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1.  The histone deacetylase SIRT2 stabilizes Myc oncoproteins 
Cell Death and Differentiation  2012;20(3):503-514.
Myc oncoproteins are commonly upregulated in human cancers of different organ origins, stabilized by Aurora A, degraded through ubiquitin–proteasome pathway-mediated proteolysis, and exert oncogenic effects by modulating gene and protein expression. Histone deacetylases are emerging as targets for cancer therapy. Here we demonstrated that the class III histone deacetylase SIRT2 was upregulated by N-Myc in neuroblastoma cells and by c-Myc in pancreatic cancer cells, and that SIRT2 enhanced N-Myc and c-Myc protein stability and promoted cancer cell proliferation. Affymetrix gene array studies revealed that the gene most significantly repressed by SIRT2 was the ubiquitin–protein ligase NEDD4. Consistent with this finding, SIRT2 repressed NEDD4 gene expression by directly binding to the NEDD4 gene core promoter and deacetylating histone H4 lysine 16. Importantly, NEDD4 directly bound to Myc oncoproteins and targeted Myc oncoproteins for ubiquitination and degradation, and small-molecule SIRT2 inhibitors reactivated NEDD4 gene expression, reduced N-Myc and c-Myc protein expression, and suppressed neuroblastoma and pancreatic cancer cell proliferation. Additionally, SIRT2 upregulated and small-molecule SIRT2 inhibitors decreased Aurora A expression. Our data reveal a novel pathway critical for Myc oncoprotein stability, and provide important evidences for potential application of SIRT2 inhibitors for the prevention and therapy of Myc-induced malignancies.
PMCID: PMC3569991  PMID: 23175188
neuroblastoma; pancreatic cancer; N-Myc; histone deacetylase; SIRT2; NEDD4
2.  Adjuvant chemotherapy in elderly patients with pancreatic cancer 
British Journal of Cancer  2013;110(2):313-319.
Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer.
We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative.
The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged ⩾70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8% P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27–2.78, P=0.002).
Patients aged ⩾70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer.
PMCID: PMC3899761  PMID: 24263063
pancreatic cancer; adjuvant chemotherapy; elderly
3.  The prognostic and predictive value of serum CA19.9 in pancreatic cancer 
Annals of Oncology  2012;23(7):1713-1722.
Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 (CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.
We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.
By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P = 0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels >90 U/ml did not benefit from adjuvant chemotherapy (P = 0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P = 0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P = 0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.
Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.
PMCID: PMC3387824  PMID: 22241899
adjuvant chemotherapy; CA19.9; pancreatic cancer; prognosis
4.  The amino-terminal fusion domain peptide of human immunodeficiency virus type 1 gp41 inserts into the sodium dodecyl sulfate micelle primarily as a helix with a conserved glycine at the micelle-water interface. 
Journal of Virology  1997;71(9):6593-6602.
A peptide based on the N-terminal fusion domain of gp41 of human immunodeficiency virus type 1 (HIV-1) and its tryptophan analog were synthesized to examine the secondary structure in the micellar environment. Nuclear magnetic resonance (NMR), circular dichroism and electron paramagnetic resonance experiments indicated that the gp41 fusion peptide inserted into the micelle primarily as a helix (59%), with substantial beta-structure (26.7%). Deep penetration of the peptide into the apolar hydrocarbon core was supported by the results of fluorescence experiments in which the tryptophan analog exhibited a blue shift of about 30 nm in the presence of a sodium dodecyl sulfate micelle, in 1,2-dimyristoyl-rac-glycero-3-phosphocholine, and in 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine vesicular solutions. The results of spin label-attenuated 1H resonance experiments show that the region C-terminal to G16, which contains a turn structure, exhibited substantial interaction with the micelle, suggesting that it lies on the surface of micelle. Molecular simulation based on data from NMR experiments revealed a flexible hinge at residues 15 and 16 (alanine and glycine, respectively) from the N terminus of the peptide located at the micelle-solution interface. The highly conserved A15-G16 dipeptide may play a role in the function of fusion domain of HIV-1 envelope glycoprotein.
PMCID: PMC191937  PMID: 9261381
5.  Hyperkalemia due to hyporeninemic hypoaldosteronism with liver cirrhosis and hypertension. 
A 49-year-old man with liver cirrhosis and hypertension was found to have hyperkalemia out of a degree of renal insufficiency and metabolic acidosis with low to normal anion gap, aggravated by volume contraction with diarrhea and medications (captopril, spironolactone and atenolol) interfering with potassium homeostasis. Plasma renin activity and serum aldosterone levels of this patient on a regular diet after discontinuation of medications were very low compared to those of five other cirrhotic patients with normokalemia as controls. Also, the renin-aldosterone stimulation testing on this patient performed by sodium restricted diet and furosemide, upright position and by angiotensin converting enzyme inhibition (captopril, 50 mg) showed the blunted renin and aldosterone responses to each of these stimuli, almost no changes from baseline renin and aldosterone levels, it was concluded that the underlying defect responsible for hyperkalemia in this case was hyporeninemic hypoaldosteronism and this was aggravated by other factors or drugs affecting potassium homeostasis.
PMCID: PMC3053877  PMID: 8179835
6.  alpha-DNA. I. Synthesis, characterization by high field 1H-NMR, and base-pairing properties of the unnatural hexadeoxyribonucleotide alpha-[d(CpCpTpTpCpC)] with its complement beta-[d(GpGpApApGpG)]. 
Nucleic Acids Research  1986;14(12):5019-5035.
The novel deoxyribonucleotide alpha-[d(CpCpTpTpCpC)] and its complement beta-[d(GpGpApApGpG)] were synthesized by the phosphotriester method. 1H-NMR-NOE examination of the alpha-hexamer revealed that the cytosine and thymine bases appear to adopt anti conformations in this strand. In addition the deoxyribose of the thymidine moieties may adopt average conformations approximating to C3'-endo while the cytidine furanose groups are close to C2'-endo conformations. Both hyperchromicity in thermal melting and detection of base paired imino protons in 1H-NMR studies in H2O provide evidence for the annealing of alpha-d[CCTTCC] with its complement beta-d[GGAAGG] in potassium phosphate buffer pH 7.1 containing 10 mM magnesium chloride. Under these conditions thermal melting begins at 38 degrees C and its complete at approximately 45 degrees C. NOE experiments do not permit a decision on the polarity of annealing (predicted to be parallel) for this particular pair of sequences.
PMCID: PMC311508  PMID: 3725590
7.  alpha-DNA-III. Characterization by high field 1H-NMR, anti-parallel self-recognition and conformation of the unnatural hexadeoxyribonucleotides alpha-[d(CpApTpGpCpG)] and alpha-[d(CpGpCpApTpG)]. Alpha-oligodeoxynucleotides as potential cellular probes for gene control. 
Nucleic Acids Research  1987;15(10):4241-4255.
High field 2-D-1H-NMR techniques permitted the assignment of all non-exchangeable protons of the unnatural deoxyribonucleotides alpha-[d(CpApTpGpCpG)] and alpha-[d(CpGpCpApTpG)]. 1-D and 2-D NOESY experiments show strong H6H8-H4' dipolar interactions for all nucleotides in both sequences. These data, together with COSY and J-resolved spectra, indicate that these two alpha-oligomers adopt 3'-exo conformations of the sugar moieties in solution with anti conformations of the glycosyl linkages. Both 1H-NMR data, and hypochromocity comparison of alpha-CATGCG and beta-CATGCG, demonstrate a higher degree of base stacking in the case of the alpha-sequence. The UV hyperchromicity at 260 nm, and symmetry considerations in the imino proton NMR experiments reveal antiparallel self-recognition and duplex annealing at positions 1-4 for alpha-[d(CATGCG)] and positions 3-6 for alpha-[d(CGCATG)]. The temperature variation of the imino proton NMR signals suggests that the hydrogen bonding in self-recognition is comparable in strength with that in a beta-DNA duplex, and NOE data are in accord with Watson-Crick rather than Hoogsteen base pairing.
PMCID: PMC340845  PMID: 3588292
8.  alpha-DNA-V. Parallel annealing, handedness and conformation of the duplex of the unnatural alpha-hexadeoxyribonucleotide alpha-[d(CpApTpGpCpG)] with its beta-complement beta-[d(GpTpApCpGpC)] deduced from high field 1H-NMR. 
Nucleic Acids Research  1987;15(17):7027-7044.
The beta-complementary hexamer, beta-d[GTACGC], to the alpha-sequence, alpha-d[CATGCG], was synthesized by the phosphotriester method. The non-exchangeable proton assignments were obtained using 1D- and 2D-NMR techniques, including NOE, COSY and NOESY. The beta-strand exists as a random coil at 21 degrees C; however, at 4 degrees C, it forms an antiparallel self-recognition duplex annealing at positions 1-4. The beta-strand was annealed to the alpha-strand, and confirmation of complete annealing was obtained by detection and assignment of the six base pair imino protons in H2O/D2O solution at 21 degrees C. 1D-NOE experiments of the alpha, beta duplex d[alpha-(CATGCG) X beta-(GTACGC)] reveal that (i) it exists in aqueous solution in a conformation that belongs to the B family, (ii) it is 70 +/- 10% right-handed, (iii) the sugar-base orientations of the beta-strand are anti, and the deoxyribose units exist predominantly in the 2'-endo-3'-exo conformation. NOE measurements of the imino proton signals in the alpha, beta duplex reveal that the duplex exhibits parallel polarity.
PMCID: PMC306190  PMID: 3658672

Results 1-8 (8)