Management of adverse effects associated with pegylated Escherichia coli asparaginase on coagulation in the treatment of patients with NK/T-cell lymphoma.

ABSTRACT: Natural killer/T-cell lymphoma (NK/TL) is a chemotherapy-sensitive disease, and asparaginase-based chemotherapy has become the standard primary treatment for patients with this malignancy recently. The objective of this study was to evaluate the adverse reactions on blood coagulation of the administered pegylated Escherichia coli (E coli) asparaginase (PEG-ASP) to the NK/TL patients. Clinical data of 71 NK/TL patients (range 13-73 years), who received 239 cycles of chemotherapy treatment containing PEG-ASP in the Hematology Department of Shanxi Province Cancer Hospital of China from January 2016 to December 2019 were analyzed retrospectively. Data of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FBG), and antithrombinIII (ATIII) were obtained at the time points routinely and statistically analyzed. There were statistical differences between the monitored parameters of baseline day0 (the day before use of PEG-ASP, named day0) and those of day3 (the 3rd day after treatment) to day6, and data showed all of the indicators could recover within 21 days. The events included PT prolonged in 33 patients (46.5%), APPT prolonged in 41 patients (57.7%, 20 patients with APTT >60 seconds), FBG decreased in 49 patients (69.0%, 12 patients with FBG <1 g/L), and ATIII decreased in 52 patients (73.2%). The patients' average number of cycles received was 2.3 for PT (>14 seconds), 2.5 for APTT (>35 seconds), 2.7 for FBG (<2 g/L), and 2.6 for D-dimer (>550 ng/mL). Compared with those at day0, PT and APTT prolonged sharply at day3 (P < .05), reached the peak at day12, maintained the prolonged level from day3 to day15, and gradually recovered at day 21. FBG and ATIII significantly decreased at day6 and day3 respectively (P < .05), both of them fell to the minimum at day12, and then returned the normal. The D-dimer levels were no significantly change during the whole treatment course. The APTT >60 seconds or FBG <1 g/L side effects were improved by symptomatic treatment of supplementation of fresh frozen plasma or cryoprecipitate infusion, no concomitant bleeding or thrombotic events emerging. Our data suggested although chemotherapy including PEG-ASP impacted moderately on the coagulation function of NK/TL patients, clinically monitored regularly were necessary and most NK/TL patients can complete the chemotherapy cycles successfully.

Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese.

Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 × 10-8) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 × 10-8). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 × 10-7) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 × 10-6) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC.

Purification, identification and profiling of serum amyloid A proteins from sera of advanced-stage cancer patients.

Surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS) is a powerful tool for screening potential biomarkers of various pathological conditions. However, low resolution and mass accuracy of SELDI-TOF-MS remain a major obstacle for determination of biological identities of potential protein biomarkers. We report here a refined workflow that combines ZipTip desalting, acetonitrile precipitation, high-performance liquid chromatography (HPLC) separation and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) analysis for the profiling, purification and identification of the targeted serum proteins found by SELDI-TOF-MS. By using this workflow, we purified ten targeted proteins from the sera of patients with various types of advanced stage (stage III-IV) cancers. These proteins were identified as isoforms of the human serum amyloid protein A (SAA) family with or without truncations at their N-terminals. This was confirmed by Western blot analysis. Different SAA expression patterns were observed by MALDI-TOF-MS profiling. SAA has long been reported as a biomarker for various cancer types such as lung cancer, ovarian cancer, and breast cancer. However, in this study we found increased SAA expression in the sera of advanced-stage cancer patients with different cancer types. Our results suggest that maybe SAA should not be used alone as a biomarker for any specific cancer type.

A comparative study on proteomics between LNCap and DU145 cells by quantitative detection and SELDI analysis.

The differences in intracellular and extracellular protein expressions between human prostate cancer lines LNCap and DU145 were examined. The proteins of the two cell lines were extracted and condensed by using protein extraction kits. And the intracellular and extracellular proteins were quantitatively detected on a micro-plate reader by using bicinchoninic acid (BCA) method. The proteins in cell culture fluid were qualitatively assayed by SELDI-TOF-MS. The results showed that the intracellular protein contents of LNCap cells were extremely higher than those of DU145 cells. After serum-free culture, both intracellular and extracellular protein contents of LNCap and DU145 were decreased to some extent. And the intracellular proteins were decreased by 5% in LNCap and by 36% in DU145 respectively, while the extracellular proteins were decreased by 89% in LNCap and 96% in DU145 respectively. SELDI assay revealed that there were 5 marker proteins in LNCap and 6 in DU145. Although both LNCap and DU145 cell lines originated from human prostate cancer, they had some differences in protein expression.

A Comparative Study on Proteomics between LNCap and DU145 Cells by Quantitative Detection and SELDI Analysis / 华中科技大学学报（医学）（英德文版）

The differences in intracellular and extracellular protein expressions between human prostate cancer fines LNCap and DU145 were examined. The proteins of the two cell lines were extracted and condensed by using protein extraction kits. And the intracellular and extracellular proteins were quantitatively detected on a micro-plate reader by using bicinchoninie acid (BCA) method. The proteins in cell culture fluid were qualitatively assayed by SELDI-TOF-MS. The results showed that the intracellular protein contents of LNCap cells were extremely higher than those of DU145 cells. After serum-free culture, both intracellular and extracellular protein contents of LNCap and DU145 were decreased to some extent. And the intracellular proteins were decreased by 5% in LNCap and by 36% in DU145 respectively, while the extracellular proteins were decreased by 89% in LNCap and 96% in DU145 respectively. SELDI assay revealed that there were 5 marker proteins in LNCap and 6 in DU145. Although both LNCap and DU145 cell lines originated from human prostate cancer, they had some differences in protein expression.

Adenovirus binding to cultured synoviocytes triggers signaling through MAPK pathways and induces expression of cyclooxygenase-2.

BACKGROUND: Recombinant adenovirus can be administered in vivo to achieve transduction of a number of cell types including human synoviocytes. Immunogenicity of adenoviruses has limited their utility as vectors for gene delivery; however, specific mechanisms underlying the acute inflammatory response to adenovirus are not well understood. Activation of a number of signal transduction pathways occurs rapidly upon adenovirus binding to cell-surface receptors. We investigated stimulated expression of mitogen-activated protein kinases (MAPKs), cyclooxygenase-2 (COX-2) and prostaglandin E(2) (PGE(2)) in human primary synovial fibroblasts to adenovirus expressing the E. coli beta-galactosidase gene. METHODS: Cultured rheumatoid synoviocytes were exposed to transduction-competent Ad/RSVlacZ recombinant adenovirus or transduction-incompetent (psoralen/UV-irradiated) Ad/RSVlacZ. The effects on COX-2 expression, PGE(2) levels and MAPK signaling in synoviocytes were assessed using a combination of reverse-transcription polymerase chain reaction amplification and immunoblotting. RESULTS: Adenovirus treatment of synoviocytes increased levels of COX-2 mRNA and protein as well as PGE(2). Psoralen-treated transcriptionally inactive adenovirus was equivalent to untreated adenovirus for early COX-2 induction suggesting that viral genes were not required. Adenovirus treatment stimulated phosphorylation of ERK-1/-2, p38 MAPK, and JNK. Inhibition of the ERK and p38 MAPK pathways inhibited COX-2 expression and PGE(2) production. CONCLUSIONS: Taken together, these data demonstrate that a MAPK-dependent increase in COX-2 results in local prostaglandin production. These findings have clinical implications for use of adenovirus as vectors for in vivo gene delivery.