The local inflammatory response in colorectal cancer – type, location or density? A systematic review and meta-analysis

Introduction: The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. Methods: A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. Results: Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. Conclusion: The evidence suggests that it is the density of a co-ordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype

The relationship between tumour budding, tumour microenvironment and survival in patients with primary operable colorectal cancer

Background: Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective: The aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC. Methods: Hematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate. Results: High budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors. Conclusions: Tumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC. Tumor budding has been defined as a single tumor cell or small cluster of four or fewer tumor cells at the invasive front12,18 and should be considered a promising and strong prognostic factor in colorectal cancer (CRC).19 Widespread reporting of tumor budding has not progressed to routine clinical practice due to a lack of consensus on scoring methods. However, routine reporting is now advocated by using the approach outlined by the International Tumour Budding Consensus Conference (ITBCC), with recommendations for the assessment and reporting of tumor budding in CRC.6 The ITBCC recommends that tumor budding should be included in future CRC guidelines and protocols and should be considered, along with other clinicopathological factors, in a multidisciplinary setting. The recent dataset for histopathological reporting of CRC by the royal pathologist stated that they would reconsider reporting tumor budding when new data become available.4 The tumor microenvironment also plays an important role in CRC outcomes. Marked peritumoral inflammation has been associated with favorable outcome,3,14 while the presence of a high tumor stroma percentage (TSP) has been validated as a stage-independent marker of reduced survival in patients with primary operable CRC.7,8. Both contribute to the development of a tumor microenvironment score that can potentially supplement the current TNM staging system.9 The aim of this study was to assess the proposed method by ITBCC in clinical practice and investigate the relationship between tumor budding and tumor factors, tumor microenvironment, and survival in primary operable CRC

No spin-glass transition in the "mobile-bond" model

The recently introduced ``mobile-bond'' model for two-dimensional spin glasses is studied. The model is characterized by an annealing temperature T_q. On the basis of Monte Carlo simulations of small systems it has been claimed that this model exhibits a non-trivial spin-glass transition at finite temperature for small values of T_q. Here the model is studied by means of exact ground-state calculations of large systems up to N=256^2. The scaling of domain-wall energies is investigated as a function of the system size. For small values T_q<0.95 the system behaves like a (gauge-transformed) ferromagnet having a small fraction of frustrated plaquettes. For T_q>=0.95 the system behaves like the standard two-dimensional +-J spin-glass, i.e. it does NOT exhibit a phase transition at T>0.Comment: 4 pages, 5 figures, RevTe

Evidence for Warped Disks of Young Stars in the Galactic Center

The central parsec around the super-massive black hole in the Galactic Center hosts more than 100 young and massive stars. Outside the central cusp (R~1") the majority of these O and Wolf-Rayet (WR) stars reside in a main clockwise system, plus a second, less prominent disk or streamer system at large angles with respect to the main system. Here we present the results from new observations of the Galactic Center with the AO-assisted near-infrared imager NACO and the integral field spectrograph SINFONI on the ESO/VLT. These include the detection of 27 new reliably measured WR/O stars in the central 12" and improved measurements of 63 previously detected stars, with proper motion uncertainties reduced by a factor of four compared to our earlier work. We develop a detailed statistical analysis of their orbital properties and orientations. Half of the WR/O stars are compatible with being members of a clockwise rotating system. The rotation axis of this system shows a strong transition as a function of the projected distance from SgrA*. The main clockwise system either is either a strongly warped single disk with a thickness of about 10 degrees, or consists of a series of streamers with significant radial variation in their orbital planes. 11 out of 61 clockwise moving stars have an angular separation of more than 30 degrees from the clockwise system. The mean eccentricity of the clockwise system is 0.36+/-0.06. The distribution of the counter-clockwise WR/O star is not isotropic at the 98% confidence level. It is compatible with a coherent structure such as stellar filaments, streams, small clusters or possibly a disk in a dissolving state. The observed disk warp and the steep surface density distribution favor in situ star formation in gaseous accretion disks as the origin of the young stars.Comment: ApJ in pres

Scaling of stiffness energy for 3d +/-J Ising spin glasses

Large numbers of ground states of 3d EA Ising spin glasses are calculated for sizes up to 10^3 using a combination of a genetic algorithm and Cluster-Exact Approximation. A detailed analysis shows that true ground states are obtained. The ground state stiffness (or domain wall) energy D is calculated. A D ~ L^t behavior with t=0.19(2) is found which strongly indicates that the 3d model has an equilibrium spin-glass-paramagnet transition for non-zero T_c.Comment: 4 pages, 4 figure

A new method for analyzing ground-state landscapes: ballistic search

A ``ballistic-search'' algorithm is presented which allows the identification of clusters (or funnels) of ground states in Ising spin glasses even for moderate system sizes. The clusters are defined to be sets of states, which are connected in state-space by chains of zero-energy flips of spins. The technique can also be used to estimate the sizes of such clusters. The performance of the method is tested with respect to different system sizes and choices of parameters. As an application the ground-state funnel structure of two-dimensional +or- J spin glasses of systems up to size L=20 is analyzed by calculating a huge number of ground states per realization. A T=0 entropy per spin of s_0=0.086(4)k_B is obtained.Comment: 10 pages, 11 figures, 35 references, revte

Constraining the initial mass function of stars in the Galactic Centre

(abridged) Here we discuss the question whether the extreme circumstances in the centre of the Milky Way may be the reason for a significant variation of the IMF. By means of stellar evolution models using different codes we show that the observed luminosity in the central parsec is too high to be explained by a long-standing top-heavy IMF, considering the limited amount of mass inferred from stellar kinematics in this region. In contrast, continuous star formation over the Galaxy's lifetime following a canonical IMF results in a mass-to-light ratio and a total mass of stellar black holes (SBHs) consistent with the observations. Furthermore, these SBHs migrate towards the centre due to dynamical friction, turning the cusp of visible stars into a core as observed in the Galactic Centre. For the first time here we explain the luminosity and dynamical mass of the central cluster and both the presence and extent of the observed core, since the number of SBHs expected from a canonical IMF is just enough to make up for the missing luminous mass. We conclude that the Galactic Centre is consistent with the canonical IMF and do not suggest a systematic variation as a result of the region's properties such as high density, metallicity, strong tidal field etc.Comment: MNRAS, accepted, 8 pages, 4 figure

Ground-state clusters of two-, three- and four-dimensional +-J Ising spin glasses

A huge number of independent true ground-state configurations is calculated for two-, three- and four-dimensional +- J spin-glass models. Using the genetic cluster-exact approximation method, system sizes up to N=20^2,8^3,6^4 spins are treated. A ``ballistic-search'' algorithm is applied which allows even for large system sizes to identify clusters of ground states which are connected by chains of zero-energy flips of spins. The number of clusters n_C diverges with N going to infinity. For all dimensions considered here, an exponential increase of n_C appears to be more likely than a growth with a power of N. The number of different ground states is found to grow clearly exponentially with N. A zero-temperature entropy per spin of s_0=0.078(5)k_B (2d), s_0=0.051(3)k_B (3d) respectively s_0=0.027(5)k_B (4d) is obtained.Comment: large extensions, now 12 pages, 9 figures, 27 reference

Quantum interference and the formation of the proximity effect in chaotic normal-metal/superconducting structures

We discuss a number of basic physical mechanisms relevant to the formation of the proximity effect in superconductor/normal metal (SN) systems. Specifically, we review why the proximity effect sharply discriminates between systems with integrable and chaotic dynamics, respectively, and how this feature can be incorporated into theories of SN systems. Turning to less well investigated terrain, we discuss the impact of quantum diffractive scattering on the structure of the density of states in the normal region. We consider ballistic systems weakly disordered by pointlike impurities as a test case and demonstrate that diffractive processes akin to normal metal weak localization lead to the formation of a hard spectral gap -- a hallmark of SN systems with chaotic dynamics. Turning to the more difficult case of clean systems with chaotic boundary scattering, we argue that semiclassical approaches, based on classifications in terms of classical trajectories, cannot explain the gap phenomenon. Employing an alternative formalism based on elements of quasiclassics and the ballistic $\sigma$-model, we demonstrate that the inverse of the so-called Ehrenfest time is the relevant energy scale in this context. We discuss some fundamental difficulties related to the formulation of low energy theories of mesoscopic chaotic systems in general and how they prevent us from analysing the gap structure in a rigorous manner. Given these difficulties, we argue that the proximity effect represents a basic and challenging test phenomenon for theories of quantum chaotic systems.Comment: 21 pages (two-column), 6 figures; references adde

1928-29: Abilene Christian College Bible Lectures - Full Text

INTRODUCTION It has been the custom of Abilene Christian College for several years to hold an annual “Lectureship” the last week in February. This is a time of gathering of brethren from all over the state and adjoining states. It is a time of a great spiritual feast. It affords an opportunity for brethren to meet and talk over the work of the Lord. It also enables us to hear again great men of God whose voices have sounded the Word of the Lord in the days of the past in great meetings. In order that those who are not permitted to hear the lectures may enjoy them it has been the custom of Abilene Christian College to publish the lectures in a book at the end of each two years. We feel that these wonderful messages from some of the greatest minds of the church ought to be preserved that they may do good even after the lips of the speakers have become silent. It is with a prayer that great good may come that this volume of lectures of 1928 and 1929 is sent forth. We regret that some of the lectures could not be included in the book. Several of the brethren neglected to send in their manuscripts; some other manuscripts were destroyed by fire, and the brethren did not replace them. Most\u27 of the lectures are in the book. BATSELL BAXTER. DELIVERED IN THE AUDITORIUM OF ABILENE CHRISTIAN COLLEGE ABILENE, TEXAS FEBRUARY 1928-1929 FIRM FOUNDATION PUBLISHING HOUSE 104-106-108 E. 9th Street Austin, Texas