Lattice study of infrared behaviour in SU(3) gauge theory with twelve massless flavours

We present details of a lattice study of infrared behaviour in SU(3) gauge theory with twelve massless fermions in the fundamental representation. Using the step-scaling method, we compute the coupling constant in this theory over a large range of scale. The renormalisation scheme in this work is defined by the ratio of Polyakov loops in the directions with different boundary conditions. We closely examine systematic effects, and find that they are dominated by errors arising from the continuum extrapolation. Our investigation suggests that SU(3) gauge theory with twelve flavours contains an infrared fixed point.Comment: 29 pages, 15 figures, 4 tables. Minor revision. Published versio

Microbeam Radiation Therapy controls local growth of radioresistant melanoma and treats out-of-field locoregional metastasis.

PURPOSE Synchrotron-generated microbeam radiotherapy (MRT) represents an innovative preclinical type of cancer radiotherapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiotherapy treatment. Currently, no data exists on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. METHODS AND MATERIALS We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in two cohorts of C57BL/6J mice, one receiving a single MRT and another receiving two MRT delivered with a 10-day interval. We compared these two cohorts with synchrotron broad beam-irradiated and non-irradiated mice. In addition, using multi-plex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either one or two MRT treatments. RESULTS Two MRT treatments were significantly more effective for local control than single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12 and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of anti-tumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors following the second MRT. CONCLUSIONS Our study highlights the importance of monitoring metastasis following MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis

Theta dependence of SU(N) gauge theories in the presence of a topological term

We review results concerning the theta dependence of 4D SU(N) gauge theories and QCD, where theta is the coefficient of the CP-violating topological term in the Lagrangian. In particular, we discuss theta dependence in the large-N limit. Most results have been obtained within the lattice formulation of the theory via numerical simulations, which allow to investigate the theta dependence of the ground-state energy and the spectrum around theta=0 by determining the moments of the topological charge distribution, and their correlations with other observables. We discuss the various methods which have been employed to determine the topological susceptibility, and higher-order terms of the theta expansion. We review results at zero and finite temperature. We show that the results support the scenario obtained by general large-N scaling arguments, and in particular the Witten-Veneziano mechanism to explain the U(1)_A problem. We also compare with results obtained by other approaches, especially in the large-N limit, where the issue has been also addressed using, for example, the AdS/CFT correspondence. We discuss issues related to theta dependence in full QCD: the neutron electric dipole moment, the dependence of the topological susceptibility on the quark masses, the U(1)_A symmetry breaking at finite temperature. We also consider the 2D CP(N) model, which is an interesting theoretical laboratory to study issues related to topology. We review analytical results in the large-N limit, and numerical results within its lattice formulation. Finally, we discuss the main features of the two-point correlation function of the topological charge density.Comment: A typo in Eq. (3.9) has been corrected. An additional subsection (5.2) has been inserted to demonstrate the nonrenormalizability of the relevant theta parameter in the presence of massive fermions, which implies that the continuum (a -> 0) limit must be taken keeping theta fixe

Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Targeted disruption of murine Cdk2ap1, an inhibitor of CDK2 function and hence G1/S transition, results in the embryonic lethality with a high penetration rate. Detailed timed pregnancy analysis of embryos showed that the lethality occurred between embryonic day 3.5 pc and 5.5 pc, a period of implantation and early development of implanted embryos. Two homozygous knockout mice that survived to term showed identical craniofacial defect, including a short snout and a round forehead. Examination of craniofacial morphology by measuring Snout Length (SL) vs. Face Width (FW) showed that the Cdk2ap1+/− mice were born with a reduced SL/FW ratio compared to the Cdk2ap1+/+ and the reduction was more pronounced in Cdk2ap1−/− mice. A transgenic rescue of the lethality was attempted by crossing Cdk2ap1+/− animals with K14-Cdk2ap1 transgenic mice. Resulting Cdk2ap1+/−:K14-Cdk2ap1 transgenic mice showed an improved incidence of full term animals (16.7% from 0.5%) on a Cdk2ap1−/− background. Transgenic expression of Cdk2ap1 in Cdk2ap1−/−:K14-Cdk2ap1 animals restored SL/FW ratio to the level of Cdk2ap1+/−:K14-Cdk2ap1 mice, but not to that of the Cdk2ap1+/+:K14-Cdk2ap1 mice. Teratoma formation analysis using mESCs showed an abrogated in vivo pluripotency of Cdk2ap1−/− mESCs towards a restricted mesoderm lineage specification. This study demonstrates that Cdk2ap1 plays an essential role in the early stage of embryogenesis and has a potential role during craniofacial morphogenesis

Flow-based pipeline for systematic modulation and analysis of 3D tumor microenvironments

The cancer microenvironment, which incorporates interactions with stromal cells, extracellular matrix (ECM), and other tumor cells in a 3-dimensional (3D) context, has been implicated in every stage of cancer development, including growth of the primary tumor, metastatic spread, and response to treatment. Our understanding of the tumor microenvironment and our ability to develop new therapies would greatly benefit from tools that allow us to systematically probe microenvironmental cues within a 3D context. Here, we leveraged recent advances in microfluidic technology to develop a platform for high-throughput fabrication of tunable cellular microniches (“microtissues”) that allow us to probe tumor cell response to a range of microenvironmental cues, including ECM, soluble factors, and stromal cells, all in 3D. We further combine this tunable microniche platform with rapid, flow-based population level analysis (n > 500), which permits analysis and sorting of microtissue populations both pre- and post-culture by a range of parameters, including proliferation and homotypic or heterotypic cell density. We used this platform to demonstrate differential responses of lung adenocarcinoma cells to a selection of ECM molecules and soluble factors. The cells exhibited enhanced or reduced proliferation when encapsulated in fibronectin- or collagen-1-containing microtissues, respectively, and they showed reduced proliferation in the presence of TGF-β, an effect that we did not observe in monolayer culture. We also measured tumor cell response to a panel of drug targets and found, in contrast to monolayer culture, specific sensitivity of tumor cells to TGFβR2 inhibitors, implying that TGF-β has an anti-proliferative affect that is unique to the 3D context and that this effect is mediated by TGFβR2. These findings highlight the importance of the microenvironmental context in therapeutic development and that the platform we present here allows the high-throughput study of tumor response to drugs as well as basic tumor biology in well-defined microenvironmental niches.American Association for Cancer Research (Stand Up to Cancer Charitable Initiative)National Institute for Biomedical Imaging and Bioengineering (U.S.) (National Research Service Award Fellowship)National Science Foundation (U.S.) (Graduate Research Fellowship Program Grant 1122374)Howard Hughes Medical Institut

The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma

BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity