FOXM1 Upregulation Is an Early Event in Human Squamous Cell Carcinoma and it Is Enhanced by Nicotine during Malignant Transformation

Cancer associated with smoking and drinking remains a serious health problem worldwide. The survival of patients is very poor due to the lack of effective early biomarkers. FOXM1 overexpression is linked to the majority of human cancers but its mechanism remains unclear in head and neck squamous cell carcinoma (HNSCC).FOXM1 mRNA and protein expressions were investigated in four independent cohorts (total 75 patients) consisting of normal, premalignant and HNSCC tissues and cells using quantitative PCR (qPCR), expression microarray, immunohistochemistry and immunocytochemistry. Effect of putative oral carcinogens on FOXM1 transcriptional activity was dose-dependently assayed and confirmed using a FOXM1-specific luciferase reporter system, qPCR, immunoblotting and short-hairpin RNA interference. Genome-wide single nucleotide polymorphism (SNP) array was used to 'trace' the genomic instability signature pattern in 8 clonal lines of FOXM1-induced malignant human oral keratinocytes. Furthermore, acute FOXM1 upregulation in primary oral keratinocytes directly induced genomic instability. We have shown for the first time that overexpression of FOXM1 precedes HNSCC malignancy. Screening putative carcinogens in human oral keratinocytes surprisingly showed that nicotine, which is not perceived to be a human carcinogen, directly induced FOXM1 mRNA, protein stabilisation and transcriptional activity at concentrations relevant to tobacco chewers. Importantly, nicotine also augmented FOXM1-induced transformation of human oral keratinocytes. A centrosomal protein CEP55 and a DNA helicase/putative stem cell marker HELLS, both located within a consensus loci (10q23), were found to be novel targets of FOXM1 and their expression correlated tightly with HNSCC progression.This study cautions the potential co-carcinogenic effect of nicotine in tobacco replacement therapies. We hypothesise that aberrant upregulation of FOXM1 may be inducing genomic instability through a program of malignant transformation involving the activation of CEP55 and HELLS which may facilitate aberrant mitosis and epigenetic modifications. Our finding that FOXM1 is upregulated early during oral cancer progression renders FOXM1 an attractive diagnostic biomarker for early cancer detection and its candidate mechanistic targets, CEP55 and HELLS, as indicators of malignant conversion and progression

Airflow Dynamics of Human Jets: Sneezing and Breathing - Potential Sources of Infectious Aerosols

10.1371/journal.pone.0059970PLoS ONE84

The regulatory mechanism of fungal elicitor-induced secondary metabolite biosynthesis in medical plants.

A wide range of external stress stimuli trigger plant cells to undergo complex network of reactions that ultimately lead to the synthesis and accumulation of secondary metabolites. Accumulation of such metabolites often occurs in plants subjected to stresses including various elicitors or signal molecules. Throughout evolution, endophytic fungi, an important constituent in the environment of medicinal plants, have known to form long-term stable and mutually beneficial symbiosis with medicinal plants. The endophytic fungal elicitor can rapidly and specifically induce the expression of specific genes in medicinal plants which can result in the activation of a series of specific secondary metabolic pathways resulting in the significant accumulation of active ingredients. Here we summarize the progress made on the mechanisms of fungal elicitor including elicitor signal recognition, signal transduction, gene expression and activation of the key enzymes and its application. This review provides guidance on studies which may be conducted to promote the efficient synthesis and accumulation of active ingredients by the endogenous fungal elicitor in medicinal plant cells, and provides new ideas and methods of studying the regulation of secondary metabolism in medicinal plants

Airflow Dynamics of Coughing in Healthy Human Volunteers by Shadowgraph Imaging: An Aid to Aerosol Infection Control

Cough airflow dynamics have been previously studied using a variety of experimental methods. In this study, real-time, non-invasive shadowgraph imaging was applied to obtain additional analyses of cough airflows produced by healthy volunteers. Twenty healthy volunteers (10 women, mean age 32.2±12.9 years; 10 men, mean age 25.3±2.5 years) were asked to cough freely, then into their sleeves (as per current US CDC recommendations) in this study to analyze cough airflow dynamics. For the 10 females (cases 1–10), their maximum detectable cough propagation distances ranged from 0.16–0.55 m, with maximum derived velocities of 2.2–5.0 m/s, and their maximum detectable 2-D projected areas ranged from 0.010–0.11 m2, with maximum derived expansion rates of 0.15–0.55 m2/s. For the 10 males (cases 11–20), their maximum detectable cough propagation distances ranged from 0.31–0.64 m, with maximum derived velocities of 3.2–14 m/s, and their maximum detectable 2-D projected areas ranged from 0.04–0.14 m2, with maximum derived expansion rates of 0.25–1.4 m2/s

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62514/1/nature04703.pd

Novel, Meso-Substituted Cationic Porphyrin Molecule for Photo-Mediated Larval Control of the Dengue Vector Aedes aegypti

Dengue is a life-threatening viral disease of growing importance, transmitted by Aedes mosquito vectors. The control of mosquito larvae is crucial to contain or prevent disease outbreaks, and the discovery of new larvicides able to increase the efficacy and the flexibility of the vector control approach is highly desirable. Porphyrins are a class of molecules which generate reactive oxygen species if excited by visible light, thus inducing oxidative cell damage and cell death. In this study we aimed at assessing the potential of this photo-mediated cytotoxic mechanism to kill Aedes (Stegomyia) aegypti mosquito larvae. The selected porphyrin molecule, meso-tri(N-methylpyridyl),meso-mono(N-tetradecylpyridyl)porphine (C14 for simplicity), killed the larvae at doses lower than 1 µM, and at light intensities 50–100 times lower than those typical of natural sunlight, by damaging their intestinal tissues. The physicochemical properties of C14 make it easily adsorbed into organic material, and we exploited this feature to prepare an ‘insecticidal food’ which efficiently killed the larvae and remained active for at least 14 days after its dispersion in water. This study demonstrated that photo-sensitizing agents are promising tools for the development of new larvicides against mosquito vectors of dengue and other human and animal diseases

Meta-Analysis of the Immunogenicity and Tolerability of Pandemic Influenza A 2009 (H1N1) Vaccines

Background: Although the 2009 (H1N1) influenza pandemic officially ended in August 2010, the virus will probably circulate in future years. Several types of H1N1 vaccines have been tested including various dosages and adjuvants, and meta-analysis is needed to identify the best formulation. Methods: We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis. Results: Eighteen RCTs could be included in all primary analyses, for a total of 76 arms (16,725 subjects). After 2 doses, all 2009 H1N1 split/subunit inactivated vaccines were highly immunogenic and overcome CPMP seroconversion criteria. After 1 dose only, all split/subunit vaccines induced a satisfactory immunogenicity (> = 70%) in adults and adolescents, while only some formulations showed acceptable results for children and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted vaccines at equal doses and their immunogenicity at doses < = 6 μg (even with as little as 1.875 μg of hemagglutinin antigen) was not significantly lower than that achieved after higher doses. Finally, the rate of serious vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of 22826 vaccinated subjects). However, mild to moderate adverse reactions were more (and very) frequent for oil-in-water adjuvanted vaccines. Conclusions: Several one-dose formulations might be valid for future vaccines, but 2 doses may be needed for children, especially if a low-dose non-adjuvanted vaccine is used. Given that 15 RCTs were sponsored by vaccine manufacturers, future trials sponsored by non-industry agencies and comparing vaccines using different types of adjuvants are needed

Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2

Human vaccinia-related kinases (VRK1 and VRK2) are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 µM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO-31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31–8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer