctions in patients with subarachnoid hemorrhage (SAH) at acute stage, neurological condition, systemic complications and plasma catecholamine (CA) level were studied in 1431 consecutive cases admitted within 72 hours after the onset. Five hundred and twenty-four cases with Glasgow Coma Scale (GCS) score 8 or less were assigned to the group of severely ill cases (G-ill), 907 cases with GCS score 9 or more to that of the less ill group (G-well). Plasma CA level was extremely high at super-acute stage within an hour after bleeding and lowered fairly quickly within 24 hours to the normal range. Assuming the value obtained from a formula of [blood sugar level (mg/dl)/serum potassium concentration (mEq/L)] as stress index (SI), SI correlates well (r = 0.4-0.6) with serum catecholamine level at acute stage. Thus, sympathetic hyperactivity after SAH can be grossly estimated with SI. SI over 40 means that patients might have considerable neurological insults as well as systemic ones. For patients in G-well, SI over 50 means that there may be risks for systemic complications even in cases with good neurological condition.

Phase 1/11 study of bi-weekly irinotecan plus cisplatin in the treatment of advanced gastric cancer.

OBJECTIVES: To conduct a phase I/II study of irinotecan with cisplatin to establish a recommended dose, and assess the safety, efficacy and feasibility of this regimen in unresectable advanced or recurrent gastric cancer. PATIENTS AND METHODS: In the phase I portion of the study, patients received a fixed dose of cisplatin (30 mg/m2) with escalating doses of irinotecan, ranging from 30 mg/m2 to 70 mg/m2, on days 1 and 15. In the phase II portion of the study, 40 patients were evaluated for response and safety at the recommended dose. RESULTS: Eighteen patients were enrolled in the phase I study. Dose-limiting toxicity (diarrhea and neutropenia) appeared at the irinotecan dose of 70 mg/m2. Therefore, the recommended irinotecan dose was 60 mg/m2. In the phase II study, 40 patients received cisplatin (30 mg/m2) plus irinotecan (60 mg/m2). Twenty-five out of 40 patients had received prior chemotherapy. The median number of cycles was 3.5. The response rate was 32.5% (13/40) overall, and 53.3% (8/15) in patients without prior chemotherapy. The median time to tumor progression (TTP) was 162 days. The median survival time was 288 days. Four patients (10%) developed grade 4 neutropenia and 3 patients (7.5%) developed grade 4 anemia. The only observed non-hematological toxicity at grade 3 or higher was diarrhea, seen in 2.5% (1/40) of the patients. CONCLUSION: Bi-weekly administration of irinotecan and cisplatin is safe and active for the management of unresectable advanced or recurrent gastric cancer.

Beneficial effect of FR183998, a Na+/H+ exchanger inhibitor, on porcine pancreas allotransplantation retrieved from non-heart-beating donors.

Activation of Na(+)/H(+) exchanger (NHE) may have an important role in the ischemia/reperfusion injury by producing intracellular calcium overload. Recent studies have shown a beneficial effect of an NHE inhibitor on the ischemia/reperfusion injury in the heart. In this study, we examined the effect of FR183998, a potent NHE inhibitor, in porcine pancreas allotransplantation from non-heart-beating Landrace pig donors (NHBDs). The four experimental groups included: untreated with no preservation (group 1; n = 3), treated with no preservation (group 2; n = 5), untreated with preservation (group 3; n = 6), and treated with preservation (group 4; n = 4). The preservation was made in ice-cold University of Wisconsin (UW) solution for 24 hours. The groups treated received 1 mg/kg FR183998 before donor cardiac arrest and 10 mg in the UW solution flush in situ. Serum blood glucose, insulin, and amylase were measured daily. An intravenous glucose tolerance test (IVGTT) was performed on the postoperative day (POD) 7 when pigs were sacrificed for histological examination. Graft survival rates on that day in groups 1,2,3, and 4 were 3 of 3; 5 of 5; 3 of 6; and 4 of 4, respectively. The mean K values of IVGTT in groups 3 and 4 were 0.78 +/- 0.10 and 1.27 +/- 0.16, respectively, which were significantly different (P < .05). Upon histological examination, pancreatic tissue in group 3 showed more severe edema and necrosis than other groups. FR183998 may be considered beneficial for ischemia/reperfusion injury to pancreatic grafts from NHBDs.

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours.

Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2'-deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5' region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5' CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

Evolutionary history of coastal tiger beetles in Japan based on a comparative phylogeography of four species.

To reveal the phylogeographical patterns of four species of coastal tiger beetles in Japan (Lophyridia angulata, Abroscelis anchoralis, Cicindela lewisii and Chaetodera laetescripta), we conducted phylogenetic and nested clade analysis (NCA) using the mitochondrial DNA sequences of two loci (COI and 16S rRNA), with specimens sampled from Japan and neighbouring countries. Abroscelis anchoralis and L. angulata have similar disjunct distributions in Japan. The NCA indicated past fragmentation involving three isolated areas of A. anchoralis. In contrast, local populations of L. angulata in Japan shared the same haplotype, indicating recent vicariance. Co-occurrence of haplotypes from several divergent clades in Japanese populations of Ch. laetescripta suggested ancient vicariance and subsequent intermixing of local populations. The tree topology of C. lewisii, with shallow branches and little geographical segregation of haplotypes between Japan and Korea or within Japan, suggested that the Japanese population was segregated from the Korean population only recently. Restricted gene flow, with isolation by distance, was inferred for various geographical associations of haplotypes for coastal tiger beetles in the NCA. Based on these phylogeographical patterns, coupled with a molecular clock approach, the evolutionary history of four species of coastal tiger beetles was deduced, with the additional consideration of the competitive relationships among those species. We also discuss the conservation of highly localized A. anchoralis populations in Japan, using the concept of evolutionarily significant units.

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells.

By presenting immunogenic peptides at the cell surface, major histocompatibility complex (MHC) class II molecules play a key role in the control of adaptive immune responses. Whether expressed constitutively or induced by interferon-gamma, expression of MHC class II molecules is regulated via coactivator class II transactivator (CIITA); moreover, suppression of their expression is one mechanism by which cancer cells escape host immunity. In this study, we surveyed the relationship between the expression of one MHC class II antigen, HLA-DR, and its coactivators in a group of haematopoietic cell lines, and explored the role of the aberrant DNA methylation in silencing HLA-DR expression. Among 26 cell lines studied, HLA-DR expression was lost from eight T-cell and two myeloid leukaemia cell lines, and this loss was closely associated with suppression of CIITA-PIV expression. Notably, nine of the 10 cell lines that lost CIITA-PIV expression showed methylation of the gene's 5' CpG island. Thus, DNA methylation is believed to inhibit the expression of MHC class II molecules in haematopoietic tumour cells by silencing its coactivator, CIITA-PIV. Furthermore, methylation of CIITA-PIV was detected in seven of 32 primary acute myeloid leukaemia specimens, indicating that epigenetic alteration is not a cell line-specific phenomenon. Collectively, these data suggest that, by suppressing expression of MHC class II molecules, epigenetic inactivation of CIITA provides a survival advantage to a subset of haematopoietic tumours.

Endovascular Treatment for Ruptured VA Dissecting Aneurysm Involving the Origin of PICA.

SUMMARY: Ruptured vertebral artery dissecting aneurysms (VADA) re-bleed frequently especially during first 24 hours, which makes the prognosis of the patients with this disease poor. Recently endovascular trapping with detachable platinum coils at an acute stage has been done for preventing re-bleeding. However, for the cases with dissecting aneurysm involving the origin of the posterior inferior cerebellar artery (PICA), these methods are hardly indicated because of the risk of ischemic complication in the PICA territory. We proposed a simple and effective therapeutic method for these cases. We occluded the affected vertebral artery (VA) near its root intending to introduce collateral blood flow from the deep cervical artery into the VA trunk. The controlled antegrade VA flow and retrograde flow from the contralateral VA make a watershed at the dissecting aneurysm, which promotes thrombosis of pseudolumen with preserving the antegrade blood flow of PICA.We treated two cases with ruptured VADA involving PICA, and in both cases thrombosis of aneurysm was obtained without any ischemic complication. This method would be considered as a treatment of choice to the cases with VADA involving PICA.

Effects of cilostazol on serum lipid concentrations and plasma fatty acid composition in type 2 diabetic patients with peripheral vascular disease.

Cilostazol is an anti-thrombotic and vasodilating agent, reported to have both anti-thrombotic and cerebral vasodilating effects. We investigated the effects of cilostazol on serum lipid concentrations and plasma fatty acid composition in type 2 diabetic patients with peripheral vascular disease. The serum concentrations of total cholesterol, triglycerides, high-density lipoprotein-cholesterol, lipoprotein (a), remnant-like particles-cholesterol, apolipoproteins, and plasma fatty acid composition were measured in 17 diabetic patients with peripheral vascular disease before and 1, 3, and 6 months after administration of cilostazol (200 mg/day). Serum triglyceride concentrations were significantly decreased after cilostazol (from 1.31+/-0.17 mmol/l to 0.86+/-0.07 mmol/l at 6 months, P<0.01). Plasma docosahexaenoic acid levels were significantly increased after cilostazol (4.11+/-0.26% to 4.94+/-0.26% at 6 months, P<0.01). Our findings show that cilostazol can induce some beneficial changes in serum lipid profile and plasma fatty acid composition.

DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers.

Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon gamma. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.