Digitally augmented, parent-led CBT versus treatment as usual for child anxiety problems in child mental health services in England and Northern Ireland: a pragmatic, non-inferiority, clinical effectiveness and cost-effectiveness randomised controlled trial.

BACKGROUND: Anxiety problems are common in children, yet few affected children access evidence-based treatment. Digitally augmented psychological therapies bring potential to increase availability of effective help for children with mental health problems. This study aimed to establish whether therapist-supported, digitally augmented, parent-led cognitive behavioural therapy (CBT) could increase the efficiency of treatment without compromising clinical effectiveness and acceptability. METHODS: We conducted a pragmatic, unblinded, two-arm, multisite, randomised controlled non-inferiority trial to evaluate the clinical effectiveness and cost-effectiveness of therapist-supported, parent-led CBT using the Online Support and Intervention (OSI) for child anxiety platform compared with treatment as usual for child (aged 5-12 years) anxiety problems in 34 Child and Adolescent Mental Health Services in England and Northern Ireland. We examined acceptability of OSI plus therapist support via qualitative interviews. Participants were randomly assigned (1:1) to OSI plus therapist support or treatment as usual, minimised by child age, gender, service type, and baseline child anxiety interference. Outcomes were assessed at week 14 and week 26 after randomisation. The primary clinical outcome was parent-reported interference caused by child anxiety at week 26 assessment, using the Child Anxiety Impact Scale-parent report (CAIS-P). The primary measure of health economic effect was quality-adjusted life-years (QALYs). Outcome analyses were conducted blind in the intention-to-treat (ITT) population with a standardised non-inferiority margin of 0·33 for clinical analyses. The trial was registered with ISRCTN, 12890382. FINDINGS: Between Dec 5, 2020, and Aug 3, 2022, 706 families (706 children and their parents or carers) were referred to the study information. 444 families were enrolled. Parents reported 255 (58%) child participants' gender to be female, 184 (41%) male, three (<1%) other, and one (<1%) preferred not to report their child's gender. 400 (90%) children were White and the mean age was 9·20 years (SD 1·79). 85% of families for whom clinicians provided information in the treatment as usual group received CBT. OSI plus therapist support was non-inferior for parent-reported anxiety interference on the CAIS-P (SMD 0·01, 95% CI -0·15 to 0·17; p<0·0001) and all secondary outcomes. The mean difference in QALYs across trial arms approximated to zero, and OSI plus therapist support was associated with lower costs than treatment as usual. OSI plus therapist support was likely to be cost effective under certain scenarios, but uncertainty was high. OSI plus therapist support acceptability was good. No serious adverse events were reported. INTERPRETATION: Digitally augmented intervention brought promising savings without compromising outcomes and as such presents a valuable tool for increasing access to psychological therapies and meeting the demand for treatment of child anxiety problems. FUNDING: Department for Health and Social Care and United Kingdom Research and Innovation Research Grant, National Institute for Health and Care (NIHR) Research Policy Research Programme, Oxford and Thames Valley NIHR Applied Research Collaboration, Oxford Health NIHR Biomedical Research Centre.

A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization.

Genetic screens in cancer cell lines inform gene function and drug discovery. More comprehensive screen datasets with multi-omics data are needed to enhance opportunities to functionally map genetic vulnerabilities. Here, we construct a second-generation map of cancer dependencies by annotating 930 cancer cell lines with multi-omic data and analyze relationships between molecular markers and cancer dependencies derived from CRISPR-Cas9 screens. We identify dependency-associated gene expression markers beyond driver genes, and observe many gene addiction relationships driven by gain of function rather than synthetic lethal effects. By combining clinically informed dependency-marker associations with protein-protein interaction networks, we identify 370 anti-cancer priority targets for 27 cancer types, many of which have network-based evidence of a functional link with a marker in a cancer type. Mapping these targets to sequenced tumor cohorts identifies tractable targets in different cancer types. This target prioritization map enhances understanding of gene dependencies and identifies candidate anti-cancer targets for drug development.

Statistical analysis plan for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice: identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i).

BACKGROUND: The Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i) trial is being conducted to establish whether 'screening and intervention', consisting of usual school practice plus a pathway comprising screening, feedback and a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety), bring clinical and health economic benefits compared to usual school practice and assessment only - 'usual school practice', for children aged 8-9 years in the following: (1) the 'target population', who initially screen positive for anxiety problems according to a two-item parent-report child anxiety questionnaire - iCATS-2, and (2) the 'total population', comprising all children in participating classes. This article describes the detailed statistical analysis plan for the trial. METHODS AND DESIGN: iCATS-i2i is a definitive, superiority, pragmatic, school-based cluster randomised controlled trial (with internal pilot), with two parallel groups. Schools are randomised 1:1 to receive either screening and intervention or usual school practice. This article describes the following: trial objectives and outcomes; statistical analysis principles, including detailed estimand information necessary for aligning trial objectives, conduct, analyses and interpretation when there are different analysis populations and outcome measures to be considered; and planned main analyses, sensitivity and additional analyses. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN76119074. Registered on 4 January 2022.

The multifaceted consequences and economic costs of child anxiety problems: A systematic review and meta-analysis.

Background: Over a quarter of people have an anxiety disorder at some point in their life, with many first experiencing difficulties during childhood or adolescence. Despite this, gaps still exist in the current evidence base of the multiple consequences of childhood anxiety problems and their costs. Methods: A systematic review of Medline, PsycINFO, EconLit and the National Health Service Economic Evaluation Database was conducted for longitudinal and economic studies reporting on the association between childhood anxiety problems and at least one individual-, family- or societal-level outcome or cost. All studies were synthesised narratively. For longitudinal studies, 'effect direction' was used as a common metric, with random effects meta-analysis undertaken where possible. Results: Eighty-three studies met inclusion criteria and were synthesised narratively. We identified 788 separate analyses from the longitudinal studies, which we grouped into 15 overarching outcome domains. Thirteen of the studies were incorporated into 13 meta-analyses, which indicated that childhood anxiety disorders were associated with future anxiety, mood, behaviour and substance disorders. Narrative synthesis also suggested associations between anxiety problems and worse physical health, behaviour, self-harm, eating, relationship, educational, health care, employment, and financial outcomes. 'Effect direction' was conflicting in some domains due to a sparse evidence base. Higher economic costs were identified for the child, their families, healthcare providers and wider society, although evidence was limited and only covered short follow-up periods, up to a maximum of 2 years. Total annual societal costs per anxious child were up to £4040 (2021 GBP). Conclusions: Childhood anxiety problems are associated with impaired outcomes in numerous domains, and considerable economic costs, which highlight the need for cost-effective interventions and policies to tackle them. More economic evidence is needed to inform models of the long-term, economic-related, consequences of childhood anxiety problems.

The COVID-19 pandemic and health-related quality of life across 13 high- and low-middle-income countries: A cross-sectional analysis.

BACKGROUND: Most research on the Coronavirus Disease 2019 (COVID-19) health burden has focused on confirmed cases and deaths, rather than consequences for the general population's health-related quality of life (HRQoL). It is also important to consider HRQoL to better understand the potential multifaceted implications of the COVID-19 pandemic in various international contexts. This study aimed to assess the association between the COVID-19 pandemic and changes in HRQoL in 13 diverse countries. METHODS AND FINDINGS: Adults (18+ years) were surveyed online (24 November to 17 December 2020) in 13 countries spanning 6 continents. Our cross-sectional study used descriptive and regression-based analyses (age adjusted and stratified by gender) to assess the association between the pandemic and changes in the general population's HRQoL, measured by the EQ-5D-5L instrument and its domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and how overall health deterioration was associated with individual-level (socioeconomic, clinical, and experiences of COVID-19) and national-level (pandemic severity, government responsiveness, and effectiveness) factors. We also produced country-level quality-adjusted life years (QALYs) associated to COVID-19 pandemic-related morbidity. We found that overall health deteriorated, on average across countries, for more than one-third of the 15,480 participants, mostly in the anxiety/depression health domain, especially for younger people (<35 years old) and females/other gender. This translated overall into a 0.066 mean "loss" (95% CI: -0.075, -0.057; p-value < 0.001) in the EQ-5D-5L index, representing a reduction of 8% in overall HRQoL. QALYs lost associated with morbidity were 5 to 11 times greater than QALYs lost based on COVID-19 premature mortality. A limitation of the study is that participants were asked to complete the prepandemic health questionnaire retrospectively, meaning responses may be subject to recall bias. CONCLUSIONS: In this study, we observed that the COVID-19 pandemic was associated with a reduction in perceived HRQoL globally, especially with respect to the anxiety/depression health domain and among younger people. The COVID-19 health burden would therefore be substantially underestimated if based only on mortality. HRQoL measures are important to fully capture morbidity from the pandemic in the general population.

Applications of single-cell RNA sequencing in drug discovery and development.

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery and development. New opportunities are emerging in target identification owing to improved disease understanding through cell subtyping, and highly multiplexed functional genomics screens incorporating scRNA-seq are enhancing target credentialling and prioritization. ScRNA-seq is also aiding the selection of relevant preclinical disease models and providing new insights into drug mechanisms of action. In clinical development, scRNA-seq can inform decision-making via improved biomarker identification for patient stratification and more precise monitoring of drug response and disease progression. Here, we illustrate how scRNA-seq methods are being applied in key steps in drug discovery and development, and discuss ongoing challenges for their implementation in the pharmaceutical industry.

Meta-Analysis of Human Cancer Single-Cell RNA-Seq Datasets Using the IMMUcan Database.

The development of single-cell RNA sequencing (scRNA-seq) technologies has greatly contributed to deciphering the tumor microenvironment (TME). An enormous amount of independent scRNA-seq studies have been published representing a valuable resource that provides opportunities for meta-analysis studies. However, the massive amount of biological information, the marked heterogeneity and variability between studies, and the technical challenges in processing heterogeneous datasets create major bottlenecks for the full exploitation of scRNA-seq data. We have developed IMMUcan scDB (https://immucanscdb.vital-it.ch), a fully integrated scRNA-seq database exclusively dedicated to human cancer and accessible to nonspecialists. IMMUcan scDB encompasses 144 datasets on 56 different cancer types, annotated in 50 fields containing precise clinical, technological, and biological information. A data processing pipeline was developed and organized in four steps: (i) data collection; (ii) data processing (quality control and sample integration); (iii) supervised cell annotation with a cell ontology classifier of the TME; and (iv) interface to analyze TME in a cancer type-specific or global manner. This framework was used to explore datasets across tumor locations in a gene-centric (CXCL13) and cell-centric (B cells) manner as well as to conduct meta-analysis studies such as ranking immune cell types and genes correlated to malignant transformation. This integrated, freely accessible, and user-friendly resource represents an unprecedented level of detailed annotation, offering vast possibilities for downstream exploitation of human cancer scRNA-seq data for discovery and validation studies. SIGNIFICANCE: The IMMUcan scDB database is an accessible supportive tool to analyze and decipher tumor-associated single-cell RNA sequencing data, allowing researchers to maximally use this data to provide new insights into cancer biology.

Cost-effectiveness of implementing a suicide prediction tool (OxMIS) in severe mental illness: Economic modeling study.

BACKGROUND: Cost-effectiveness analysis needs to be considered when introducing new tools and treatments to clinical services. The number of new assessment tools in mental health has rapidly expanded, including suicide risk assessment. Such suicide-based assessments, when linked to preventative interventions, are integral to high-quality mental health care for people with severe mental illness (SMI). We examined the cost implications of implementing Oxford Mental Illness and Suicide (OxMIS), an evidence-based, scalable suicide risk assessment tool that provides probabilistic estimates of suicide risk over 12 months for people with SMI in England. METHODS: We developed a decision analytic model using secondary data to estimate the potential cost-effectiveness of incorporating OxMIS into clinical decision-making in secondary care as compared to usual care. Cost-effectiveness was measured in terms of costs per quality-adjusted life years (QALYs) gained. Uncertainty was addressed with deterministic and probabilistic sensitivity analysis. RESULTS: Conducting suicide risk assessment with OxMIS was potentially cheaper than clinical risk assessment alone by £250 (95% confidence interval, -786;31) to £599 (-1,321;-156) (in 2020-2021 prices) per person with SMI and associated with a small increase in quality of life (0.01 [-0.03;0.05] to 0.01 QALY, [-0.04;0.07]). The estimated incremental cost-effectiveness ratio of implementing OxMIS was cost saving. Using probabilistic sensitivity analysis, 99.96% of 10,000 simulations remained cost saving. CONCLUSION: Cost-effectiveness analysis can be conducted on risk prediction models. Implementing one such model that focuses on suicide risk in a high-risk population can lead to cost savings and improved health outcomes, especially if explicitly linked to preventative treatments.

Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i): protocol for a cluster randomised controlled trial to compare screening, feedback and intervention for child anxiety problems to usual school practice.

BACKGROUND: Systematically screening for child anxiety problems, and offering and delivering a brief, evidence-based intervention for children who are identified as likely to benefit would minimise common barriers that families experience in accessing treatment. We have developed a short parent-report child anxiety screening questionnaire, and procedures for administering screening questionnaires, sharing screening outcomes with families, and offering and delivering a brief parent-led online intervention (OSI: Online Support and Intervention for child anxiety) through schools. This trial aims to evaluate clinical and health economic outcomes for (1) children (aged 8-9) who screen positive for anxiety problems at baseline (target population) and (2) the wider population of all children in participating classes (total population) in schools randomly allocated to receive identification-to-intervention procedures and usual school practice ('screening and intervention'), compared to assessment and usual school practice only ('usual school practice').  METHODS: The trial design is a parallel-group, superiority cluster randomised controlled trial, with schools (clusters) randomised to 'screening and intervention' or 'usual school practice' arms in a 1:1 ratio stratified according to the level of deprivation within the school. We will recruit schools and participants in two phases (a pilot phase (Phase 1) and Phase 2), with progression criteria assessed prior to progressing to Phase 2. In total, the trial will recruit 80 primary/junior schools in England, and 398 children (199 per arm) who screen positive for anxiety problems at baseline (target population). In schools allocated to 'screening and intervention': (1) parents/carers will complete a brief parent-report child anxiety screening questionnaire (at baseline) and receive feedback on their child's screening outcomes (after randomisation), (2) classes will receive a lesson on managing fears and worries and staff will be provided with information about the intervention and (3) parents/carers of children who screen positive for anxiety problems (target population) will be offered OSI. OSI will also be available for any other parents/carers of children in participating classes (total population) who request it. We will collect child-, parent- and teacher-report measures for the target population and total population at baseline (before randomisation), 4 months, 12 months and 24 months post-randomisation. The primary outcome will be the proportion of children who screen positive for anxiety problems at baseline (target population) who screen negative for anxiety problems 12 months post-randomisation. DISCUSSION: This trial will establish if systematic screening for child anxiety problems, sharing screening outcomes with families and delivering a brief parent-led online intervention through schools is effective and cost-effective. TRIAL REGISTRATION: ISRCTN registry ISRCTN76119074. Prospectively registered on 4.1.2022.

An integrative approach of digital image analysis and transcriptome profiling to explore potential predictive biomarkers for TGFß blockade therapy.

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes (TILs) is associate with response to immunotherapies. Recent studies have identified TGFß activity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 blockade. Here we coupled the artificial intelligence (AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGFß pathway activity. Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns. The digital image analysis approach achieves 74% concordance with the pathologist assessment for tumor-immune phenotypes. The transcriptomic profiling suggests that the TIL score was negatively correlated with TGFß pathway activation, together with elevated TGFß signaling activity observed in excluded and desert tumor phenotypes. The present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes: immune desert, immune excluded or immune inflamed. The association between "cold" tumor-immune phenotypes and TGFß signature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGFß blockade.

Identifying Child Anxiety Through Schools-identification to intervention (iCATS-i2i): protocol for single-arm feasibility trial.

BACKGROUND: Anxiety disorders are common among primary-school aged children, but few affected children receive evidence-based treatment. Identifying and supporting children who experience anxiety problems through schools would address substantial treatment access barriers that families and school staff often face. We have worked with families and school staff to co-design procedures that incorporate screening, feedback for parents, and the offer of a brief intervention in primary schools. This study sets out to assess the feasibility of a subsequent school-based cluster randomised controlled trial to evaluate these procedures. Our objectives are to ensure our procedures for identifying and supporting children with anxiety difficulties through primary schools are acceptable and there are no negative impacts, to estimate recruitment and retention rates, and to identify any changes needed to study procedures or measures. METHODS: We will recruit six primary/junior schools in England (2 classes per school), and invite all children (aged 8-9) (n = 360) and their parent/carer and class teacher in participating classes to take part. Children, parents and class teachers will complete questionnaires at baseline and 12-week follow-up. Children who 'screen positive' on a 2-item parent-report child anxiety screen at baseline will be the target population (expected n = 43). Parents receive feedback on screening questionnaire responses, and where the child screens positive the family is offered support (OSI: Online Support and Intervention for child anxiety). OSI is a brief, parent-led online intervention, supported by short telephone sessions with a Children's Wellbeing Practitioner. Participants' experiences of study procedures will be assessed through qualitative interviews/discussion groups. DISCUSSION: Evidence-based procedures for identifying and supporting children with anxiety difficulties through primary schools would improve children's access to timely, effective intervention for anxiety difficulties. TRIAL REGISTRATION: ISRCTN registry: ISRCTN30032471 . Retrospectively registered on 18 May 2021.

YAP1 is essential for malignant mesothelioma tumor maintenance.

Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.

Vertical integration of primary care practices with acute hospitals in England and Wales: why, how and so what? Findings from a qualitative, rapid evaluation.

OBJECTIVES: To understand the rationale, implementation and early impact of vertical integration between primary care medical practices and the organisations running acute hospitals in the National Health Service in England and Wales. DESIGN AND SETTING: A qualitative, cross-comparative case study evaluation at two sites in England and one in Wales, consisting of interviews with stakeholders at the sites, alongside observations of strategic meetings and analysis of key documents. RESULTS: We interviewed 52 stakeholders across the three sites in the second half of 2019 and observed four meetings from late 2019 to early 2020 (further observation was prevented by the onset of the COVID-19 pandemic). The single most important driver of vertical integration was found to be to maintain primary care local to where patients live and thereby manage demand pressure on acute hospital services, especially emergency care. The opportunities created by maintaining local primary care providers-to develop patient services in primary care settings and better integrate them with secondary care-were exploited to differing degrees across the sites. There were notable differences between sites in operational and management arrangements, and in organisational and clinical integration. Closer organisational integration was attributed to previous good relationships between primary and secondary care locally, and to historical planning and preparation towards integrated working across the local health economy. The net impact of vertical integration on health system costs is argued by local stakeholders to be beneficial. CONCLUSIONS: Vertical integration is a valuable option when primary care practices are at risk of closing, and may be a route to better integration of patient care. But it is not the only route and vertical integration is not attractive to all primary care physicians. A future evaluation of vertical integration is intended; of patients' experience and of the impact on secondary care service utilisation.

Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Local immunotherapy ideally stimulates immune responses against tumors while avoiding toxicities associated with systemic administration. Current strategies for tumor-targeted, gene-based delivery, however, are limited by adverse effects such as off-targeting or antivector immunity. We investigated the intratumoral administration of saline-formulated messenger (m)RNA encoding four cytokines that were identified as mediators of tumor regression across different tumor models: interleukin-12 (IL-12) single chain, interferon-α (IFN-α), granulocyte-macrophage colony-stimulating factor, and IL-15 sushi. Effective antitumor activity of these cytokines relied on multiple immune cell populations and was accompanied by intratumoral IFN-γ induction, systemic antigen-specific T cell expansion, increased granzyme B+ T cell infiltration, and formation of immune memory. Antitumor activity extended beyond the treated lesions and inhibited growth of distant tumors and disseminated tumors. Combining the mRNAs with immunomodulatory antibodies enhanced antitumor responses in both injected and uninjected tumors, thus improving survival and tumor regression. Consequently, clinical testing of this cytokine-encoding mRNA mixture is now underway.

Demonstrating trustworthiness when collecting and sharing genomic data: public views across 22 countries.

BACKGROUND: Public trust is central to the collection of genomic and health data and the sustainability of genomic research. To merit trust, those involved in collecting and sharing data need to demonstrate they are trustworthy. However, it is unclear what measures are most likely to demonstrate this. METHODS: We analyse the 'Your DNA, Your Say' online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle- and high-income countries, gathered in 15 languages. We examine how participants perceived the relative value of measures to demonstrate the trustworthiness of those using donated DNA and/or medical information. We examine between-country variation and present a consolidated ranking of measures. RESULTS: Providing transparent information about who will benefit from data access was the most important measure to increase trust, endorsed by more than 50% of participants across 20 of 22 countries. It was followed by the option to withdraw data and transparency about who is using data and why. Variation was found for the importance of measures, notably information about sanctions for misuse of data-endorsed by 5% in India but almost 60% in Japan. A clustering analysis suggests alignment between some countries in the assessment of specific measures, such as the UK and Canada, Spain and Mexico and Portugal and Brazil. China and Russia are less closely aligned with other countries in terms of the value of the measures presented. CONCLUSIONS: Our findings highlight the importance of transparency about data use and about the goals and potential benefits associated with data sharing, including to whom such benefits accrue. They show that members of the public value knowing what benefits accrue from the use of data. The study highlights the importance of locally sensitive measures to increase trust as genomic data sharing continues globally.

An experimental model of anti-PD-1 resistance exhibits activation of TGFß and Notch pathways and is sensitive to local mRNA immunotherapy.

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or ß2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFß and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFß and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models.

Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

Estimating the global economic benefits of physically active populations over 30 years (2020-2050).

OBJECTIVES: We assess the potential benefits of increased physical activity for the global economy for 23 countries and the rest of the world from 2020 to 2050. The main factors taken into account in the economic assessment are excess mortality and lower productivity. METHODS: This study links three methodologies. First, we estimate the association between physical inactivity and workplace productivity using multivariable regression models with proprietary data on 120 143 individuals in the UK and six Asian countries (Australia, Malaysia, Hong Kong, Thailand, Singapore and Sri Lanka). Second, we analyse the association between physical activity and mortality risk through a meta-regression analysis with data from 74 prior studies with global coverage. Finally, the estimated effects are combined in a computable general equilibrium macroeconomic model to project the economic benefits of physical activity over time. RESULTS: Doing at least 150 min of moderate-intensity physical activity per week, as per lower limit of the range recommended by the 2020 WHO guidelines, would lead to an increase in global gross domestic product (GDP) of 0.15%-0.24% per year by 2050, worth up to US$314-446 billion per year and US$6.0-8.6 trillion cumulatively over the 30-year projection horizon (in 2019 prices). The results vary by country due to differences in baseline levels of physical activity and GDP per capita. CONCLUSIONS: Increasing physical activity in the population would lead to reduction in working-age mortality and morbidity and an increase in productivity, particularly through lower presenteeism, leading to substantial economic gains for the global economy.

Pan-TGFß inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade.

TGFß is a pleiotropic cytokine that may have both tumor inhibiting and tumor promoting properties, depending on tissue and cellular context. Emerging data support a role for TGFß in suppression of antitumor immunity. Here we show that SAR439459, a pan-TGFß neutralizing antibody, inhibits all active isoforms of human and murine TGFß, blocks TGFß-mediated pSMAD signaling, and TGFß-mediated suppression of T cells and NK cells. In vitro, SAR439459 synergized with anti-PD1 to enhance T cell responsiveness. In syngeneic tumor models, SAR439459 treatment impaired tumor growth, while the combination of SAR439459 with anti-PD-1 resulted in complete tumor regression and a prolonged antitumor immunity. Mechanistically, we found that TGFß inhibition with PD-1 blockade augmented intratumoral CD8+ T cell proliferation, reduced exhaustion, evoked proinflammatory cytokines, and promoted tumor-specific CD8+ T cell responses. Together, these data support the hypothesis that TGFß neutralization using SAR439459 synergizes with PD-1 blockade to promote antitumor immunity and formed the basis for the ongoing clinical investigation of SAR439459 in patients with cancer (NCT03192345).