The predicted spectral phase of a fiber continuum pulsed source rigorously quantified by the scalar generalized nonlinear Schrödinger equation is found to be in excellent agreement with that measured by multiphoton intra-pulse interference phase scan (MIIPS) with background subtraction. This cross-validation confirms the absolute pulse measurement by MIIPS and the transform-limited compression of the fiber continuum pulses by the pulse shaper performing the MIIPS measurement, and permits the subsequent coherent control on the fiber continuum pulses by this pulse shaper. The combination of the fiber continuum source with the MIIPS-integrated pulse shaper produces compressed transform-limited 9.6 fs (FWHM) pulses or arbitrarily shaped pulses at a central wavelength of 1020 nm, an average power over 100 mW, and a repetition rate of 76 MHz. In comparison to the 229-fs pump laser pulses that generate the fiber continuum, the compressed pulses reflect a compression ratio of 24.

Background:

Recent data suggest a link between blood leukocyte DNA methylation, and cancer risk. However, reports on DNA methylation from a prospective study are unavailable for gastric cancer.

Methods:

We explored the association between methylation in pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case–control study nested in the prospective Shanghai Women's Health Study cohort. Incident gastric cancer cases (n=192) and matched controls (n=384) were included in the study. Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders.

Results:

Alu methylation was inversely associated with gastric cancer risk, mainly among cases diagnosed one or more years after blood collection. After excluding cases diagnosed during the first year of follow-up, the ORs for the third, second, and first quartiles of Alu methylation compared with the highest quartile were 2.43 (1.43–4.13), 1.47(0.85–2.57), and 2.22 (1.28–3.84), respectively. This association appeared to be modified by dietary intake, particularly isoflavone. In contrast, LINE-1 methylation levels were not associated with gastric cancer risk.

Conclusion:

Evidence from this prospective study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk, including risk of gastric cancer.

This work investigates the effects of oxidative stress due to exhaustive training on uncoupling protein 2 (UCP2) and Bcl-2/Bax in rat skeletal muscles. A total of 18 Sprague-Dawley female rats were randomly divided into three groups: the control group (CON), the trained control group (TC), and the exhaustive trained group (ET). Malondialdehyde (MDA), superoxide dismutase (SOD), xanthine oxidase (XOD), ATPase, UCP2, and Bcl-2/Bax ratio in red gastrocnemius muscles were measured. Exhaustive training induced ROS increase in red gastrocnemius muscles, which led to a decrease in the cell antiapoptotic ability (Bcl-2/Bax ratio). An increase in UCP2 expression can reduce ROS production and affect mitochondrial energy production. Thus, oxidative stress plays a significant role in overtraining.

The tumor-suppressor p53 can induce various biological responses. Yet, it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using chromatin immunoprecipitation (ChIP)-seq revealed ‘p53 default program', that is, the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, reactivation of p53 and induction of tumor cell apoptosis (RITA) or 5-fluorouracil in breast cancer cells, despite different biological outcomes. Parallel analysis of gene expression allowed identification of 280 novel p53 target genes, including p53-repressed AURKA. We identified Sp1 as one of the p53 modulators, which confer specificity to p53-mediated transcriptional response upon RITA. Further, we found that STAT3 antagonizes p53-mediated repression of a subset of genes, including AURKA.

Inactivation of the p53 tumour suppressor, either by mutation or by overexpression of its inhibitors Hdm2 and HdmX is the most frequent event in cancer. Reactivation of p53 by targeting Hdm2 and HdmX is therefore a promising strategy for therapy. However, Hdm2 inhibitors do not prevent inhibition of p53 by HdmX, which impedes p53-mediated apoptosis. Here, we show that p53 reactivation by the small molecule RITA leads to efficient HdmX degradation in tumour cell lines of different origin and in xenograft tumours in vivo. Notably, HdmX degradation occurs selectively in cancer cells, but not in non-transformed cells. We identified the inhibition of the wild-type p53-induced phosphatase 1 (Wip1) as the major mechanism important for full engagement of p53 activity accomplished by restoration of the ataxia telangiectasia mutated (ATM) kinase-signalling cascade, which leads to HdmX degradation. In contrast to previously reported transactivation of Wip1 by p53, we observed p53-dependent repression of Wip1 expression, which disrupts the negative feedback loop conferred by Wip1. Our study reveals that the depletion of both HdmX and Wip1 potentiates cell death due to sustained activation of p53. Thus, RITA is an example of a p53-reactivating drug that not only blocks Hdm2, but also inhibits two important negative regulators of p53 – HdmX and Wip1, leading to efficient elimination of tumour cells.

Background:

The influence of different types and intensities of physical activity on risk for breast cancer is unclear.

Methods:

In a prospective cohort of 73 049 Chinese women (40–70 years), who had worked outside the home, we studied breast cancer risk in relation to specific types of self-reported and work history-related physical activity, including adolescent and adult exercise and household activity and walking and cycling for transportation. Occupational sitting time and physical activity energy expenditure were assigned based on lifetime occupational histories.

Results:

In all, 717 incident breast cancer cases were diagnosed. Breast cancer risk was lower for women in the lowest quartile of average occupational sitting time and in the highest quartile of average occupational energy expenditure (adjusted hazard ratio (HR): 0.81 and 0.73, respectively, P⩽0.05). Adult exercise at or above the recommended level (8 metabolic equivalent (MET) h per week per year) was associated with lower risk (adjusted HR: 0.73, P<0.05) in post-menopausal women. Analysis of joint effects showed that having both an active job and exercise participation did not confer an additional benefit. Other common daily activities were not associated with lower risk.

Interpretation:

These findings suggest that both exercise and occupational activity are associated with lower breast cancer risk, which supports current health promotion campaigns promoting exercise.

For over thirty years it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently relatively little was understood about the events that result in commitment to endocrine differentiation or the eventual segregation of over 10 different hormone expressing cell types in the gastrointestinal tract. Enteroendocrine cells arise from pluripotent intestinal stem cells. Differentiation of enteroendocrine cells is controlled by the sequential expression of three basic helix loop helix transcription factors, Math1, Neurogenin 3, and NeuroD. Math1 expression is required for specification and segregation of the intestinal secretory lineage (Paneth, goblet, and enteroendocrine cells) from the absorptive enterocyte lineage. Neurogenin 3 represents the earliest stage of enteroendocrine differentiation and in its absence enteroendocrine cells fail to develop. Subsequent expression of NeuroD appears to represent a later stage of differentiation for maturing enteroendocrine cells. Enteroendocrine cell fate is inhibited by the Notch signaling pathway, which appears to inhibit both Math1 and Neurogenin 3. Understanding enteroendocrine cell differentiation will become increasingly important for identifying potential future targets for common diseases like diabetes and obesity.

The strategy of clinically targeting cancerous cells at their most vulnerable state during mitosis has instigated numerous studies into the mitotic cell death (MCD) pathway. As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells. Moreover, these antimitotic drugs are also highly selective and sensitive. Despite the robust rate of discovery and the development of mitosis-selective inhibitors, the unpredictable complexities of the human body's response to these drugs still herald the biggest challenge towards clinical success. Undoubtedly, the need to bridge the gap between promising preclinical trials and effective translational bedside treatment prompts further investigations towards mapping out the mechanistic pathways of MCD, understanding how these drugs work as medicine in the body and more comprehensive target validations. In this review, current antimitotic agents are summarized with particular emphasis on the evaluation of their clinical efficacy as well as their limitations. In addition, we discuss the basis behind the lack of activity of these inhibitors in human trials and the potential and future directions of mitotic anticancer strategies.

Objective:

To investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally.

Methods:

In 121 community-dwelling participants of the Chicago Health and Aging Project, serum markers of vitamin B12 status were related to summary measures of neuropsychological tests of 5 cognitive domains and brain MRI measures obtained on average 4.6 years later among 121 older adults.

Results:

Concentrations of all vitamin B12–related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume.

Conclusions:

Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.

Objective

This study aimed to quantify intratumoural viable tissue perfusion with contrast-enhanced greyscale ultrasound to evaluate tumour response to anti-angiogenic treatment.

Methods

H22 hepatoma-bearing mice were treated with low-dose thalidomide (Group B), high-dose thalidomide (Group C) or 0.5% carboxylmethylcellulose (Group A). Contrast-enhanced greyscale ultrasound was performed after 7 days of treatments to evaluate the percentage of non-enhanced area for each tumour; regions of interest within the enhanced area were analysed offline to determine the area under the curve (AUC), maximum intensity (IMAX), perfusion index (PI), mean transit time (MTT), time to peak (TTP) and quality of fit (QOF). Immunohistochemical analysis was performed for evaluation of microvascular density (MVD).

Results

The percentage of non-enhanced area was significantly larger in Group C than in Groups A and B (p<0.05); however, there was no significant difference between Groups A and B. Treatment with thalidomide resulted in a significant decrease in AUC, PI and IMAX compared with Group A (p<0.05). Immunohistochemistry showed significant decreases in MVD in Groups B and C compared with Group A (p<0.05); however, there was no significant difference in MVD between Groups B and C. MVD was positively correlated with IMAX (r = 0.419, p = 0.023) and PI (r = 0.455, p = 0.013).

Conclusion

Quantitatively analysing intratumoural viable tissue perfusion enables early evaluation of tumour response to anti-angiogenic therapy before apparent changes in tumour necrosis.

Background:

Persistent activation of signal transducers and activators of transcription 3 (STAT3) is commonly detected in many types of cancer, including colon cancer. To date, whether STAT3 is activated and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, in colon cancer stem cells are still unknown.

Methods:

Flow cytometry was used to isolate colon cancer stem cells, which are characterised by both aldehyde dehydrogenase (ALDH)-positive and CD133-positive subpopulations (ALDH+/CD133+). The levels of STAT3 phosphorylation and the effects of STAT3 inhibition by a newly developed curcumin analogue, GO-Y030, that targets STAT3 in colon cancer stem cells were examined.

Results:

Our results observed that ALDH+/CD133+ colon cancer cells expressed higher levels of phosphorylated STAT3 than ALDH-negative/CD133-negative colon cancer cells, suggesting that STAT3 is activated in colon cancer stem cells. GO-Y030 and curcumin inhibited STAT3 phosphorylation, cell viability, tumoursphere formation in colon cancer stem cells. GO-Y030 also reduced STAT3 downstream target gene expression and induced apoptosis in colon cancer stem cells. Furthermore, GO-Y030 suppressed tumour growth of cancer stem cells from both SW480 and HCT-116 colon cancer cell lines in the mouse model.

Conclusion:

Our results indicate that STAT3 is a novel therapeutic target in colon cancer stem cells, and inhibition of activated STAT3 in cancer stem cells by GO-Y030 may offer an effective treatment for colorectal cancer.

Amyloid β-protein (Aβ) is central to the pathology of Alzheimer’s disease (AD). Of the two predominant Aβ alloforms, Aβ1–40 and Aβ1–42, the latter forms more toxic oligomers. C-terminal fragments (CTFs) of Aβ were recently shown to inhibit Aβ1–42 toxicity in vitro. Here we studied Aβ1–42 assembly in the presence of three effective CTF inhibitors and an ineffective fragment, Aβ21–30. Using a discrete molecular dynamics approach that recently was shown to capture key differences between Aβ1–40 and Aβ1–42 oligomerization, we compared Aβ1–42 oligomer formation in the absence and presence of CTFs or Aβ21–30 and identified structural elements of Aβ1–42 that correlated with Aβ1–42 toxicity. CTFs co-assembled with Aβ1–42 into large heterooligomers containing multiple Aβ1–42 and inhibitor fragments. In contrast, Aβ21–30 co-assembled with Aβ1–42 into heterooligomers containing mostly a single Aβ1–42 and multiple Aβ21–30 fragments. The CTFs, but not Aβ21–30, decreased the β-strand propensity of Aβ1–42 in a concentration-dependent manner. CTFs and Aβ21–30 had a high binding propensity to the hydrophobic regions of Aβ1–42 but only CTFs were found to bind the Aβ1–42 region A2-F4. Consequently, only CTFs but not Aβ21–30 reduced the solvent accessibility of Aβ1–42 in the region D1-R5. The reduced solvent accessibility of Aβ1–42 in the presence of CTFs was comparable to the solvent accessibility of Aβ1–40 oligomers formed in the absence of Aβ fragments. These findings suggest that the region D1-R5, which was more exposed to the solvent in Aβ1–42 than in Aβ1–40 oligomers, is involved in mediating Aβ1–42 oligomer neurotoxicity.

Objective

We aimed to determine which combination of physical examination (pe), mammography (mam), and ultrasonography (us) would optimize breast cancer detection in China.

Methods

We conducted a trial of screening with pe, mam, and us among Chinese women 25 years of age and older. All initial screenings using the three modalities were completed within 30 days of each other, and subjects were followed approximately 1 year later. The performances of the three screening methods used alone, in parallel, or in series were compared. Data were analyzed using exact confidence intervals (cis) and the McNemar test.

Results

Between March 2009 and July 2011, 3028 eligible women completed all study examinations. At a mean follow-up of 1.3 years, 33 breast cancers were identified in the study population. Mammography detected 28 cancers; us, 24 cancers; and pe, 22 cancers. During the follow-up period, 2 false-negative cases occurred clinically. The highest sensitivity for breast cancer screening (93.9%) was achieved by paralleling mam with us, but came at the cost of a higher recall rate (12.15%). Using us alone at the first stage, followed by mam when indicated, offered high specificity (99.4%) and the lowest recall rate (1.82%), which were not reached at the expense of sensitivity (84.8%). Used in series, us and mam achieved a sensitivity similar to that for the same modalities used in parallel (McNemar p > 0.05).

Conclusions

Taking limited health resources into consideration, the strategy of screening with us alone at the first stage, followed by mam when indicated, may optimize breast cancer detection in most regions of China.

Mitotic death is a major form of cell death in cancer cells that have been treated with chemotherapeutic drugs. However, the mechanisms underlying this form of cell death is poorly understood. Here, we report that the loss of chromosome integrity is an important determinant of mitotic death. During prolonged mitotic arrest, caspase-3 is activated and it cleaves Cap-H, a subunit of condensin I. The depletion of Cap-H results in the loss of condensin I complex at the chromosomes, thus affecting the integrity of the chromosomes. Consequently, DNA fragmentation by caspase-activated DNase is facilitated, thus driving the cell towards mitotic death. By expressing a caspase-resistant form of Cap-H, mitotic death is abrogated and the cells are able to reenter interphase after a long mitotic delay. Taken together, we provide new insights into the molecular events that occur during mitotic death.

The main pathway of bacterial sugar phosphorylation utilizes specific phosphoenolpyruvate phosphotransferase system (PTS) enzymes. In addition to the classic PTS system, a PTS-independent secondary system has been described in which nucleotide-dependent sugar kinases are used for monosaccharide phosphorylation. Fructokinase (FK) that phosphorylates d-fructose with ATP as a cofactor has been shown to be a member of this secondary system. Bioinformatics analysis has shown that FK is a member of the “ROK” (bacterial Repressors, uncharacterized Open reading frames, and sugar Kinases) sequence family. In this study, we report the crystal structures of ROK FK from Bacillus subtilis (YdhR) (a) apo and in the presence of (b) ADP and (c) ADP/dfructose. All structures show that YdhR is a homo-dimer with a monomer composed of two similar α/βdomains forming a large cleft between domains that bind ADP and d-fructose. Enzymatic activity assays support YdhR function as an ATP-dependent fructose kinase.

Array comparative genomic hybridization was used to identify copy number alterations in clear cell renal cell carcinoma (ccRCC) patient tumors to identify associations with patient/clinical characteristics. Of 763 ccRCC patients, 412 (54%) provided frozen biopsies. Clones were analyzed for significant copy number differences, adjusting for multiple comparisons and covariates in multivariate analyses. Frequent alterations included losses on: 3p (92.2%), 14q (46.8%), 8p (38.1%), 4q (35.4%), 9p (32.3%), 9q (31.8%), 6q (30.8%), 3q (29.4%), 10q (25.7%), 13q (24.5%), 1p (23.5%) and gains on 5q (60.2%), 7q (39.6%), 7p (30.6%), 5p (26.5%), 20q (25.5%), 12q (24.8%), 12p (22.8%). Stage and grade were associated with 1p, 9p, 9q, 13q and 14q loss and 12q gain. Males had more alterations compared with females, independent of stage and grade. Significant differences in the number/types of alterations were observed by family cancer history, age at diagnosis and smoking status. Von Hippel–Lindau (VHL) gene inactivation was associated with 3p loss (P