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Mouse CT26 colorectal tumors are heavily infiltrated by tumor-specific CD8 T cells, but nevertheless grow rapidly in Balb/c mice. These tumors are partially responsive to anti-PD-1 (α-PD-1) monoclonal antibody therapy, which suggests that an active suppression of the tumor-specific cytotoxic T cells exists in the untreated tumor. As chemokine receptor 2 (CCR2) is expressed by a potentially suppressive leukocyte subset within these tumors (monocytic myeloid derived suppressor cells aka M-MDSCs), we aimed to test whether CCR2 blockade could enhance the anti-tumor effects of α-PD-1. We have found that the therapeutic effects of α-PD-1 therapy are appreciably enhanced by specific blockade of CCR2 via a small molecule antagonist. This combined α-PD-1/CCR2i approach significantly decreases overall tumor size and increases the proportion of long-term survivors, with more than 50% of the mice (up to 73%) showing complete regression of a previously established tumor. The effects of this combined therapy are dependent on the presence of CD8+ T cells, as tumors do not respond to the therapy in CD8-depleted mice. The anti-CT26 tumor response is specific: long term survivors are resistant to re-inoculation with the CT26 tumor (even without further dosing of either drug) but are not resistant to the 4T1 breast tumor. CCR2 antagonism alters the tumor microenvironment by reducing the number of M-MDSC per gram of tumor (a CCR2hi population phenotypically defined as CD11b+/Ly6G-/Ly6Chi). Reduction in tumor size is inversely proportional to the ratio of CD8 T cells to M-MDSC. These data are consistent with a hypothesis that CCR2 antagonism enhances α-PD-1 therapy by preventing M-MDSC from accumulating within the tumor, thus reducing their suppressive effects on cytotoxic T cells. Citation Format: James J. Campbell, Christine Janson, Linda Ertl, Chris Li, Zhenhua Miao, Antoni Krasinski, Rebecca Lui, Venkat Mali, Jeffrey McMahon, Yibin Zheng, Yu Wang, Xiaoping Zang, Vicky Chhina, Marta Vilalta, Alice Kumamoto, Ton Dang, Shirley Liu, Simon Yao, Penglie Zhang, Thomas J. Schall, Rajinder Singh. Inhibition of chemokine receptor 2 (CCR2) with a small molecule antagonist enhances the effectiveness of checkpoint inhibition by altering the tumor microenvironment in mouse colorectal tumors: Reducing tumor size and increasing long term survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1745.

Pancreatic cancer is an aggressive malignancy with a 5 year survival rate of less than five percent. The predominant immune cells infiltrating the tumor microenvironment are monocytes/macrophages, which are reported to support tumor growth by suppressing host immune responses to the tumor. Recruitment of monocytes to various tissues, including tumors, is dependent upon activation of the chemokine receptor CCR2 by one or more of the chemokines CCL2, CCL8 and CCL13. In preclinical and clinical studies, inhibition of CCR2 in pancreatic cancer has shown to decrease tumor progression by blocking recruitment and accumulation of monocytes/macrophages in the tumor microenvironment. Analysis of human pancreatic tumors revealed elevation of both CCL2 and CSF1, which recruit monocytes, as well as the monocyte marker CD14, in advanced pancreatic cancers. Current immunotherapy using checkpoint inhibitors are effective in some tumors, but lack efficacy in immune insensitive cancers, including pancreatic cancer. Here, we report that the inhibition of CCR2 using a small molecule antagonist potentiates anti-PD-1 immunotherapy in a syngeneic, orthotropic mouse model of pancreatic cancer. Our data reveal that blocking CCR2 decreases tumor burden by blocking monocyte infiltration and creating a microenvironment more favorable for CD8 T cells activity, and provide a mechanistic rationale for investigating the combination of a CCR2 antagonist and an immune checkpoint inhibitor in pancreatic cancer. Citation Format: Christine Janson, Heiyoun Jung, Linda Ertl, Shirley Liu, Ton Dang, Yibin Zeng, Antoni Krasinski, Jeff McMahon, Penglie Zhang, Israel Charo, Rajinder Singh, Thomas J. Schall. Inhibition of CCR2 potentiates checkpoint inhibitor immunotherapy in murine model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5655. doi:10.1158/1538-7445.AM2017-5655

We show how a complex Snell's law can be used to describe the refraction of surface plasmon polaritons (SPPs) at an interface between two metals, validating its predictions with 3-D electrodynamics simulations. Refraction gives rise to peculiar SPP features including inhomogeneities in the waveform and dispersion relations that depend on the incident wave and associated material. These features make it possible to generate SPPs propagating away from the interface with significant confinement normal to the propagation direction. We also show that it is possible to encode optical properties of the incident material into the refracted SPP. These consequences of metal-metal SPP refraction provide new avenues for the design of plasmonics-based devices., 13 pages, 3 figures

Type 1 diabetes (T1D) is mediated by destruction of pancreatic β-cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B(9-23) or Ins B(15-23), but not GAD65(509-528), GAD65(524-543) or IGRP(206-214), protected 4-6 week old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19-21 week old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B(9-23) is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B(9-23) emerge during disease progression.

\textit{Ab initio} random structure searching based on density functional theory is used to determine the ground-state structures of ice at high pressures. Including estimates of lattice zero-point energies, ice is found to adopt three novel crystal phases. The underlying sub-lattice of O atoms remains similar among them, and the transitions can be characterized by reorganizations of the hydrogen bonds. The symmetric hydrogen bonds of ice X and $Pbcm$ are initially lost as ice transforms to structures with symmetries $Pmc2_1$ (800 - 950 GPa) and $P2_1$ (1.17 TPa), but they are eventually regained at 5.62 TPa in a layered structure $C2/m$. The $P2_1 \rightarrow C2/m$ transformation also marks the insulator-to-metal transition in ice, which occurs at a significantly higher pressure than recently predicted., 10 pages; 5 figures

Ab initio random structure searching with density functional theory was used to determine the zero-temperature structures of atomic metallic hydrogen from 500 GPa to 5 TPa. Including zero point motion in the harmonic approximation, we estimate that molecular hydrogen dissociates into a monatomic body-centered tetragonal structure near 500 GPa (r_s = 1.225), which then remains stable to 2.5 TPa (r_s = 0.969). At higher pressures, hydrogen stabilizes in an ...ABCABC... planar structure that is remarkably similar to the ground state of lithium, which compresses to the face-centered cubic lattice beyond 5 TPa (r_s < 0.86). At this level of theory, our results provide a complete ab initio description of the atomic metallic structures of hydrogen, resolving one of the most fundamental and long outstanding issues concerning the structures of the elements., 9 pages; 4 figures

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Shades of New York in Algren’s Chicago. Many critics and readers regard Nelson Algren’s Chicago: City on the Make as “the best book about Chicago.” Fifty years after its initial publication, the essay continues to win praise for capturing the essence of the city. This thesis examines the symbolic and structural elements within the text that have produced those impressions in readers. It refutes the usual explanations—that Algren captures an essential Chicago that exists outside of time, or that Algren captures a real Chicago that existed in history—as mystical or impossible, and shows instead how Algren builds a convincing textual city through complex systems of reference to prior literary depictions. Chief among Algren’s source texts is Carl Sandburg’s poem “Chicago,” a textual portrait that has defined the city since 1914. In this poem, Sandburg personifies Chicago as a series of character types: a worker with big shoulders, a laughing fighter, a tall, bold slugger. Algren fleshes out these characters, filling his essay with big shoulders, laughing fighters, and bold sluggers. Because they connect to Sandburg’s personifications of Chicago, Algren’s characters stand in for the city as a whole; their actions reveal not only their individual character but the urban character of the city. But Algren’s Chicago also depends on unexpected literary sources, and this thesis presents original research showing that Algren draws upon poetry of New York to paint his picture of Chicago. Algren alters Sandburg’s Chicago through an elaborate system of reference to Ben Maddow’s 1940 poem of New York, “The City,” and Algren’s controlling metaphor follows the literary ethic of another New York poet: Walt Whitman.

Background Non-alcoholic fatty liver disease (NAFLD) is a common condition, in which hepatic steatosis is present in up to a third of individuals, whereas the more severe non-alcoholic steatohepatitis (NASH) is seen in about 10%. NAFLD is closely associated with the metabolic syndrome: up to 75% of people with diabetes mellitus, and almost all morbidly obese individuals, have NALFD. Obesity-associated macrophage infiltration of adipose and hepatic tissue is mediated by C-C chemokine receptor type 2 (CCR2), where CCR2+ CD11b+ F4/80+ macrophages contribute to chronic inflammation and insulin resistance. We investigated the efficacy of a small molecule inhibitor of CCR2, CCX872, which is in phase 1 clinical development, for treatment of obesity-associated hepatic steatohepatitis in mice. Methods C57BL/6 mice aged 6 weeks were fed a high-fat diet for 16 weeks. After 8 weeks on this diet, mice were treated with CCX872 (ChemoCentryx, Mountain View, CA, USA) 30 mg/kg once daily or vehicle, both administered subcutaneously. Liver injury was assessed with serum alanine aminotransferase concentration, liver triglyceride content, and flow cytometry of infiltrating cells. Adipose tissue macrophage infiltration was assessed with flow cytometry. Insulin sensitivity was measured by glucose and insulin challenges. Groups were compared with two-tailed Student's t tests. Findings Mice treated with CCX872 had better insulin sensitivity (p vs 532·8 [353·6], p=0·028). Hepatic triglyceride accumulation was significantly lower in CCX872-treated mice (mean 159·9 mg/g [SD 2·6] vs 296·6 [98·5], p vs 16·0 [1·9], p=0·03; mean fluorescence intensity [MFI] 6919 [SD 107·7] vs 7365 [162·9], p=0·04) and in omental adipose tissue (9·2% of CD45+ cells [1·9] vs 21·8 [3·7], p=0·02; MFI 6212 [469·2] vs 7952 [379·5], p=0·02). Interpretation Treatment with a clinical-stage small molecule inhibitor of CCR2 improved steatohepatitis and insulin sensitivity in mice kept on a high-fat diet. Funding UK Medical Research Council.