Patterns of eating and movement that best maintain reduction in overweight

Two studies of the influences of specific patterns of eating and exercising behaviour on body weight in English Midlands women were re-analysed using correlations as the measure of effect size. As predicted from computational modelling of hunger-sating mechanisms, avoiding energy-containing drinks and foods at the ends of and between meals was the behaviour most influencing year-long weight loss. However, although eating between meals is often called snacking, the term 'snack' appeared to be too ambiguous in this culture for its use in helping efforts to control weight. Avoidance of particular sorts of fat-rich foods was also associated with longer-term weight loss. Attempts at severe restriction of intake at mealtimes were associated with weight loss during a period of intensive dieting, but did not contribute to maintenance of that weight reduction. Using diet formulae to attain rapid weight loss was associated with significant weight gain over a year. These results support the suggestion that the first line of defence against weight gain is avoiding all sources of energy during drink breaks, with personally relevant advice on lower fat versions of particular foods also being important. Continued neglect of the behaviour-specific correlational approach to gaining evidence for less fattening habits does nothing to slow the rise in obesity.     

Effects of age on DNA double-strand breaks and apoptosis in human sperm

OBJECTIVE: This study was designed to explore the relationship between men's age and DNA damage and apoptosis in human spermatozoa. DESIGN: Semen samples were collected from men between the ages of 20 and 57 years. Sperm DNA double-strand breaks were assessed using the neutral microgel electrophoresis (comet) assay, and apoptosis was estimated using the DNA diffusion assay. SETTING: Academic medical center. PATIENT(S): Sixty-six men aged 20 to 57 years were recruited from infertility laboratory and general populations and consented to donate a semen sample. Recruitment was determined by time and day of analysis; the only exclusions were for azoospermia, prostatitis, or prior cancer therapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA damage and apoptosis in human sperm. RESULT(S): Age correlated with an increasing percentage of sperm with highly damaged DNA (range: 0-83%) and tended to inversely correlate with percentage of apoptotic sperm (range: 0.3%-23%). For example, percentage of sperm with highly damaged DNA, comet extent, DNA break number, and other comet measures was statistically significantly higher in men aged 36-57 years than in those aged 20-35 years, but percentage apoptosis was statistically significantly lower in the older group. Semen analysis showed percentage motility to be significantly higher in younger age groups. CONCLUSION(S): This study clearly demonstrates an increase in sperm double-stranded DNA breaks with age. Our findings also suggest for the first time an age-related decrease in human sperm apoptosis. These novel findings may indicate deterioration of healthy sperm cell selection process with age.     

Effects of (−)-epigallocatechin gallate (EGCG) on DNA strand breaks as evaluated by single-cell gel electrophoresis (SCG) in human lymphocytes

(−)-Epigallocatechin gallate (EGCG), a catechin polyphenol component, is the main ingredient of green tea extract. Although the anti-carcinogenic and cancer inhibitory effects of EGCG have been widely reported, its genotoxicity is not clear and seldom reported. In this study, we examined the effects of EGCG on DNA strand breaks in the isolated lymphocytes and whole blood lymphocytes obtained from two smoking subjects and a nonsmoking healthy subject using a single cell gel electrophoresis (SCG) assay. The results showed that after 2 hrs of treating the isolated lymphocytes from the smokers, EGCG induced a significant, increase in DNA strand breaks at concentrations from 2.5×10⁻⁵ M to 2.0×10⁻⁴ M, while after 2 hrs of treating the whole blood obtained from the same smokers, EGCG suppressed the DNA strand breaks in the lymphocytes at concentrations of 1.0×10⁻⁴ M and 2.0×10⁻⁴ M. A similar suppressive result was also shown in the whole blood lymphocytes from the nonsmoker at nearly the same concentrations, while at concentrations of 1.0×10⁻³ M or 2.0×10⁻³ M, EGCG induced a significant increase in DNA strand breaks in the whole blood lymphocytes from the nonsmoker. This result suggests that EGCG is not only inhibitory against DNA strand breaks in whole blood, but also genotoxic to the isolated or whole blood lymphocytes at high concentrations. Thus, more research is needed to comprehensively assess the effects of EGCG on genetic materials.     

“彗星”分析法检测鼻咽癌细胞DNA放射损伤与修复

目的　探讨“彗星”分析法(CometAssay)检测鼻咽癌细胞DNA放射与修复反应的可能性。　方法　采用碱性“彗星”分析法的微胶电泳技术,定量检测评价人高、低分化鼻咽癌细胞系CNE1和CNE2Z细胞在接受X射线照射后,其DNA单链断裂(SingleStrandBreaks,SSBs)的程度,及其与放射剂量的关系和DNA的SSBs在不同检测时间的自身修复情况。　结果　用碱性“彗星”分析法可准确地检测出2Gy单一放射剂量所诱导的两系细胞DNA的SSBs;可见DNA损伤程度在不同照射剂量其结果不同,随剂量递增DNA的损伤加重,与放射剂量呈良好线性相关。15Gy诱导两系细胞的DNA损伤后,10min即可定量检测出受损DNA的确切恢复变化,在照射30min内,其修复较迅速,其损伤程度可降至初时的一半以下,其后修复缓慢,约需持续2h才能复至无照射细胞水平。　结论　“彗星”分析法检测结果能准确反映人鼻咽癌细胞DNA的定量损伤程度及其与放射剂量的关系,以及损伤后自身修复能力在受测时间中的定量变化情况     

Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins

The bone marrow (BM) is one of the organs that is sensitive to acute exposure of ionizing radiation (IR); however, the mechanism of its high sensitivity to IR remains to be elucidated. BM is differentiated into dendritic cells (DC) with granulocyte macrophage-colony stimulating factor (GM-CSF). Using this in vitro model, we studied whether radiosensitivity is distinctly regulated in undifferentiated and differentiated BM. We discovered that levels of DNA damage repair (DDR) proteins are extremely low in BM, and they are markedly increased upon differentiation to DC. Efficiency of both homologous recombination (HR)- and non-homologous end joining (NHEJ)-mediated repair of DNA double strand breaks (DSBs) is much lower in BM compared with that of DC. Consistent with this, immunofluorescent γH2AX is highly detected in BM after IR. These results indicate that increased radiosensitivity of BM is at least due to low expression of the DNA repair machinery.     

Least squares estimation and tests of breaks in mean and variance under misspecification

Summary In this paper we investigate the consequences of misspecification on the large sample properties of change‐point estimators and the validity of tests of the null hypothesis of linearity versus the alternative of a structural break. Specifically this paper concentrates on the interaction of structural breaks in the mean and variance of a time series when either of the two is omitted from the estimation and inference procedures. Our analysis considers the case of a break in mean under omitted‐regime‐dependent heteroscedasticity and that of a break in variance under an omitted mean shift. The large and finite sample properties of the resulting least‐squares‐based estimators are investigated and the impact of the two types of misspecification on inferences about the presence or absence of a structural break subsequently analysed.     

Novel derivatives of spirohydantoin induce growth inhibition followed by apoptosis in leukemia cells

Hydantoin derivatives possess a variety of biochemical and pharmacological properties and consequently are used to treat many human diseases. However, there are only few studies focusing on their potential as cancer therapeutic agents. In the present study, we have examined anticancer properties of two novel spirohydantoin compounds, 8-(3,4-difluorobenzyl)-1′-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1] octane-3,4′-imidazolidine]-2′,5′-dione (DFH) and 8-(3,4-dichlorobenzyl)-1′-(pent-4-enyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′,5′-dione (DCH). Both the compounds exhibited dose- and time-dependent cytotoxic effect on human leukemic cell lines, K562, Reh, CEM and 8E5. Incorporation of tritiated thymidine ([³H] thymidine) in conjunction with cell cycle analysis suggested that DFH and DCH inhibited the growth of leukemic cells. Downregulation of PCNA and p-histone H3 further confirm that the growth inhibition could be at the level of DNA replication. Flow cytometric analysis indicated the accumulation of cells at subG1 phase suggesting induction of apoptosis, which was further confirmed and quantified both by fluorescence-activated cell sorting (FACS) and confocal microscopy following annexin V-FITC/propidium iodide (PI) staining. Mechanistically, our data support the induction of apoptosis by activation of the mitochondrial pathway. Results supporting such a model include, elevated levels of p53, and BAD, decreased level of BCL2, activation and cleavage of caspase 9, activation of procaspase 3, poly (ADP-ribosyl) polymerase (PARP) cleavage, downregulation of Ku70, Ku80 and DNA fragmentation. Based on these results we discuss the mechanism of apoptosis induced by DFH and its implications in leukemia therapy.     

Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines

Zalypsis^® is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has a reactive carbinolamine group. This functionality can lead to the formation of a covalent bond with the amino group of selected guanines in the DNA double helix, both in the absence and in the presence of methylated cytosines. The resulting complex is additionally stabilized by the establishment of one or more hydrogen bonds with adjacent nucleotides in the opposite strand as well as by van der Waals interactions within the minor groove. Fluorescence-based thermal denaturation experiments demonstrated that the most favorable DNA triplets for covalent adduct formation are AGG, GGC, AGC, CGG and TGG, and these preferences could be rationalized on the basis of molecular modeling results. Zalypsis^®-DNA adducts eventually give rise to double-strand breaks, triggering S-phase accumulation and apoptotic cell death. The potent cytotoxic activity of Zalypsis^® was ascertained in a 24 cell line panel. The mean IC₅₀ value was 7 nM and leukemia and stomach tumor cell lines were amongst the most sensitive. Zalypsis^® administration in four murine xenograft models of human cancer demonstrates significant tumor growth inhibition that is highest in the Hs746t gastric cancer cell line with no weight loss of treated animals. Taken together, these results indicate that the potent antitumor activity of Zalypsis^® supports its current development in the clinic as an anticancer agent.     

Anticlastogenic and antigenotoxic effects of selenomethionine on doxorubicin-induced damage in vitro in human lymphocytes.

The use of antioxidants during chemotherapy has been shown to reduce or prevent the undesirable effects experienced by healthy cells. Micronutrient selenium is well known for its antioxidant properties; however, selenium exhibits a bimodal nature in that both its beneficial and toxic properties lie within a limited and narrow dose range. The present study investigated the possible protective effects of selenomethionine (SM) on the cytotoxicity, genotoxicity and clastogenicity of the chemotherapic doxorubicin (DXR), a key chemotherapic used in cancer treatment. Human peripheral lymphocytes were treated in vitro with varying concentrations of SM (0.25 microM, 0.5 microM, 1.0 microM and 2.0 microM), tested in combination with DXR (0.15 microg/mL). SM alone was not cytotoxic and when combined with DXR treatment, reduced the DNA damage index significantly, the frequency of chromosomal aberrations, the number of aberrant metaphases and the frequency of apoptotic cells. The mechanism of chemoprotection of SM may be related to its antioxidant properties as well as its ability to interfere with DNA repair pathways. Therefore this study showed that SM is effective in reducing the genetic damage induced by the antitumoral agent DXR.     

T—2毒素诱发哺乳动物细胞DNA单链断裂效应

用总洗脱时间为2h 的碱洗脱技术测定不同剂量~(60)Co-γ线照射后 L_(1210)细胞的 DNA 单链断裂,能获得与照射剂量呈直线关系的洗脱动力学曲线,剂量效应关系 r=-0.9986。0.1、1、10和100μg/ml 的 T-2毒索与哺乳动物细胞(L_(1210)和 HEL)作用3或24h均诱导轻度 DNA 单链断裂,相对 DNA 单链断裂度为11%～19%。