Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators

Proliferation and aneusomy predict survival of young patients with astrocytoma grade II

The clinical course of astrocytoma grade II (AII) is highly variable and not reflected by histological characteristics. As one of the best prognostic factors, higher age identifies rapid progressive A II. For patients over 35 years of age, an aggressive treatment is normally propagated. For patients under 35 years, there is no clear guidance for treatment choices, and therefore also the necessity of histopathological diagnosis is often questioned. We studied the additional prognostic value of the proliferation index and the detection of genetic aberrations for patients with A II. The tumour samples were obtained by stereotactic biopsy or tumour resection and divided into two age groups, that is 18–34 years (n=19) and 35 years (n=28). Factors tested included the proliferation (Ki-67) index, and numerical aberrations for chromosomes 1, 7, and 10, as detected by in situ hybridisation (ISH). The results show that age is a prognostic indicator when studied in the total patient group, with patients above 35 years showing a relatively poor prognosis. Increased proliferation index in the presence of aneusomy appears to identify a subgroup of patients with poor prognosis more accurately than predicted by proliferation index alone. We conclude that histologically classified cases of A II comprise a heterogeneous group of tumours with different biological and genetic constitution, which exhibit a highly variable clinical course. Immunostaining for Ki-67 in combination with the detection of aneusomy by ISH allows the identification of a subgroup of patients with rapidly progressive A II. This is an extra argument not to defer stereotactic biopsy in young patients with radiological suspicion of A II

The Assembly of Individual Chaplin Peptides from Streptomyces coelicolor into Functional Amyloid Fibrils

The self-association of proteins into amyloid fibrils offers an alternative to the natively folded state of many polypeptides. Although commonly associated with disease, amyloid fibrils represent the natural functional state of some proteins, such as the chaplins from the soil-dwelling bacterium Streptomyces coelicolor, which coat the aerial mycelium and spores rendering them hydrophobic. We have undertaken a biophysical characterisation of the five short chaplin peptides ChpD-H to probe the mechanism by which these peptides self-assemble in solution to form fibrils. Each of the five chaplin peptides produced synthetically or isolated from the cell wall is individually surface-active and capable of forming fibrils under a range of solution conditions in vitro. These fibrils contain a highly similar cross-β core structure and a secondary structure that resembles fibrils formed in vivo on the spore and mycelium surface. They can also restore the growth of aerial hyphae to a chaplin mutant strain. We show that cysteine residues are not required for fibril formation in vitro and propose a role for the cysteine residues conserved in four of the five short chaplin peptides

Cancer mortality patterns in Ghana: a 10-year review of autopsies and hospital mortality

BACKGROUND: Cancer mortality pattern in Ghana has not been reviewed since 1953, and there are no population-based data available for cancer morbidity and mortality patterns in Ghana due to the absence of a population-based cancer registry anywhere in the country. METHODS: A retrospective review of autopsy records of Department of Pathology, and medical certificate of cause of death books from all the wards of the Korle-Bu Teaching Hospital (KBTH), Accra, Ghana during the 10-year period 1991–2000 was done. RESULTS: The present study reviews 3659 cancer deaths at the KBTH over the 10-year period. The male-to-female ratio was 1.2:1. The mean age for females was 46.5 [Standard Deviation (SD), 20.8] years, whilst that of males was 47.8 (SD, 22.2) years. The median age was 48 years for females and 50 years for males.Both sexes showed a first peak in childhood, a drop in adolescence and young adulthood, and a second peak in the middle ages followed by a fall in the elderly, with the second peak occurring a decade earlier in females than in males. The commonest cause of cancer death in females was malignancies of the breast [Age-Standardized Cancer Ratio (ASCAR), 17.24%], followed closely by haematopoietic organs (14.69%), liver (10.97%) and cervix (8.47%). Whilst in males, the highest mortality was from the liver (21.15%), followed by prostate (17.35%), haematopoietic organs (15.57%), and stomach (7.26%). CONCLUSION: Considering the little information available on cancer patterns in Ghana, this combined autopsy and death certification data from the largest tertiary hospital is of considerable value in providing reliable information on the cancer patterns in Ghana

An in vitro co-culture model of esophageal cells identifies ascorbic acid as a modulator of cell competition

<p>Abstract</p> <p>Background</p> <p>The evolutionary dynamics between interacting heterogeneous cell types are fundamental properties of neoplastic progression but can be difficult to measure and quantify. Cancers are heterogeneous mixtures of mutant clones but the direct effect of interactions between these clones is rarely documented. The implicit goal of most preventive interventions is to bias competition in favor of normal cells over neoplastic cells. However, this is rarely explicitly tested. Here we have developed a cell culture competition model to allow for direct observation of the effect of chemopreventive or therapeutic agents on two interacting cell types. We have examined competition between normal and Barrett's esophagus cell lines, in the hopes of identifying a system that could screen for potential chemopreventive agents.</p> <p>Methods</p> <p>One fluorescently-labeled normal squamous esophageal cell line (EPC2-hTERT) was grown in competition with one of four Barrett's esophagus cell lines (CP-A, CP-B, CP-C, CP-D) under varying conditions and the outcome of competition measured over 14 days by flow cytometry.</p> <p>Results</p> <p>We demonstrate that ascorbic acid (vitamin C) can help squamous cells outcompete Barrett's cells in this system. We are also able to show that ascorbic acid's boost to the relative fitness of squamous cells was increased in most cases by mimicking the pH conditions of gastrointestinal reflux in the lower esophagus.</p> <p>Conclusions</p> <p>This model is able to integrate differential fitness effects on various cell types, allowing us to simultaneously capture effects on interacting cell types without having to perform separate experiments. This model system may be used to screen for new classes of cancer prevention agents designed to modulate the competition between normal and neoplastic cells.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

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

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388