Supersymmetry of Noncompact MQCD-like Membrane Instantons and Heat Kernel Asymptotics

We perform a heat kernel asymptotics analysis of the nonperturbative superpotential obtained from wrapping of an M2-brane around a supersymmetric noncompact three-fold embedded in a (noncompact) G_2-manifold as obtained in [1], the three-fold being the one relevant to domain walls in Witten's MQCD [2], in the limit of small "zeta", a complex constant that appears in the Riemann surfaces relevant to defining the boundary conditions for the domain wall in MQCD. The MQCD-like configuration is interpretable, for small but non-zero zeta as a noncompact/"large" open membrane instanton, and for vanishing zeta, as the type IIA D0-brane (for vanishing M-theory cicle radius). We find that the eta-function Seeley de-Witt coefficients vanish, and we get a perfect match between the zeta-function Seeley de-Witt coefficients (up to terms quadratic in zeta) between the Dirac-type operator and one of the two Laplace-type operators figuring in the superpotential. This is an extremely strong signature of residual supersymmetry for the nonperturbative configurations in M-theory considered in this work.Comment: 21 pages, LaTeX; v3: several clarifying remarks added, to appear in JHE

A Note on Fluxes and Superpotentials in M-theory Compactifications on Manifolds of G_2 Holonomy

We consider the breaking of N=1 supersymmetry by non-zero G-flux when M-theory is compactified on a smooth manifold X of G_2 holonomy. Gukov has proposed a superpotential W to describe this breaking in the low-energy effective theory. We check this proposal by comparing the bosonic potential implied by W with the corresponding potential deduced from the eleven-dimensional supergravity action. One interesting aspect of this check is that, though W depends explicitly only on G-flux supported on X, W also describes the breaking of supersymmetry by G-flux transverse to X.Comment: 15 pages, harvmac, v2: reference adde

Iron imaging reveals tumor and metastasis macrophage hemosiderin deposits in breast cancer.

Iron-deposition is a metabolic biomarker of macrophages in both normal and pathological situations, but the presence of iron in tumor and metastasis-associated macrophages is not known. Here we mapped and quantified hemosiderin-laden macrophage (HLM) deposits in murine models of metastatic breast cancer using iron and macrophage histology, and in vivo MRI. Iron MRI detected high-iron pixel clusters in mammary tumors, lung metastasis, and brain metastasis as well as liver and spleen tissue known to contain the HLMs. Iron histology showed these regions to contain clustered macrophages identified by their common iron status and tissue-intrinsic association with other phenotypic macrophage markers. The in vivo MRI and ex vivo histological images were further processed to determine the frequencies and sizes of the iron deposits, and measure the number of HLMs in each deposit to estimate the in vivo MRI sensitivity for these cells. Hemosiderin accumulation is a macrophage biomarker and intrinsic contrast source for cellular MRI associated with the innate function of macrophages in iron metabolism systemically, and in metastatic cancer

Tumor-Associated Macrophages Suppress the Cytotoxic Activity of Antimitotic Agents.

Antimitotic agents, including Taxol, disrupt microtubule dynamics and cause a protracted mitotic arrest and subsequent cell death. Despite the broad utility of these drugs in breast cancer and other tumor types, clinical response remains variable. Tumor-associated macrophages (TAMs) suppress the duration of Taxol-induced mitotic arrest in breast cancer cells and promote earlier mitotic slippage. This correlates with a decrease in the phosphorylated form of histone H2AX (γH2AX), decreased p53 activation, and reduced cancer cell death in interphase. TAMs promote cancer cell viability following mitotic slippage in a manner sensitive to MAPK/ERK kinase (MEK) inhibition. Acute depletion of major histocompatibility complex class II low (MHCIIlo) TAMs increased Taxol-induced DNA damage and apoptosis in cancer cells, leading to greater efficacy in intervention trials. MEK inhibition blocked the protective capacity of TAMs and phenocopied the effects of TAM depletion on Taxol treatment. TAMs suppress the cytotoxic effects of Taxol, in part through cell non-autonomous modulation of mitotic arrest in cancer cells, and targeting TAM-cancer cell interactions potentiates Taxol efficacy

Imaging endogenous macrophage iron deposits reveals a metabolic biomarker of polarized tumor macrophage infiltration and response to CSF1R breast cancer immunotherapy.

Iron deposits are a phenotypic trait of tumor-associated macrophages (TAMs). Histological iron imaging and contrast-agent free magnetic resonance imaging (MRI) can detect these deposits, but their presence  in human cancer, and correlation with immunotherapeutic response is largely untested. Here, primarily using these iron imaging approaches, we evaluated the spatial distribution of polarized macrophage populations containing high endogenous levels of iron in preclinical murine models and human breast cancer, and used them as metabolic biomarkers to correlate TAM infiltration with response to immunotherapy in preclinical trials. Macrophage-targeted inhibition of the colony stimulating factor 1 receptor (CSF1R) by immunotherapy was confirmed to inhibit macrophage accumulation and slow mammary tumor growth in mouse models while also reducing hemosiderin iron-laden TAM accumulation as measured by both iron histology and in vivo iron MRI (FeMRI). Spatial profiling of TAM iron deposit infiltration defined regions of maximal accumulation and response to the CSF1R inhibitor, and revealed differences between microenvironments of human cancer according to levels of polarized macrophage iron accumulation in stromal margins. We therefore demonstrate that iron deposition serves as an endogenous metabolic imaging biomarker of TAM infiltration in breast cancer that has high translational potential for evaluation of immunotherapeutic response

Metabolic origins of spatial organization in the tumor microenvironment.

The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity

Re-education of macrophages as a therapeutic strategy in cancer.

Tumor-associated macrophages (TAMs) can be educated within the tumor microenvironment to promote cancer development and progression. While TAM-targeted agents have largely focused on macrophage depletion as an anticancer strategy, it is becoming increasingly evident that TAM re-education may represent a more effective approach. In this perspective, we discuss different means to achieve TAM re-education, and review the beneficial effects of these strategies, particularly when combined with immune checkpoint inhibitors

Transient domain walls and lepton asymmetry in the Left-Right symmetric model

It is shown that the dynamics of domain walls in Left-Right symmetric models, separating respective regions of unbroken SU(2)_L and SU(2)_R in the early universe, can give rise to baryogenesis via leptogenesis. Neutrinos have a spatially varying complex mass matrix due to CP-violating scalar condensates in the domain wall. The motion of the wall through the plasma generates a flux of lepton number across the wall which is converted to a lepton asymmetry by helicity-flipping scatterings. Subsequent processing of the lepton excess by sphalerons results in the observed baryon asymmetry, for a range of parameters in Left-Right symmetric models.Comment: v2 version accepted for publication in Phys. Rev. D. Discussion in Introduction and Conclusion sharpened. Equation (12) corrected. 16 pages, 3 figure files, RevTeX4 styl