A mutational signature associated with alcohol consumption and prognostically significantly mutated driver genes in esophageal squamous cell carcinoma.

Background: Esophageal squamous cell carcinoma (ESCC) is often diagnosed at an advanced and incurable stage. Information on driver genes and prognosticators in ESCC remains incomplete. The objective was to elucidate significantly mutated genes (SMGs), mutational signatures, and prognosticators in ESCC. Patients and methods: Three MutSig algorithms (i.e. MutSigCV, MutSigCL and MutSigFN) and '20/20+' ratio-metric were employed to identify SMGs. Nonnegative matrix factorization was used to decipher mutational signatures. Kaplan-Meier survival analysis, multivariate Cox and logistic regression models were applied to analyze association between mutational features and clinical parameters. Results: We identified 26 SMGs, including 8 novel (NAV3, TENM3, PTCH1, TGFBR2, RIPK4, PBRM1, USP8 and BAP1) and 18 that have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including clocklike C>T at CpG, APOBEC overactive C>T at TpCp[A/T], and a signature featured by T>C substitution. The T>C mutational signature was significantly correlated with alcohol consumption (OR: 3.59; 95% CI: 2.30-5.67; P < 0.001). This alcohol consumption signature was also observed in liver cancer and head and neck squamous cell carcinoma, and its mutational activity was substantially higher in samples with mutations in TP53. Survival analysis revealed that TENM3 mutations (HR: 5.54; CI: 2.68-11.45; P < 0.001) and TP53 hotspot mutation p.R213* (HR: 3.37; CI: 1.73-8.06; P < 0.001) were significantly associated with shortened survival outcome. The association remained statistically significant after controlling for age, gender, TNM stage and tumor grade. Conclusions: We have uncovered several new SMGs in ESCC and defined an alcohol consumption related mutational signature. TENM3 mutations and the TP53 hotspot mutation p.R213* are independent prognosticators for poor survival in ESCC.

[The prognostic value of cloned genetic mutations detected by second-generation sequencing in RUNX1-RUNX1T1 positive acute myeloid leukemia patients receiving intensive consolidation therapy].

Objective: To investigate the prognostic value of clonal gene mutations detected by second-generation sequencing in patients with positive RUNX1-RUNX1T1 acute myeloid leukemia (AML) who received high-dose chemotherapy or autologous transplantation (intensive consolidation therapy) in the first complete remission (CR(1)) state. Methods: 79 AML patients with positive RUNX1-RUNX1T1 who received intensive consolidation therapy in CR(1) state from July 2011 to August 2017 were analyzed retrospectively. Kaplan-Meier curve and Cox regression model were used to figure out the effect of leukocyte counts at onset and gene mutations for prognosis. Results: C-KIT, FLT3, CEBPA and DNMT3A gene mutations were found in 25 (31.6%) , 6 (7.6%) , 7 (8.9%) and 1 (1.3%) patient among the population. Mutations in C-KIT exon17 and C-KIT exon8 were detected in 19 (24.1%) and 5 (6.3%) cases, respectively, and mutations of FLT3-ITD were confirmed in 5 (6.3%) cases. The higher leukocyte counts presented at onset of leukemia, the shorter overall survival (OS) was seen in these patients (P=0.03) . Patients with C-KIT exon17 mutation had significantly shorter OS (P=0.01) and disease free survival (DFS) (P=0.006) compared with those without gene mutations, and patients with FLT3-ITD gene mutation got the inferior OS (P=0.048) and DFS (P=0.071) . Conclusion: In AML patients with positive RUNX1-RUNX1T1 receiving intensive consolidation therapy, the white blood cell counts at onset of leukemia, C-KIT mutations in exon 17, and FLT3-ITD gene mutations suggest poor prognosis, which would contribute to elaborate risk stratification, personalized treatment and predict prognosis for these patients.

Effect of genistein on the gene expressions of androgen generating key enzymes StAR, P450scc and CYP19 in rat ovary.

In this investigation, the effects of genistein (GEN) on the expression of steroidogenic genes such as steroidogenic acute regulatory protein (StAR), side-chain cleavage enzymes (P450scc) and cytochrome P450 aromatase (CYP19) were assessed. For this study, forty young female Sprague Dawley (SD) rats at aged 2-3 months (200±20 g) and forty aged female SD rats aged 10-12 months (490±20 g) were selected. Also, based on weight they were divided into a negative control group (NC), three different GEN dose groups, which received GEN of 15, 30, 60 mg/kg, and a positive control group (PC). The experiment lasted 30 days. Concentrations of serum hormones were determined by Enzyme-linked immunosorbent assay (ELISA). Gene and protein expressions of StAR, P450scc and CYP19 were determined by Real-Time PCR and western blot techniques. It was observed that 30-60 mg/kg GEN could increase the expression of androgen generating key enzymes in the young rat ovary. GEN also significantly increased progesterone and E2 levels in the serum of aged rats and reduced the levels of LH and FSH in the serum of both young and aged rats. Compared with young rats, the effect of GEN on the ovary of aged rats was stronger and a lower dose of GEN (15 mg/kg) showed an obvious effect on these indicators. GEN influenced both estrogen level and indicators associated with estrogen and androgen transformation processes, which indicates that GEN can impair the growth and maturation of the ovary.

[The application of alpha-globin-3'HVR probe for DNA fingerprinting in forensic science].

Using alpha-globin-3'HVR as the molecular hybridization probe, A clear and readable DNA fingerprint has been obtained. Based on the DNA fingerprint analysis of 200 unrelated individuals living in Beijing area, the probability of chance association of two random individuals was 4.0 x 10(-12). The study of 32 related individuals of 6 families showed that the inheritance of DNA fingerprint bands conformed to the Mendelian law. The method is reliable for the individual identification and paternity test. It provides a scientific basis for solving cases such as rape, homicide etc. and it has been used in our actual case work.

[Researches on the forensic application of DNA probe. I. The determination of paternity and the identification of individual using PYNH24 probe].

Restriction fragment length polymorphism of genomic DNA digested with MspI was analyzed using specific probe PYNH 24. The clear and readable patterns were obtained. Of 190 unrelated individuals tested, the polymorphism is 95%. Inheritance of alleles in 45 related individuals of 8 families is consistent with Mendelian Law.

[Preventive effect of endothelin-1 mRNA antisense oligonucleotide on acute myocardial ischemic arrhythmia in rats].

Acute myocardial ischemia was induced by occlusion of the anterior descending of left coronary artery (LAD) in rats; the resultant arrhythmia in 1 h after LAD occlusion was evaluated. In order to prevent expression of endothelin-1 mRNA, human endothelin-1 mRNA antisense oligonucleotide (ET-1 AS-ODN) was intravenously injected 2 h before LAD occlusion. The effect of AS-ODN on plasma ET-1 concentration and the acute ischemic arrhythmia were observed. The results showed that plasma ET-1 was significantly decreased in rats pretreated with AS-ODN, and both the incidence and severity of the acute ischemic arrhythmia were decreased dose-dependently as compared with normal saline control and sense oligonucleotide control, indicating that ET-1 AS-ODN could prevent acute myocardial ischemic arrhythmia and that endogenous endothelin-1 may play an important role in the development of acute ischemic arrhythmia in rats.

[Model transfer in multivariate calibration].

This paper introduces the backgrounds, principles and some popular algorithms used for resolving calibration transfer in multivariate calibration of chemometrics. The algorithms include S/B, DS, PDS, FIR, and Shenk's algorithm. The recent development of calibration transfer in the past two years is also reviewed. A number of key applications of different calibration transfer algorithms are summarized, which will be helpful for the further research of calibration transfer principles and algorithms. 51 references are cited.

[Effect of microwave contraception on human serum testosterone and luteinizing hormone].

Using home-made match kits and radioimmunoassay, both serum luteinizing hormone (LH) and testosterone (T) were measured in 53 healthy adult males using microwave contraception and 76 normal fertility males as control. The results showed that in contraceptive group the serum T level was significantly decreased (p 0.0001), while serum LH was apparently elevated (p 0.01) as compared whith the normal controls. Furthermore, the longer exposure duration the lower serum T declined and the higher serum LH increased (p 0.001). The present study suggests that the microwave dose used for contraception seems to cause damage in Leydig cell function in terms of T production, and then influence endocrine function of testis. The progressively increased LH level also indicates certain degree damage of the Leydig cells. However, the damage might be reversible. The results may be useful for further clinical investigation.

The effects of high iodine on the brain development of mice.

C57 mice were divided into two groups: (A): experiment group (H group). Each female mouse was injected with 20 microliter iodized oil; (B): control group (N group). Both groups were mated 8 days after iodized oil injection. Urine iodine contents/24 h of H group was 20 times higher than that in N group 7 days after injection and 18 times higher two months later. Serum T4 values were determined. Brain protein, DNA, body weight, motility and learning ability were measured in the progeny. The results indicate that there was no statistically significant difference between the groups in any of the parameters mentioned above. This strongly suggests that a high iodine dose, given as iodized oil, does not have obvious damaging effects on brain development, at least in mice.