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The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients. There is a clinical need to monitor immune-related toxicities of immune checkpoint blockade therapy. Here, the authors develop a digital SERS platform for multiplexed single cytokine counting to track immune-toxicities and demonstrate the ability to use pre-screening to identify patients at higher risk.

Sustainable investing is of tremendous interest in both academia and the investment industry. However, despite the interest and the surge in assets under management (AUM) inflow, environment, social, and governance (ESG) data currently remain a fundamental challenge because they are deficient in quantity, consistency, and quality. In light of this data challenge, many investors and academics have come to rely on commercial ESG raters to assess the ESG quality of various corporations. However, the commercial ESG ratings still suffer some notable biases. This article documents one possible bias, termed quantity bias. The authors find that the amount of ESG data available for a given company is positively correlated with the commercial ESG rating of that company and the weighted average cost of its capital. The implication for investors is that they should do their homework and examine what the ESG data actually say rather than simply check the box. For corporations, it implies that they will get favorable treatment in the capital market if they publish more ESG data. Key Findings ▪ The current state of ESG data is severely deficient. To get around ESG data challenges, people have come to rely on commercial ESG raters. However, commercial ESG ratings also exhibit various biases. The bias documented in this article is termed the quantity bias. ▪ The authors found this bias to be statistically significant; not only does it lead to higher commercial ESG ratings, but more importantly for corporations, it leads to lower cost of funding. ▪ The implication of this bias is twofold. For corporations, publishing more ESG data helps the bottom line. For investors, one must carefully examine what the ESG data say about the company’s sustainability practices, rather than performing a simple box-ticking exercise.

Purpose There is provocative, yet inconsistent, evidence that sleep deficiency may influence the development of breast cancer. The purpose of this study was to evaluate the risk of breast cancer associated with sleep deficiency among postmenopausal women in the California Teachers Study (CTS). Methods We conducted a case–control study of 2,856 invasive breast cancer cases and 38,649 cancer-free controls, nested within the CTS. Self-administered questionnaires were used to ascertain several components of sleep deficiency, including quality, latency, duration, disturbance and use of sleep medications. Additionally, a Global Sleep Index (GSI) was created by summing the individual sleep components and categorizing into quartiles. Multivariable logistic regression analyses were used to estimate odds ratios and 95% confidence intervals (OR, 95% CI). Results Increased breast cancer risks were associated with sleep deficiency. With the exception of duration, linear increases in risk were associated with all the other individual components of sleep deficiency ( p -trend ≤ 0.002). The OR for the highest GSI quartile vs. lowest was 1.24, 95% CI 1.12–1.38; p -trend < 0.001). Conclusions Sleep deficiency may be a risk factor for breast cancer. Additional prospective studies and those aimed at elucidating underlying mechanism are warranted.

A growing number of studies have shown that γδ T cells play a pivotal role in mediating the clearance of tumors and pathogen-infected cells with their potent cytotoxic, cytolytic, and unique immune-modulating functions. Unlike the more abundant αβ T cells, γδ T cells can recognize a broad range of tumors and infected cells without the requirement of antigen presentation via major histocompatibility complex (MHC) molecules. Our group has recently demonstrated parts of the mechanisms of T-cell receptor (TCR)-dependent activation of Vγ9Vδ2 + T cells by tumors following the presentation of phosphoantigens, intermediates of the mevalonate pathway. This process is mediated through the B7 immunoglobulin family-like butyrophilin 2A1 (BTN2A1) and BTN3A1 complexes. Such recognition results in activation, a robust immunosurveillance process, and elicits rapid γδ T-cell immune responses. These include targeted cell killing, and the ability to produce copious quantities of cytokines and chemokines to exert immune-modulating properties and to interact with other immune cells. This immune cell network includes αβ T cells, B cells, dendritic cells, macrophages, monocytes, natural killer cells, and neutrophils, hence heavily influencing the outcome of immune responses. This key role in orchestrating immune cells and their natural tropism for tumor microenvironment makes γδ T cells an attractive target for cancer immunotherapy. Here, we review the current understanding of these important interactions and highlight the implications of the crosstalk between γδ T cells and other immune cells in the context of anti-tumor immunity.

Real-time monitoring of cancer cells’ phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as “cell signature”), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields. Monitoring the heterogeneity of circulating tumour cells (CTCs) and their phenotypic changes during treatment is a challenge. This study describes and tests a method for detection and quantitative heterogeneity analysis of melanoma CTCs in 10 stage-IV melanoma patients.

The initial contact of pathogens with host cells is usually mediated by their adhesion to glycan structures present on the cell surface in order to enable infection. Furthermore, glycans play important roles in the modulation of the host immune responses to infection. Understanding the carbohydrate-pathogen interactions are of importance for the development of novel and efficient strategies to either prevent, or interfere with pathogenic infection. Synthetic glycopeptides and mimetics thereof are capable of imitating the multivalent display of carbohydrates at the cell surface, which have become an important objective of research over the last decade. Glycopeptide based constructs may function as vaccines or anti-adhesive agents that interfere with the ability of pathogens to adhere to the host cell glycans and thus possess the potential to improve or replace treatments that suffer from resistance. Additionally, synthetic glycopeptides are used as tools for epitope mapping of antibodies directed against structures present on various pathogens and have become important to improve serodiagnostic methods and to develop novel epitope-based vaccines. This review will provide an overview of the most recent advances in the synthesis and application of glycopeptides and glycopeptide mimetics exhibiting a peptide-like backbone in glycobiology.

ObjectivesWe assessed the efficacy of trainings with Vietnamese nail salon owners and workers on knowledge and behaviors that could reduce exposures to toxic chemicals in nail products.MethodsWe trained Vietnamese salon owners in California (n = 77) who then trained their workers (n = 200) on best practices. In a cluster randomized controlled trial, we assessed the efficacy of the training on change in knowledge and self-reported behaviors. Data were collected from 2013 to 2016 and analyzed from 2016 to 2017.ResultsCompared to the control group, the intervention group had significantly greater increases in knowledge about: safer nail polishes [odds ratio (OR) 3.7 (95% confidence interval (CI) 1.9, 7.2)]; proper ventilation methods (OR 4.2; 95% CI 2.2, 8.1); recommended glove types (OR 3.4; 95% CI 1.9, 6.3); and recommended product handling and storage (OR 4.1; 95% CI 1.7, 9.9). The intervention also increased best practices: using safer nail polishes (OR 3.6; 95% CI 1.9, 6.8); reading product labels (OR 2.6; 95% CI 1.3, 5.0); and wearing long sleeves (OR 2.4; 95% CI 1.3, 4.2).ConclusionsThe owner-to-worker intervention with culturally and linguistically appropriate training for salon owners who then trained workers was effective in promoting knowledge and self-reported behaviors that can reduce workplace chemical exposures.

A prospective study explored the heterogeneous nature of metastatic melanoma using Multiplex immunohistochemistry (IHC) and flow cytometry (FACS). Multiplex IHC data quantitated immune subset number present intra-tumoral (IT) vs the tumor stroma, plus distance of immune subsets from the tumor margin (TM). In addition, mIHC showed a close association between the presence of IT CD8 + T cells and PDL1 expression in melanoma, which was more prevalent on macrophages than on melanoma cells. In contrast, FACS provided more detailed information regarding the T cell subset differentiation, their activation status and expression of immune checkpoint molecules. Interestingly, mIHC detected significantly higher Treg numbers than FACS and showed preferential CD4 + T cell distribution in the tumor stroma. Based on the mIHC and FACS data, we provide a model which defines metastatic melanoma immune context into four categories using the presence or absence of PDL1 + melanoma cells and/or macrophages, and their location within the tumor or on the periphery, combined with the presence or absence of IT CD8 + T cells. This model interprets melanoma immune context as a spectrum of tumor escape from immune control, and provides a snapshot upon which interpretation of checkpoint blockade inhibitor (CBI) therapy responses can be built.

Multivalent interactions at biological interfaces occur frequently in nature and mediate recognition and interactions in essential physiological processes such as cell-to-cell adhesion. Multivalency is also a key principle that allows tight binding between pathogens and host cells during the initial stages of infection. One promising approach to prevent infection is the design of synthetic or semisynthetic multivalent binders that interfere with pathogen adhesion1–4. Here, we present a multivalent binder that is based on a spatially defined arrangement of ligands for the viral spike protein haemagglutinin of the influenza A virus. Complementary experimental and theoretical approaches demonstrate that bacteriophage capsids, which carry host cell haemagglutinin ligands in an arrangement matching the geometry of binding sites of the spike protein, can bind to viruses in a defined multivalent mode. These capsids cover the entire virus envelope, thus preventing its binding to the host cell as visualized by cryo-electron tomography. As a consequence, virus infection can be inhibited in vitro, ex vivo and in vivo. Such highly functionalized capsids present an alternative to strategies that target virus entry by spike-inhibiting antibodies5 and peptides6 or that address late steps of the viral replication cycle7.Phage capsids modified with spatially defined patterns of host cell ligands can act as multivalent binders for the influenza A virus to prevent viral infection.

Malignant melanoma is one of the most difficult cancers to treat due to its resistance to chemotherapy. Despite recent successes with BRAF inhibitors and immune checkpoint inhibitors, many patients do not respond or become resistant to these drugs. Hence, alternative treatments are still required. Due to the importance of the BCL-2-regulated apoptosis pathway in cancer development and drug resistance, it is of interest to establish which proteins are most important for melanoma cell survival, though the outcomes of previous studies have been conflicting. To conclusively address this question, we tested a panel of established and early passage patient-derived cell lines against several BH3-mimetic drugs designed to target individual or subsets of pro-survival BCL-2 proteins, alone and in combination, in both 2D and 3D cell cultures. None of the drugs demonstrated significant activity as single agents, though combinations targeting MCL-1 plus BCL-XL, and to a lesser extent BCL-2, showed considerable synergistic killing activity that was elicited via both BAX and BAK. Genetic deletion of BFL-1 in cell lines that express it at relatively high levels only had minor impact on BH3-mimetic drug sensitivity, suggesting it is not a critical pro-survival protein in melanoma. Combinations of MCL-1 inhibitors with BRAF inhibitors also caused only minimal additional melanoma cell killing over each drug alone, whilst combinations with the proteasome inhibitor bortezomib was more effective in multiple cell lines. Our data show for the first time that therapies targeting specific combinations of BCL-2 pro-survival proteins, namely MCL-1 plus BCL-XL and MCL-1 plus BCL-2, could have significant benefit for the treatment of melanoma.