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Supplementary Figure from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies.Significance:We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach.See related commentary by Capparelli and Aplin, p. 1413.This article is highlighted in the In This Issue feature, p. 1397

Supplementary Data from Characterization of INCB086550: A Potent and Novel Small-Molecule PD-L1 Inhibitor

Mobility patterns in South Asia are complex, defined by temporary and circular migration of low waged labourers within and across national borders. They move, live and work in conditions that expose them to numerous hazards and health risks that result in chronic ailments and physical and mental health problems. Yet, public policies and discourses either ignore migrants’ health needs or tend to pathologise them, framing them as carriers of diseases. Their structural neglect was exposed by the ongoing pandemic crisis. In this paper, we take stock of the evidence on the health of low-wage migrants in South Asia and examine how their health is linked to their social, political and work lives. The paper derives from a larger body of work on migration and health in South Asia and draws specifically on content analysis and scoping review of literature retrieved through Scopus from 2000 to 2021 on health of low-income migrants. Utilising the lens of precarity and building on previous applications, we identify four dimensions of precarity and examine how these influence health: i) Work-based, concerned with hazardous and disempowering work conditions, ii) Social position-based, pertaining to the social stratification and intersecting oppressions faced by migrants, iii) Status-based, derived from vulnerabilities arising from the mobile and transient nature of their lives and livelihoods, and iv) Governmentality-based, relating to the formal policies and informal procedures of governance that disenfranchise migrants. We illustrate how these collectively produce distinct yet interrelated and interlocking oppressive states of insecurity, disempowerment, dispossession, exclusion, and disposability that define health outcomes, health-seeking pathways, and lock migrants in a continuing cycle of precarity, impoverishment and ill-health.

This paper examines determinants of ethnic disparities in workplace risks of COVID-19 among health and social care workers (HCWs) in the UK. This was undertaken to inform public health policy in the management of COVID-19 relating to health and social care provision. A cross-sectional survey was administered in July–August 2020 (n = 456) to elicit HCWs’ experiences of COVID-19 management in the workplace and their perceptions of exposure, personal protection against infection, involvement in local clinical management, and other workplace hazards. Findings suggest minority ethnic HCWs were twice as likely as White HCWs to be in a patient-facing role (OR = 2.14, 95% CI:1.21; 3.78, P < 0.01) and twice as likely (63% vs 39%) to be caring for COVID-19 positive patients (OR = 2.68, 95% CI: 1.77; 4.06, P < 0.01). Those in nursing, were three times as likely to be redeployed to a COVID-19 care setting (OR = 3.33, 95%CI: 1.23; 9.02, P= 0.02). Minority ethnic HCWs within lower- and mid-level roles carried a higher burden of frontline clinical management of COVID-19 positive patients than their White counterparts. This study found evidence of ethnic disparities across several workplace hazards, with increased exposure to and less protection against infection, more responsibility for the clinical management of infection, and evidence of systemic racial bias in the disproportionate redeployment of minority ethnic nursing staff to COVID-19 areas. An NHS-wide review is required to assess procedural fairness, ensure safe practices now, and to avert future crises.

Magnetism in wide band gap materials is of great interests for future spintronic device applications. We prepared MgO and Fe-doped MgO films ‘in-situ’ on substrates by inkjet printing, and investigated the ferromagnetism tuned by the doping of Fe, the annealing temperature and the film thickness. It is found that the Fe-doping improves the crystallinity of the films with lattice structure changed by annealing temperature. The saturation magnetization (Ms) of the films enhanced by ~5 times comparing with the pure MgO thin film of similar thickness (~90 nm), because of both the long-range ordering of localized 3d electrons in Fe and the defects induced magnetism. The Ms at 5 K decreases with the film thickness, which is mainly attributed to the interface induced ferromagnetism. The Fe-doped MgO films with ferromagnetism in this work can be used in future spintronic devices.

Significant progress has been achieved in the field of sexual and reproductive health (SRH) in the last three decades as evident in global commitments and national legislative, policy and programme level reforms. However, such progress is truncated by decades of low prioritisation, weak political commitment and funding,1 political backlash, and systematic assault on the broader set of socioeconomic and civil-political rights necessary for SRH. Amid these challenges, adoption of the Sustainable Development Goals (SDGs) is promising for its explicit recognition of the importance of SRH rights for development, and for offering an integrated framework of goals that address both entitlements (ie, positive right to services, medicines and information) and freedoms (from violence and discrimination) necessary for full realisation of the broad spectrum of sexual and reproductive health and rights (SRHR) (see box 1). Their ‘universal’ premise, however, calls for a more nuanced assessment of how systems and provisions can be made more responsive to the SRH needs of those who are left behind and remain excluded from mainstream policy and planning. Such assessment will benefit from an explicit adoption of the ‘lens’ of intersectionality in examining and tackling SRH challenges. Box 1 ### Synergies between SRHR and SDGs #### Goal 3: Ensure healthy lives and promote well-being for all at all ages. Target 3.1 By 2030, reduce the global maternal mortality ratio to less than 70 per 100 000 births. Target 3.7 By 2030, ensure universal access to sexual and reproductive health care services, including for family planning, information and education, and the integration of reproductive health into national strategies and programmes. Target 3.8 Achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all. #### Goal 4: Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all. Target 4.7 By 2030, ensure that all learners acquire the knowledge and skills needed to promote sustainable development, including, among others, through education for sustainable development and sustainable lifestyles, human …

This column addresses the need to strengthen human rights in global health, looking to violations of human rights law in the pandemic response to recommend rights-based reforms in global health law. The column opens by examining the fundamental importance of human rights, recognizing the centrality of human rights in global health governance. Notwithstanding the evolution of health-related human rights under international law, the COVID-19 pandemic response has posed sweeping implications for the realization of human rights, with state responses failing to comply with their domestic and international human rights obligations. Raising an imperative to strengthen human rights in global health law, this column presents recommendations to advance health through the United Nations (UN) human rights system, extend human rights in revisions of the International Health Regulations (IHR), and mainstream human rights in WHO governance.

The identification of lattice multiphases in TiO2 nanocrystals is studied by high resolution transmission electron microscope and electron diffraction patterns. Based on the spectroscopic analysis using soft x-ray absorption and resonant inelastic soft x-ray scattering, it is believed that the oxygen vacancies at the interface exhibit structural distortion of the TiO68−cluster around the defect site as for the multiphase lattice. We elucidate that the extra 3d electrons nearby induce the inelastic scattering features with the excitation energy dependence owing to different energy relaxation processes, a characteristic of the electron-phonon coupling or the nature of the electron-hole pair at the intermediate state. The manifold dd excitations driven by the strong interaction between Ti-3d and O-2p electrons are noticeably rich, coexisting on both Ti and O sites. This sophisticated experiment can advance the perspective of nanocomposite TiO2 for various interactions of surface Ti3+ in applications of future devices.

Blocking the activity of the programmed cell death protein 1 (PD-1) inhibitory receptor with therapeutic antibodies against either the ligand (PD-L1) or PD-1 itself has proven to be an effective treatment modality for multiple cancers. Contrasting with antibodies, small molecules could demonstrate increased tissue penetration, distinct pharmacology, and potentially enhanced antitumor activity. Here, we describe the identification and characterization of INCB086550, a novel, oral, small-molecule PD-L1 inhibitor. In vitro, INCB086550 selectively and potently blocked the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, and induced stimulation-dependent cytokine production in primary human immune cells. In vivo, INCB086550 reduced tumor growth in CD34+ humanized mice and induced T-cell activation gene signatures, consistent with PD-L1/PD-1 pathway blockade. Preliminary data from an ongoing phase I study confirmed PD-L1/PD-1 blockade in peripheral blood cells, with increased immune activation and tumor growth control. These data support continued clinical evaluation of INCB086550 as an alternative to antibody-based therapies. Significance: We have identified a potent small-molecule inhibitor of PD-L1, INCB086550, which has biological properties similar to PD-L1/PD-1 monoclonal antibodies and may represent an alternative to antibody therapy. Preliminary clinical data in patients demonstrated increased immune activation and tumor growth control, which support continued clinical evaluation of this approach. See related commentary by Capparelli and Aplin, p. 1413. This article is highlighted in the In This Issue feature, p. 1397

SummaryCOVID-19 has changed our lives and it appears to be especially harmful for some groups more than others. Black and Asian ethnic minorities are at particular risk and have reported greater mortality and intensive care needs. Mental illnesses are more common among Black and ethnic minorities, as are crisis care pathways including compulsory admission. This editorial sets out what might underlie these two phenomena, explaining how societal structures and disadvantage generate and can escalate inequalities in crises.

Non-state actors, including humanitarian agencies, play a prominent role in providing health care in low- and middle-income countries. Between 2007 and 2009, Musina, a South African municipality bordering Zimbabwe, became the site of several interventions by non-state organisations as an unprecedented number of Zimbabweans crossed the border, putting strain on already burdened local systems. After the initial need for humanitarian relief dissipated, organisations started to implement projects that were more developmental in nature. For example, Médecins sans Frontières developed a mobile clinic programme to improve health care access for migrant farm workers, a programme that was subsequently integrated into the Department of Health. Since the handover of the programme, it has faced multiple challenges. Using qualitative methodology and a case study approach, this paper traces the development of the programme, exploring the changing relationship between MSF and the state during this time. This research raises questions about the implications of short-term ‘innovative’ interventions targeting the access that migrants have to care, within a context in which policy and programmatic responses to health are not migration aware. Furthermore, it highlights the ways in which the energies and resources of local DoH employees were redirected by MSF's involvement in the area.

The observation of a spontaneous electron enrichment at the apexes of bismuth vanadate (BiVO4) nanopyramidal arrays is achieved by performing synchrotron-based angular dependent X-ray absorption spectroscopy. In accordance with density function theory calculations, the formation of (112) facets enriched apexes is proposed. Such intrinsically electron-enriched (112) facets at the apexes produce a potential facilitating the diffusion of photoexcited holes, which not only mitigates the recombination with the photoexcited electrons, but also provide an active reaction site for the photoassisted selective growth of cobalt phosphate (CoPi), a well known and highly active co-catalyst for water oxidation at the apex of BiVO4 nanopyramids. Benefiting from the element-resolved properties of synchrotron-based X-ray spectroscopy, 3d electrons on the vanadium site are directly resolved by resonant inelastic X-ray scattering measurements. Due to this unique morphology, the charge at the apex is expected to induce a strong interaction with CoPi, as a result of the metal-to-ligand charge transfer spectroscopy feature observed from the cobalt site. Substantial evidences are collected by means of comprehensive soft X-ray spectroscopy techniques with high spectral resolution revealing the atomic-scale origin and the nature of the synergy as well as the strong correlation between its unique structural properties and the electronic structure of this novel highly-ordered hybrid photocatalyst and its significantly improved photoelectrochemical performance.

Summary box Relations of power are intrinsic to the social determinants of sexual and reproductive health (SRH); they influence the content, quality and outcomes of SRH care; and they shape the negotiation and realisation of sexual and reproductive health and rights (SRHR) more broadly. Power dynamics pervade how SRHR is understood, studied and acted on, in ways that are distinct from other health issues.1 For example, the deeply held personal beliefs about women’s sexuality and childbearing, cultural mores regarding adolescent sexuality and state goals related to fertility all mark SRHR as a sphere with distinct and deeply contested power dynamics. Unmasking power as a central element in SRHR research is therefore crucial to developing a research agenda that can produce …

Indian cities attract a considerable number of low-income migrants from marginal rural households experiencing difficult economic, political and social conditions at home. Based on fieldwork in Jalandhar and Guwahati, this article focuses on the precarity of low-income migrants in Indian cities. It argues that the concept of precarity, used in the context of migrant labour, should be extended to capture multiple and reinforcing forms of vulnerability, examining the relationship between structural inequalities, including difficult conditions at home, exclusion from public services and poor access to justice. It puts forward a proposition that the widespread media representations of migrant workers returning home in the context of COVID-19 are not simply a result of the sudden outbreak of the coronavirus but that these journeys must be seen as part of the history of the circulatory system of labour.