Peroxiredoxin-5 is a negative survival predictor in ovarian cancer

Objectives: Peroxiredoxins (PRDXs) constitute a family of antioxidant enzymes which are also involved in the process of carcinogenesis. They are composed of six identified isoforms (PRDX-1-6) and are supposed to play different roles in tumor progression, depending on type of cancer and member of the PRDX family. The aim of the study was to assess the prog- nostic value of PRDXs in ovarian cancer. Material and methods: a dataset of patients with ovarian cancer from The Cancer Genome Atlas was analyzed. Expression of PRDX-1 to 6 mRNA was evaluated in 260 samples. The prognostic value of PRDXs was assessed using the Cox regression model which included the following clinical and pathological data: age, clinical stage, tumor grade, and residual disease. Results: Within the PRDXs family, only higher expression of PRDX-5 was associated with worse overall survival both, in unselected patients and > 50-year-olds. PRDX-5 expression and residual disease were independent negative prognostic factors of patient survival. Conclusions: PRDX-5 is a negative predictor of survival in ovarian cancer.

Modulation of Age- and Cancer-Associated DNA Methylation Change in the Healthy Colon by Aspirin and Lifestyle

Background Aberrant DNA methylation in gene promoters is associated with aging and cancer, but the circumstances determining methylation change are unknown. We investigated the impact of lifestyle modulators of colorectal cancer (CRC) risk on the stability of gene promoter methylation in the colonic mucosa. Methods We measured genome-wide promoter CpG methylation in normal colon biopsies (n = 1092) from a female screening cohort, investigated the interaction of lifestyle factors with age-dependent increase in methylation with log-linear multivariable regression, and related their modifying effect to hypermethylation in CRC. All statistical tests were two-sided. Results Of 20025 promoter-associated CpGs analyzed, 1713 showed statistically significant age-dependent methylation gains. Fewer CpGs acquired methylation in users of aspirin (≥2 years) and hormonal replacement therapy (HRT age ≥50 years) compared with nonusers (43 vs 1355; 1 vs1377, respectively), whereas more CpGs were affected in smokers (≥20 years) and individuals with a body mass index (BMI) of 25kg/m2 and greater compared with control groups (180 vs 39; 554 vs 144, respectively). Fifty percent of the CpGs showing age-dependent methylation were found hypermethylated in CRC (odds ratio [OR] = 20; 95% confidence interval [CI] = 18 to 23; P < 2×10-16). These loci gained methylation with a higher median rate compared with age-only methylated sites (P = 2×10-76) and were enriched for polycomb regions (OR = 3.67). Importantly, aspirin (P < .001) and HRT use (P < .001) reduced the methylation rate at these cancer-related genes, whereas smoking (P < .001) and high BMI (P = .004) increased it. Conclusions Lifestyle, including aspirin use, modulates age-associated DNA methylation change in the colonic epithelium and thereby impacts the evolution of cancer methylome

Dimeric peroxiredoxins are druggable targets in human Burkitt lymphoma

Burkitt lymphoma is a fast-growing tumor derived from germinal center B cells. It is mainly treated with aggressive chemotherapy, therefore novel therapeutic approaches are needed due to treatment toxicity and developing resistance. Disturbance of red-ox homeostasis has recently emerged as an efficient antitumor strategy. Peroxiredoxins (PRDXs) are thioredoxin-family antioxidant enzymes that scavenge cellular peroxides and contribute to red-ox homeostasis. PRDXs are robustly expressed in various malignancies and critically involved in cell proliferation, differentiation and apoptosis. To elucidate potential role of PRDXs in lymphoma, we studied their expression level in B cell-derived primary lymphoma cells as well as in cell lines. We found that PRDX1 and PRDX2 are upregulated in tumor B cells as compared with normal counterparts. Concomitant knockdown of PRDX1 and PRDX2 significantly attenuated the growth rate of lymphoma cells. Furthermore, in human Burkitt lymphoma cell lines, we isolated dimeric 2-cysteine peroxiredoxins as targets for SK053, a novel thiol-specific small-molecule peptidomimetic with antitumor activity. We observed that treatment of lymphoma cells with SK053 triggers formation of covalent PRDX dimers, accumulation of intracellular reactive oxygen species, phosphorylation of ERK1/2 and AKT and leads to cell cycle arrest and apoptosis. Based on site-directed mutagenesis and modeling studies, we propose a mechanism of SK053-mediated PRDX crosslinking, involving double thioalkylation of active site cysteine residues. Altogether, our results suggest that peroxiredoxins are novel therapeutic targets in Burkitt lymphoma and provide the basis for new approaches to the treatment of this disease

Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells

Acute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase

Fast implementations of secret-key block ciphers using mixed inner- and outer-round pipelining. In:

ABSTRACT The new design methodology for secret-key block ciphers, based on introducing an optimum number of pipeline stages inside of a cipher round is presented and evaluated. This methodology is applied to five well-known modern ciphers, Triple DES, Rijndael, RC6, Serpent, and Twofish, with the goal to first obtain the architecture with the optimum throughput to area ratio, and then the architecture with the highest possible throughput. All ciphers are modeled in VHDL, and implemented using Xilinx Virtex FPGA devices. It is demonstrated that all investigated ciphers can operate with similar maximum clock frequencies, in the range from 95 to 131 MHz, limited only by the delay of a single CLB layer and delays of interconnects. Rijndael, RC6, Twofish, and Serpent achieve throughputs in the range from 12.1 Gbit/s to 16.8 Gbit/s; and Triple DES achieves the throughput of 7.5 Gbit/s. Because of the optimum speed to cost ratio, the proposed architecture seems to be very well suited for practical implementations of secret-key block ciphers using both FPGAs and custom ASICs. We also show that using this architecture for comparing hardware performance of secret-key block ciphers, such as AES candidates, operating in non-feedback cipher modes, leads to the more prudent and fairer analysis than comparisons based on other types of pipelined architectures

Experimental Testing of the Gigabit IPSec-Compliant Implementations of Rijndael and Triple DES Using SLAAC-1V FPGA Accelerator Board

. In this paper, we present the results of the first phase of a project aimed at implementing a full suite of IPSec cryptographic transformations in reconfigurable hardware. Full implementations of the new Advanced Encryption Standard, Rijndael, and the older American federal standard, Triple DES, were developed and experimentally tested using the SLAAC-1V FPGA accelerator board, based on Xilinx Virtex 1000 devices. The experimental clock frequencies were equal to 91 MHz for Triple DES, and 52 MHz for Rijndael. This translates to the throughputs of 116 Mbit/s for Triple DES, and 577, 488, and 423 Mbit/s for Rijndael with 128-, 192-, and 256-bit keys respectively. We also demonstrate a capability to enhance our circuit to handle the encryption and decryption throughputs of over 1 Gbit/s regardless of the chosen algorithm. Our estimates show that this gigabit-rate, double-algorithm, encryption/decryption circuit will fit in one Virtex 1000 FPGA taking approximately 80% of the area. 1

ICEPOLE: High-speed, hardware-oriented authenticated encryption

This paper introduces our dedicated authenticated encryption scheme ICEPOLE. ICEPOLE is a high-speed hardware-oriented scheme, suitable for high-throughput network nodes or generally any environment where specialized hardware (such as FPGAs or ASICs) can be used to provide high data processing rates. ICEPOLE-128 (the primary ICEPOLE variant) is very fast. On the modern FPGA device Virtex 6, a basic iterative architecture of ICEPOLE reaches 41 Gbits/s, which is over 10 times faster than the equivalent implementation of AES-128-GCM. The throughput-to-area ratio is also substantially better when compared to AES-128-GCM. We have carefully examined the security of the algorithm through a range of cryptanalytic techniques and our findings indicate that ICEPOLE offers high security level

Barrett's esophagus associates with a variant of IL23R gene

Gastroesophageal reflux disease is regarded as a spectrum of diseases: non-erosive reflux disease (NERD), erosive reflux disease (ERD), and the far end of the spectrum represented by patients with Barrett's esophagus. Among predisposing factors, both risk and protective polymorphic variants of several genes may influence the clinical outcomes of reflux disease. Consequently, different molecular mechanisms are likely to underlie the development of clinical variants of reflux disease. Ninety six patients with reflux disease were screened for polymorphisms of CARD15, SLC22A4 (OCTN1), SLC22A5 (OCTN2), DLG5, ATG16L1 and IL23R genes which had previously been found to associate with immune-mediated chronic inflammatory disorders. While none of the polymorphisms were associated with NERD or ERD, the 1142G/A variant of the IL23R gene was found to be a risk variant in Barrett's esophagus patients. The IL23/IL23R pathway may modulate STAT3 transcriptional activity which is an essential regulator not only of immune-mediated inflammation, but also of inflammatory-associated apoptosis resistance. Although the mechanisms of metaplastic transition of inflamed squamous epithelium are undetermined as yet, our findings suggest potential involvement of alternations in the IL23/IL23R pathway as a molecular background of Barrett's esophagus development