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Aggregation-induced emission (AIE)-active luminogens (AIEgens) have demonstrated exciting potential for the application in cancer phototheranostics. However, simultaneously achieving tumor-activated bright emission, enhanced reactive oxygen species (ROS) generation, high tumor accumulation, and minimized ROS depletion remains challenging. Here, a metal-organic framework (MOF) hybrid AIEgen theranostic platform is designed, termed A-NUiO@DCDA@ZIF-Cu, composed of an AIEgen-loaded hydrophobic UiO-66 (A-NUiO@DCDA) core and a Cu-doped hydrophilic ZIF-8 (ZIF-Cu) shell. The fluorescence emission and therapeutic ROS activity of AIEgens are restrained during delivery. After uptake by tumor tissues, ZIF-Cu decomposition occurs in response to an acidic tumor microenvironment (TME), and the hydrophobic A-NUiO@DCDA cores self-assemble into large particles, extremely increasing the tumor accumulation of AIEgens. This results in enhanced fluorescence imaging (FLI) and highly improved

Supplementary Figure 4 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 3 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 6 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 1 A-C from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Tables 1-3 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 1 D-H from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 5 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Figure 2 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

Supplementary Materials, Figure Legends 1-6 from R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer

CNTs that consist of Co nanoparticles and atomically-dispersed Co atoms efficiently generate hydrogen from AB at a rate of 7833 mLH2 gCo−1 min−1.

High-capacity Ni-rich layered metal oxide cathodes are highly desirable to increase the energy density of lithium-ion batteries. However, these materials suffer from poor cycling performance, which is exacerbated by increased cell voltage. We demonstrate here the detrimental effect of ethylene carbonate (EC), a core component in conventional electrolytes, when NMC811 (LiNi0.8Mn0.1Co0.1O2) is charged above 4.4 V vs. Li/Li+ – the onset potential for lattice oxygen release. Oxygen loss is enhanced by EC-containing electrolytes – compared to EC-free – and correlates with more electrolyte oxidation/breakdown and cathode surface degradation, which increase concurrently above 4.4 V. In contrast, NMC111 (LiNi0.33Mn0.33Co0.33O2), which does not release oxygen up to 4.6 V, shows similar extents of degradation irrespective of the electrolyte. This work highlights the incompatibility between conventional EC-based electrolytes and Ni-rich cathodes (more generally, cathodes that release lattice oxygen such as Li-/Mn-rich and disordered rocksalt cathodes), and motivates further work on wider classes of electrolytes and additives., The present research has been supported by the Faraday Institution degradation project (FIRG001) and EPSRC (EP/S003053/1). W. M. D., M. F. L. D., and C. P. G. acknowledge funding from Cambridge Royce facilities grant EP/P024947/1 and Sir Henry Royce Institute grant EP/R00661X/1. The authors are grateful to A. Jansen, S.E. Trask, B.J. Polzin, and A.R. Dunlop at the U.S. Department of Energy’s CAMP (Cell Analysis, Modeling, and Prototyping) Facility, Argonne National Laboratory, for producing and supplying the electrodes in this work. We thank Nigel Howard for assistance with the ICP-OES measurements, and Bernardine Rinkel and Jennifer Allen for useful discussions.

Menin is a scaffold protein that has been recognized for its role in T2DM as a key regulator of β-cell proliferation. Menin inhibition has previously been shown to improve glycemic control in diabetic mice. Herein, we report the first evidence that BMF-219, an orally bioavailable, selective, irreversible menin inhibitor, restores glycemic control in Zucker Diabetic Fatty (ZDF) Rat and Streptozotocin-induced Rat (STZ) models of T2DM. Rats were treated daily with BMF-219, vehicle, or pioglitazone for 16 days. BMF-2was well tolerated throughout the conduct of the study. BMF-2treatment resulted in a significant 50% reduction in fasting and non-fasting blood glucose levels, reduced serum insulin and c-peptide levels (p Disclosure T. Butler: Employee; Biomea Fusion Inc. W. Li: None. B. Law: Stock/Shareholder; Biomea Fusion Inc., Mirum Pharmaceuticals. T. Archer: Employee; Biomea Fusion. T. Kinoshita: None. P. Somanath: Employee; Biomea Fusion, Inc. Stock/Shareholder; Biomea Fusion, Inc.

Menin is an epigenetic regulatory protein that plays a key role in beta-cell proliferation and function, as previously demonstrated though increased beta-cell mass generation in Men1 knockout mice (Ja et al., 2021;13 (5) :e13524) . Here, we demonstrate the marked potential of an oral menin inhibitor, BMF-219, in durable glycemic control following a short course treatment in a Type 2 Diabetes Mellitus (T2DM) Zucker Diabetic Fatty Rat model. Rats were treated daily with BMF-219, liraglutide or vehicle for 28 days and monitored for an additional 28 days post-treatment. All animals tolerated BMF-219 well throughout the study. Notably, BMF-219 treatment resulted in a significant reduction in HbA1C at Day 21, which reached 3.5% absolute reduction in HbA1C versus vehicle, compared to liraglutide (1.7% reduction) at Day 29 and remained reduced throughout the entire study, including post-treatment. The high-dose arm of BMF-219 showed a strong reduction in 4-hour fasting blood glucose during the treatment up to Day 29. Both BMF-219 dose groups showed improved glycemic control by oral glucose tolerance test (OGTT) on day 25, in contrast to vehicle and liraglutide-treated animals. Additionally, insulin levels, HOMA-IR, HOMA-B, OGTT, HbA1C, and C-peptide levels measured at Day 57 across all groups will be reported. Collectively, these data demonstrate the novel long-acting potential of BMF-219 as an oral treatment for T2DM, in maintaining glycemic control after short-term dosing. Disclosure P. Somanath: Employee; Biomea Fusion, Inc., Stock/Shareholder; Biomea Fusion, Inc. M. Balakrishnan: Employee; Biomea Fusion, Inc., Other Relationship; Gilead Sciences, Inc., Stock/Shareholder; Biomea Fusion, Inc., Gilead Sciences, Inc. T. Butler: Employee; Biomea Fusion Inc. S. Mourya: Employee; Biomea Fusion, Stock/Shareholder; Ascendis Pharma A/S. W. Li: None. T. C. Archer: Employee; Biomea Fusion. B. Law: Stock/Shareholder; Biomea Fusion Inc., Mirum Pharmaceuticals. D. Lu: Employee; Biomea Fusion Inc., Stock/Shareholder; AbbVie Inc. T. Rughwani: None. L. Kumar: None. T. Kinoshita: None.

Cycling performance is very important to device application. Herein, a facile and controllable approach is proposed to synthesize high stability CuCo2O4 nanoneedle array on a conductive substrate. The electrode presents excellent performances in a large specific capacitance up to 2.62 F cm−2 (1747 F g−1) at 1 mV s−1 and remarkable electrochemical stability, retaining 164% even over 70 000 cycles. In addition, the asymmetric supercapacitor assembled with the optimized CuCo2O4 nanoneedle array (cathode) and active carbon (anode), which exhibits superior specific capacity (146 F g−1), energy density (57 W h kg−1), and cycling stability (retention of 83.9% after 10 000 cycles). These outstanding performances are mainly ascribed to the ordered binder-free nanoneedle array architecture and holds great potential for the new-generation energy storage devices.

The chemical and electrochemical reactions at the positive electrode–electrolyte interface in Li-ion batteries are hugely influential on cycle life and safety. Ni-rich layered transition metal oxides exhibit higher interfacial reactivity than their lower Ni-content analogues, reacting via mechanisms that are poorly understood. Here, we study the pivotal role of the electrolyte solvent, specifically cyclic ethylene carbonate (EC) and linear ethyl methyl carbonate (EMC), in determining the interfacial reactivity at charged LiNi0.33Mn0.33Co0.33O2(NMC111) and LiNi0.8Mn0.1Co0.1O2(NMC811) cathodes by using both single-solvent model electrolytes and the mixed solvents used in commercial cells. While NMC111 exhibits similar parasitic currents with EC-containing and EC-free electrolytes during high voltage holds in NMC/Li4Ti5O12(LTO) cells, this is not the case for NMC811. Online gas analysis reveals that the solvent-dependent reactivity for Ni-rich cathodes is related to the extent of lattice oxygen release and accompanying electrolyte decomposition, which is higher for EC-containing than EC-free electrolytes. Combined findings from electrochemical impedance spectroscopy (EIS), TEM, solution NMR, ICP, and XPS reveal that the electrolyte solvent has a profound impact on the degradation of the Ni-rich cathode and the electrolyte. Higher lattice oxygen release with EC-containing electrolytes is coupled with higher cathode interfacial impedance, a thicker oxygen-deficient rock-salt surface reconstruction layer, more electrolyte solvent and salt breakdown, and higher amounts of transition metal dissolution. These processes are suppressed in the EC-free electrolyte, highlighting the incompatibility between Ni-rich cathodes and conventional electrolyte solvents. Finally, new mechanistic insights into the chemical oxidation pathways of electrolyte solvents and, critically, the knock-on chemical and electrochemical reactions that further degrade the electrolyte and electrodes curtailing battery lifetime are provided.

The Herenping gold deposit is a typical gold deposit in the Xuefengshan arcuate tectonic zone in the southern margin of the Yangtze Craton, and the major feature of the gold mineralisation in the zone is the varying degrees of tungsten and antimony mineralisation in the ore deposits. The Herenping gold deposit occurs in the reddish-purple sandy slate in the middle section of the Madiyi Formation of the Neoproterozic Banxi Group and is controlled by the fault-fold zone associated with the Liulincha anticlinorium and F8 fault zone. However, its sources of mineralisation and relationships between hydrothermal fluids and magmatic rocks are unclear, which similar to those of many gold deposits in metasedimentary terranes in the worldwide. The mineralisation can be divided into four stages: an albite-quartz stage (I), an albite-quartz-pyrite-gold stage (II), a quartz-gold-polymetallic sulphide stage (III), and a quartz-carbonate stage (IV). The gold mineralisation occurred in albite-quartz veins in stage II and in sulphide-rich quartz veins in stage III in the deposit. A study of the fluid inclusions reveals that the homogenisation temperature and salinity were slightly higher in stage II (Th., 186–348 °C; W., 5.2–17.43 wt% NaCl equiv.) than in stage III (Th., 145–249 °C; W., 2.9–15.57 wt% NaCl equiv.), indicating that the temperature and salinity of the ore-forming fluid are gradually decreasing. The H-O (δD = −62.3 to −53.0‰; δ18O = 4.2–11.8‰) isotope characteristics reveals that the ore-forming fluid is a magmatic hydrothermal source. The sulphur (δ34S, −4.8–2.0‰) isotope characteristics and the alteration mineral assemblage (sericite-chlorite-pyrite) indicates that the ore-forming fluids was reduced. The lead (206Pb/204Pb = 17.419–17.436, 207Pb/204Pb = 15.519–15.535, and 208Pb/204Pb = 37.86–37.90) isotope characteristics reflect the ore-forming materials were likely derived from a deep magmatic source. In addition, the geochemical characteristics of albitite veins show that they are silicon rich (64.02–66.26 wt%) and significantly reduced. Notably, the Herenping gold deposit is located in the western portion of the tungsten/tin metallogenic provinces in South China, is host in epimetamorphic detrital rocks and was formed at least two stages of mineralisation; typical gold-bearing albite-quartz veins developed during the primary stage. These characteristics are consistent with those of reduced intrusion-related deposits such as the Muruntau, Kumtor and Telfer deposits. Thus, the Herenping gold deposit may be a sediment-hosted intrusion-related gold deposit. Based on the phase transition pattern from sulphide-rich quartz veins to albite-quartz veins to albitite veins with increasing depth in the deposit, we propose that reduced intrusions deep in the Herenping gold deposit could be discovered in the future, which implies the possible existence of a reduced intrusion-related gold system in the Xuefengshan arcuate tectonic zone.

In recent years, extensive research has been performed on high energy cathode materials for lithium ion batteries being used in electric vehicles to reduce carbon emissions. Compared to the commercial layered cathode materials, the absence of cobalt in the spinel LiMn1.5Ni0.5O4 (LMNO) makes this material more environmentally friendly and cheaper.1 Spinel LMNO cathodes also reveal attractive gravimetric and volumetric energy densities of 635Whkg−1 and 2820WhL−1, respectively.2 According to the distribution of transition metals (TM) within the cubic crystal structure, spinel LMNO can be categorized into either ordered or disordered. Normally, disordered LMNO materials are produced at temperatures higher than the theoretical oxygen release temperature of spinel LMNO (715 °C).3 The formation of O vacancies is accompanied by some Mn4+ atoms being reduced to Mn3+ to maintain the electroneutrality of spinel LMNO. Ordered LMNO can be obtained through calcination at temperatures lower than 715 °C or post-annealing disordered LMNO materials at 700 °C.4 The reversible extraction and insertion of O atoms accompanied with different distribution of TM during spinel LMNO preparation drive up a hypothesis that the oxygen activity during cycling of spinel LMNO may be affected by the distribution of TM atoms, especially since the operating voltage of spinel LMNO (> 4.7 V) is high enough to trigger oxygen redox in other lithium transition metal oxides.5 To explore the feasibility of oxygen activity during cycling of spinel LMNO, the normal, core-shell and sandwich designed synthesis are performed using special Mn0.75Ni0.25(OH)2 precursors to arrange different distributions of TM atoms in the obtained N-, CS- and SW-LMNO. As shown in Figure 1(a) – (c), the three materials show similar XRD patterns in the pristine state, yet different reflection peaks are observed in the three materials after charging to 4.9 V. The unclear phase transition of SW-LMNO indicates it show stable structure. The three materials also show different CV curves, see Figure 1(d). This indicates the extraction and insertion of Li atoms lead to different redox reactions in the three materials. Besides, differential electrochemical mass spectrometry (DEMS), in-situ transmission electron microscope (TEM) as well as hard and soft X-ray absorption spectroscopy (XAS) measurements are utilized to further investigate the oxygen activity during cycling of spinel LMNO. Reference 1. Li, M. & Lu, J. Cobalt in lithium-ion batteries. Science 367, 979-980 (2020). 2. Hagh, N. M. & Amatucci, G. G. A new solid-state process for synthesis of LiMn1. 5Ni0. 5O4−δ spinel. Journal of Power Sources 195, 5005-5012 (2010). 3. Manthiram, A., Chemelewski, K. & Lee, E.-S. A perspective on the high-voltage LiMn1.5Ni0.5O4 spinel cathode for lithium-ion batteries. Energy & Environmental Science 7, 1339-1350 (2014). 4. Chemelewski, K. R., Shin, D. W., Li, W. & Manthiram, A. Octahedral and truncated high-voltage spinel cathodes: the role of morphology and surface planes in electrochemical properties. Journal of Materials Chemistry A 1, 3347-3354 (2013). 5. Seo, D.-H. et al. The structural and chemical origin of the oxygen redox activity in layered and cation-disordered Li-excess cathode materials. Nature chemistry 8, 692-697 (2016). Figure 1. Operando X-ray diffraction patterns of N- (a), CS- (b) and SW- (c) LiMn1.5Ni0.5O4 in the pristine states and at the charge states of 4.9 V and the corresponding cyclic voltammetry curves of the three materials (d) Figure 1

Dysregulated metabolism is a hallmark of cancer that manifests through alterations in bioenergetic and biosynthetic pathways to enable tumor cell proliferation and survival. Tumor cells exhibit high rates of glycolysis, a phenomenon known as the Warburg effect, and an increase in glutamine consumption to support the tricarboxylic acid (TCA) cycle. Renal cell carcinoma (RCC) tumors express high levels of glutaminase (GLS), the enzyme required for the first step in metabolic conversion of glutamine to glutamate and the entry of glutamine into the TCA cycle. We found that RCC cells are highly dependent on glutamine for proliferation, and this dependence strongly correlated with sensitivity to telaglenstat (CB-839), an investigational, first-in-class, selective, orally bioavailable GLS inhibitor. Metabolic profiling of RCC cell lines treated with telaglenastat revealed a decrease in glutamine consumption, which was concomitant with a decrease in the production of glutamate and other glutamine-derived metabolites, consistent with GLS inhibition. Treatment of RCC cells with signal transduction inhibitors everolimus (mTOR inhibitor) or cabozantinib (VEGFR/MET/AXL inhibitor) in combination with telaglenastat resulted in decreased consumption of both glucose and glutamine and synergistic anti-proliferative effects. Treatment of mice bearing Caki-1 RCC xenograft tumors with cabozantinib plus telaglenastat resulted in reduced tumor growth compared to either agent alone. Enhanced anti-tumor activity was also observed with the combination of everolimus plus telaglenastat. Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption.

Background Tumors evade destruction by the immune system through multiple mechanisms including altering metabolism in the tumor microenvironment. Metabolic control of immune responses occurs through depletion of essential nutrients or accumulation of toxic metabolites that impair immune cell function and promote tumor growth. The secreted enzyme interleukin 4 (IL-4)-induced gene 1 (IL4I1) is an L-phenylalanine oxidase that catabolizes phenylalanine and produces phenyl-pyruvate and hydrogen peroxide. IL4I1 regulates several aspects of adaptive immunity in mice, including inhibition of cytotoxic T cells through its production of hydrogen peroxide (reviewed in1). In human tumors, IL4I1 expression is significantly elevated relative to normal tissues and is notably high in ovarian tumors and B cell lymphomas. Motivated by the hypothesis that IL4I1 is an immuno-metabolic enzyme that suppresses anti-tumor immunity, we discovered CB-668, the first known small-molecule inhibitor of IL4I1. Methods IL4I1 enzymatic activity was measured using an HRP-coupled enzyme assay. RNA in-situ hybridization was carried out on the RNAScope platform. Syngeneic mouse tumor models were used to evaluate the anti-tumor activity of CB-668. The level of phenyl-pyruvate in tumor homogenates was measured by LC/MS. Results Our clinical candidate, CB-668 is a potent and selective non-competitive inhibitor of IL4I1 (IC50 = 15 nM). CB-668 has favorable in vitro ADME properties and showed low clearance and high oral bioavailability in rodents. Twice-daily oral administration of CB-668 was well-tolerated in mice and resulted in single-agent anti-tumor activity in the syngeneic mouse tumor models B16-F10, A20, and EG7. Oral CB-668 administration reduced the levels of phenyl-pyruvate in the tumor, consistent with inhibition of IL4I1 enzymatic activity. Anti-tumor activity of CB-668 was immune cell-mediated since efficacy was abrogated in CD8-depleted mice, and CB-668 treatment caused increased expression of pro-inflammatory immune genes in the tumor. Moreover, CB-668 had no direct anti-proliferative activity on tumor cells grown in vitro (IC50 > 50 µM). CB-668 also favorably combined with anti-PD-L1 therapy to reduce tumor growth in the B16-F10 tumor model. Conclusions These data support an immune-mediated anti-tumor effect of IL4I1 inhibition by CB-668, and suggest inhibition of IL4I1 represents a novel strategy for cancer immuno-therapy. References Molinier-Frenkel V, Prevost-Blondel A, and Castellano F. The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells 2019;8:1–9.

Cycling performance is very important to device application. Herein, a facile and controllable approach is proposed to synthesize high stability CuCo

Yolk-shell carbon-coated silicon nanoparticles (Si@void@C NPs) have been demonstrated to have a great promise in solving the problem of significant volume change of silicon-based anode materials during lithiation and delithiation cycling. However, our in situ lithiation experiments show that Si@void@C NPs may still subject to fracture upon lithiation, depending on their characteristic structural features such as the size of Si yolk, the thickness of carbon shell, and the interspace between the yolk and shell. Given the size of Si yolk, to ensure structural integrity of Si@void@C NPs during lithiation and delithiation, thicker carbon shell and larger yolk-shell interspace are preferred. On the other hand, from the perspective of attaining higher effective capacity, thinner carbon shell and smaller yolk-shell interspace are favored. To find the optimal structural design which yields the maximum capacity and meanwhile ensure the integrity of Si@void@C NPs during lithiation, mechanics-based theoretical modeling is carried out. A diagram for structural optimizations is obtained, by which the optimized Si@void@C NPs are synthesized and found to have improved capacity and capacity retention compared to the unoptimized ones. The results of this paper provide a guideline for the design of Si@void@C NPs as anode materials for high-capacity lithium ion battery.

// Yun Guan 1 , Weiqun Li 1 , Zhaohua Hou 1 , Qiuju Han 1 , Peixiang Lan 1 , Jian Zhang 1 , Zhigang Tian 2 and Cai Zhang 1 1 Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China 2 Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China Correspondence to: Cai Zhang, email: // Keywords : hepatitis B virus; MICA; hepatocarcinoma; GATA-2; GATA-3; Immunology and Microbiology Section; Immune response; Immunity Received : March 30, 2016 Accepted : August 01, 2016 Published : August 12, 2016 Abstract Decreased expression of NKG2D ligands on HBV-infected human hepatoma cells impairs NK cells lysis. However, which components of HBV exert this effect and the precise mechanisms need to be further investigated. In the present study, we observed that the HBx and HBc genes significantly down-regulated MICA expression. Through analysis with the chromatin immunoprecipitation assay, we found that HBV infection promotes the expression of transcription factors GATA-2 and GATA-3, which specifically suppressed MICA/B expression by directly binding to the promoter region of MICA/B. HBx protein, acting as a co-regulator, forms a tripolymer with GATA2 and GATA3, thus promotes the GATA-2 or GATA-3-mediated of MICA/B suppression. HBc protein inhibits MICA/B expression via directly binding to the CpG island in the MICA/B promoter. Thus, our study identified the novel role of transcription factors GATA-2 and GATA-3 in suppressing MICA/B expression and clarified the mechanisms of HBx and HBc in downregulation of MICA/B expression. These findings provide novel mechanisms for the contribution of HBV to hepatoma cells escape from NK cell surveillance.

Previous studies on silicon (Si) indicate that lithiation-induced fracture of crystalline Si nanoparticles can be greatly inhibited if their diameter is reduced to below a critical scale of around 150 nm. In this paper, in situ lithiation of individual carbon-coated Si nanoparticles (Si@C NPs) is conducted which shows that Si@C NPs will fracture during lithiation even though their diameter is much smaller than 150 nm, implying a deleterious effect of the carbon coating on the integrity of the Si@C NPs during lithiation. To shed light on this effect, finite element analysis is carried out which reveals that the carbon coating, if fractured during lithiation, will induce cracks terminating at the C/Si interface. Such cracks, upon further lithiation, can immediately propagate into the Si core due to the elevated driving force caused by material inhomogeneity between the coating and core. To prevent the fracture of the carbon coating so as to protect the Si core, a design guideline is proposed by controlling the ratio between the diameter of Si core and the thickness of carbon coating. The results in this paper should be of practical value to the design and application of Si-based core-shell structured anode materials for lithium ion batteries.

Background Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. Methods CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively. Results CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor-infiltrating CD8+ T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1+ myeloid cells. Plasma samples from cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers. Conclusions These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell-mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses.

Carbon-coated SnO2 nanowires (NWs) were fabricated and applied as electrode to study the lithiation process using in situ transmission electron microscopy. A critical coating thickness (∼9 nm) was found, above which the carbon coating is able to constrain the lithiation-induced expansion of SnO2 core without failure. Theoretical modeling and numerical simulation were performed and revealed that such thickness-dependent fracture can be attributed to the thickness-dependent maximum stress developed in the carbon coating during the lithiation of SnO2 core. Our work provides direct evidence of the mechanical robustness of thick carbon coating and offers a minimum thickness of carbon coating for constraining the deformation of anode materials with large lithiation-induced volume change.