The peritoneal tumour microenvironment of high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSC) disseminates early and extensively throughout the peritoneal space, causing multiple lesions that are a major clinical problem. The aim of this study was to investigate the cellular composition of peritoneal tumour deposits in patient biopsies and their evolution in mouse models using immunohistochemistry, intravital microscopy, confocal microscopy, and 3D modelling. Tumour deposits from the omentum of HGSC patients contained a prominent leukocyte infiltrate of CD3(+) T cells and CD68(+) macrophages, with occasional neutrophils. Alpha-smooth muscle actin(+) (α-SMA(+) ) pericytes and/or fibroblasts surrounded these well-vascularized tumour deposits. Using the murine bowel mesentery as an accessible mouse peritoneal tissue that could be easily imaged, and two different transplantable models, we found multiple microscopic tumour deposits after i.p. injection of malignant cells. Attachment to the peritoneal surface was rapid (6-48 h) with an extensive CD45(+) leukocyte infiltrate visible by 48 h. This infiltrate persisted until end point and in the syngeneic murine ID8 model, it primarily consisted of CD3(+) T lymphocytes and CD68(+) macrophages with α-SMA(+) cells also involved from the earliest stages. A majority of tumour deposits developed above existing mesenteric blood vessels, but in avascular spaces new blood vessels tracked towards the tumour deposits by 2-3 weeks in the IGROV-1 xenografts and 6 weeks in the ID8 syngeneic model; a vigorous convoluted blood supply was established by end point. Inhibition of tumour cell cytokine production by stable expression of shRNA to CXCR4 in IGROV-1 cells did not influence the attachment of cells to the mesentery but delayed neovascularization and reduced tumour deposit size. We conclude that the multiple peritoneal tumour deposits found in HGSC patients can be modelled in the mouse. The techniques described here may be useful for assessing treatments that target the disseminated stage of this disease

Continuity theorems for the M/M/1/nM/M/1/n queueing system

In this paper continuity theorems are established for the number of losses during a busy period of the $M/M/1/n$ queue. We consider an $M/GI/1/n$ queueing system where the service time probability distribution, slightly different in a certain sense from the exponential distribution, is approximated by that exponential distribution. Continuity theorems are obtained in the form of one or two-sided stochastic inequalities. The paper shows how the bounds of these inequalities are changed if further assumptions, associated with specific properties of the service time distribution (precisely described in the paper), are made. Specifically, some parametric families of service time distributions are discussed, and the paper establishes uniform estimates (given for all possible values of the parameter) and local estimates (where the parameter is fixed and takes only the given value). The analysis of the paper is based on the level crossing approach and some characterization properties of the exponential distribution.Comment: Final revision; will be published as i

Relativistic predictions of exclusive 208Pb(p⃗,2p)207Tℓ^{208}Pb(\vec{p},2p) ^{207}T\ell analyzing powers at an incident energy of 202 MeV

Within the framework of the relativistic distorted wave impulse approximation (DWIA), we investigate the sensitivity of the analyzing power - for exclusive proton knockout from the 3s$_{1/2}$, 2d$_{3/2}$ and 2d$_{5/2}$ states in $^{208}$Pb, at an incident laboratory kinetic energy of 202 MeV, and for coincident coplanar scattering angles ($28.0^{\circ}$, $-54.6^{\circ}$) - to different distorting optical potentials, finite-range (FR) versus zero-range (ZR) approximations to the DWIA, as well as medium-modified coupling constants and meson masses. Results are also compared to the nonrelativistic DWIA predictions based on the Schr\"{o}dinger equation. Whereas the nonrelativistic model fails severely, both ZR and FR relativistic DWIA models provide an excellent description of the data. For the FR predictions, it is necessary to invoke a 20% reduction of sigma-nucleon and omega-nucleon coupling constants as well as for $\sigma$-, $\rho$- and $\omega$-meson masses, by the nuclear medium. On the other hand, the ZR predictions suggest that the strong interaction in the nuclear medium is adequately represented by the free nucleon-nucleon interaction associated with the impulse approximation. We also demonstrate that, although the analyzing power is relatively insensitive to the use different relativistic global optical potential parameter sets, the prominent oscillatory behavior of this observable is largely attributed to distortion of the scattering wave functions relative to their plane wave values.Comment: 16 pages, 3 figures, submitted to Phys. Rev.

Supersymmetry in carbon nanotubes in a transverse magnetic field

Electron properties of Carbon nanotubes in a transverse magnetic field are studied using a model of a massless Dirac particle on a cylinder. The problem possesses supersymmetry which protects low energy states and ensures stability of the metallic behavior in arbitrarily large fields. In metallic tubes we find suppression of the Fermi velocity at half-filling and enhancement of the density of states. In semiconducting tubes the energy gap is suppressed. These features qualitatively persist (although to a smaller degree) in the presence of electron interactions. The possibilities of experimental observation of these effects are discussed.Comment: A new section on electron interaction effects added and explanation on roles of supersymmetry expanded. Revtex4, 6 EPS figure file

Antarctic ice sheet discharge driven by atmosphere-ocean feedbacks at the Last Glacial Termination

Reconstructing the dynamic response of the Antarctic ice sheets to warming during the Last Glacial Termination (LGT; 18,000–11,650 yrs ago) allows us to disentangle ice-climate feedbacks that are key to improving future projections. Whilst the sequence of events during this period is reasonably well-known, relatively poor chronological control has precluded precise alignment of ice, atmospheric and marine records, making it difficult to assess relationships between Antarctic ice-sheet (AIS) dynamics, climate change and sea level. Here we present results from a highly-resolved ‘horizontal ice core’ from the Weddell Sea Embayment, which records millennial-scale AIS dynamics across this extensive region. Counterintuitively, we find AIS mass-loss across the full duration of the Antarctic Cold Reversal (ACR; 14,600–12,700 yrs ago), with stabilisation during the subsequent millennia of atmospheric warming. Earth-system and ice-sheet modelling suggests these contrasting trends were likely Antarctic-wide, sustained by feedbacks amplified by the delivery of Circumpolar Deep Water onto the continental shelf. Given the anti-phase relationship between inter-hemispheric climate trends across the LGT our findings demonstrate that Southern Ocean-AIS feedbacks were controlled by global atmospheric teleconnections. With increasing stratification of the Southern Ocean and intensification of mid-latitude westerly winds today, such teleconnections could amplify AIS mass loss and accelerate global sea-level rise

Probing a Supersymmetric Model for Neutrino Masses at Ultrahigh Energy Neutrino Telescopes

A bilinear R-Parity breaking SUSY model for neutrino mass and mixing predicts the lightest superparticle to decay mainly into a pair of tau leptons or b quarks along with a neutrino for relatively light SUSY spectra. This leads to a distinctive triple bang signature of SUSY events at ultrahigh energy neutrino telescopes like IceCube or Antares. While the expected signal size is only marginal at IceCube, it will be promising for a future multi-km^3 size neutrino telescope.Comment: 11 pages pdf including 2 figures. Discussion added. Final version to appear in Physics Letters

Learning difficulties : a portuguese perspective of a universal issue

In this article we present findings of a study that was conducted with the purpose of deepening the knowledge about the field of learning difficulties in Portugal. Therefore, within these findings we will discuss across several cultural boundaries, themes related with the existence of learning difficulties as a construct, the terminology, the political, social and scientific influences on the field, and the models of identification and of ongoing school support for students. While addressing the above-mentioned themes we will draw attention to the different, yet converging, international understandings of learning difficulties

Development of a polygenic risk score to improve screening for fracture risk: A genetic risk prediction study

Background Since screening programs identify only a small proportion of the population as eligible for an intervention, genomic prediction of heritable risk factors could decrease the number needing to be screened by removing individuals at low genetic risk. We therefore tested whether a polygenic risk score for heel quantitative ultrasound speed of sound (SOS)—a heritable risk factor for osteoporotic fracture—can identify low-risk individuals who can safely be excluded from a fracture risk screening program. Methods and findings A polygenic risk score for SOS was trained and selected in 2 separate subsets of UK Biobank (comprising 341,449 and 5,335 individuals). The top-performing prediction model was termed “gSOS”, and its utility in fracture risk screening was tested in 5 validation cohorts using the National Osteoporosis Guideline Group clinical guidelines (N = 10,522 eligible participants). All individuals were genome-wide genotyped and had measured fracture risk factors. Across the 5 cohorts, the average age ranged from 57 to 75 years, and 54% of studied individuals were women. The main outcomes were the sensitivity and specificity to correctly identify individuals requiring treatment with and without genetic prescreening. The reference standard was a bone mineral density (BMD)–based Fracture Risk Assessment Tool (FRAX) score. The secondary outcomes were the proportions of the screened population requiring clinical-risk-factor-based FRAX (CRF-FRAX) screening and BMD-based FRAX (BMD-FRAX) screening. gSOS was strongly correlated with measured SOS (r2 = 23.2%, 95% CI 22.7% to 23.7%). Without genetic prescreening, guideline recommendations achieved a sensitivity and specificity for correct treatment assignment of 99.6% and 97.1%, respectively, in the validation cohorts. However, 81% of the population required CRF-FRAX tests, and 37% required BMD-FRAX tests to achieve this accuracy. Using gSOS in prescreening and limiting further assessment to those with a low gSOS resulted in small changes to the sensitivity and specificity (93.4% and 98.5%, respectively), but the proportions of individuals requiring CRF-FRAX tests and BMD-FRAX tests were reduced by 37% and 41%, respectively. Study limitations include a reliance on cohorts of predominantly European ethnicity and use of a proxy of fracture risk. Conclusions Our results suggest that the use of a polygenic risk score in fracture risk screening could decrease the number of individuals requiring screening tests, including BMD measurement, while maintaining a high sensitivity and specificity to identify individuals who should be recommended an intervention