Summary The haemophagocytic syndrome (HPS) is a rare but frequently fatal disorder of immune regulation caused by hypercytokinemia. Using cytometric bead array technique, the serum T‐helper cell type 1 (Th1) and 2 (Th2) cytokines including interferon‐γ (IFN‐γ), tumour necrosis factor (TNF), interleukin (IL)‐10, IL‐6, IL‐4 and IL‐2 were determined in 24 children with de novo HPS and 87 children as control. The median levels of serum IFN‐γ, IL‐10 and IL‐6 in the acute phase of HPS were 901·7, 879·0 and 63·8 pg/ml, respectively, significantly higher than those after remission, and in the healthy volunteers and patients with viral infection. IL‐4 was slightly elevated while IL‐2 and TNF were within normal range in acute phase. Patients with bacterial sepsis showed an extremely high level of IL‐6 and moderate level of IL‐10, whereas IFN‐γ was only slightly elevated. Five patients were diagnosed with HPS according to the Th1/Th2 cytokine pattern 3–13 d earlier than they fulfilled the relevant diagnostic criteria. IL‐10 level >2000 pg/ml was an unfavorable prognostic factor for HPS treatment response (P = 0·033) and outcome (P = 0·009). We conclude that the significant increase of IFN‐γ and IL‐10 and a slightly increased level of IL‐6 is an early, specific and prognostic cytokine pattern for childhood HPS.

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Metal-containing aromatic systems (metalla-aromatics) are unique and important both experimentally and theoretically. Among metalla-aromatics, six-membered metallabenzenes and metallabenzynes have attracted much attention in recent years. However, reports on their superior homologues are rare. In this work, the first series of aromatic dicupra[10]annulenes were isolated from the reaction of dilithio reagents and copper salts. Single-crystal X-ray structural analysis revealed dicupra[10]annulenes with averaged bond lengths. (7)Li NMR spectra and theoretical calculations revealed considerable aromatic character. XPS data suggested that the oxidation state of Cu atom in dicupra[10]annulenes was more likely to be Cu(I), indicating that the dilithio moieties in dicupra[10]annulenes participated as noninnocent ligands. This work demonstrates a novel approach to construct macrocyclic metalla-aromatics.

High sensitivity imaging tools could provide a more holistic view of target antigen expression to improve the identification of patients who might benefit from cancer immunotherapy. We developed for immunoPET a novel recombinant human IgG1 (termed C4) that potently binds an extracellular epitope on human and mouse PD-L1 and radiolabeled the antibody with zirconium-89. Small animal PET/CT studies showed that 89Zr-C4 detected antigen levels on a patient derived xenograft (PDX) established from a non-small-cell lung cancer (NSCLC) patient before an 8-month response to anti-PD-1 and anti-CTLA4 therapy. Importantly, the concentration of antigen is beneath the detection limit of previously developed anti-PD-L1 radiotracers, including radiolabeled atezolizumab. We also show that 89Zr-C4 can specifically detect antigen in human NSCLC and prostate cancer models endogenously expressing a broad range of PD-L1. 89Zr-C4 detects mouse PD-L1 expression changes in immunocompetent mice, suggesting that endogenous PD-1/2 will not confound human imaging. Lastly, we found that 89Zr-C4 could detect acute changes in tumor expression of PD-L1 due to standard of care chemotherapies. In summary, we present evidence that low levels of PD-L1 in clinically relevant cancer models can be imaged with immunoPET using a novel recombinant human antibody.

This perspective includes the synthesis and future challenges of aromatic dianion metalloles and their analogues.

CONSPECTUS: Switchable catalysts incorporate stimuli-responsive features and allow synthetic tasks that are difficult or impossible to accomplish in other ways. They mimic biological processes in that they can provide both spatial and temporal control, unlike most reactions promoted by human-made catalysts that usually occur according to carefully optimized conditions. In the area of switchable catalysis, redox-switchable ring-opening polymerization (ROP) has attracted much attention, emerging as a powerful strategy for the development of environmentally friendly biodegradable copolymers, especially those containing blocks with complementary properties. Controlling the sequence and regularity of each copolymeric building block can affect the material properties significantly since they are directly related to the respective microstructures. Such control can be exerted with a well-designed redox-switchable catalyst by timing the oxidation and reduction events. In highly selective systems, one form of the catalyst reacts with a monomer until the redox state of the catalyst is altered, at which point the altered state of the catalyst reacts with another monomer. The reaction time may be varied from one cycle to another to generate various designer multiblock copolymers. The first instance of redox-mediated ROP was described by N. Long and co-workers in 2006. This example, as well as many early reported redox-switchable catalysts, could only achieve an on/off switch of activity toward a single monomer or substrate. However, our efforts brought on a general strategy for designing redox-switchable metal complexes that can catalyze different reactions in two oxidation states. In recent years, our contributions to this research field led to the synthesis of several multiblock copolymers prepared from biorenewable resources. This Account provides an overview of reported redox-switchable polymerization catalysts that allow for complementary reactivity in different oxidation states and highlights the potential of this strategy in preparing biodegradable materials. First, we define the field of redox-switchable catalysis and illustrate the design and significance of our ferrocene-chelating ligands, in which the oxidation state of iron in ferrocene can control the reactivity of the resulting metal complexes remotely. Next, we illustrate recent advances in the synthesis of new biodegradable copolymers including (1) how to tune the activity of the ROP catalysts by exploring various metal centers and ferrocene-based ligand combinations; (2) how to synthesize new multiblock copolymers of cyclic esters, epoxides, and carbonates by redox-switchable ROP; and (3) how to understand the mechanism of these reactions by discussing both experimental and theoretical investigations. By the application and development of redoxswitchable strategies, various novel materials and reactions can be expected in the future.

Since the concept of aromaticity represents one of the most fundamental principles in chemistry, the search for unprecedented and exciting aromatic systems, therefore, continues to drive research in this area. Herein we report the synthesis and characterization of spiro metalla-aromatics, in which the transition metal (Pd, Pt, or Rh) is the spiro atom, that cross-conjugates two aromatic five-membered metallacycles. These spiro metalla-aromatics tend to take square planar geometries, with the dihedral angle being influenced by the steric repulsion between the α-positioned substituents. Rationalized and classified via both experimental measurements (X-ray structural analysis, NMR spectroscopy, XPS, etc.) and theoretical analysis (DFT calculation, ISE, AICD, NICS, and CMOs), all these fundamental observations extend the concept of aromaticity and organometallic chemistry.

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