Slipping Anchor?: Testing the Vignettes Approach to Identification and Correction of Reporting Heterogeneity

We propose tests of the two assumptions under which anchoring vignettes identify heterogeneity in reporting of categorical evaluations. Systematic variation in the perceived difference between any two vignette states is sufficient to reject vignette equivalence. Response consistency—the respondent uses the same response scale to evaluate the vignette and herself—is testable given sufficiently comprehensive objective indicators that independently identify response scales. Both assumptions are rejected for reporting of cognitive and physical functioning in a sample of older English individuals, although a weaker test resting on less stringent assumptions does not reject response consistency for cognition

Slipping anchor? Testing the vignettes approach to identification and correction of reporting heterogeneity

Anchoring vignettes are increasingly used to identify and correct heterogeneity in the reporting of health, work disability, life satisfaction, political efficacy, etc. with the aim of improving interpersonal comparability of subjective indicators of these constructs. The method relies on two assumptions: vignette equivalence – the vignette description is perceived by all to correspond to the same state; and, response consistency - individuals use the same response scales to rate the vignettes and their own situation. We propose tests of these assumptions. For vignette equivalence, we test a necessary condition of no systematic variation with observed characteristics in the perceived difference in states corresponding to any two vignettes. To test response consistency we rely on the assumption that objective indicators fully capture the covariation between the construct of interest and observed individual characteristics, and so offer an alternative way to identify response scales, which can then be compared with those identified from the vignettes. We also introduce a weaker test that is valid under a less stringent assumption. We apply these tests to cognitive functioning and mobility related health problems using data from the English Longitudinal Survey of Ageing. Response consistency is rejected for both health domains according to the first test, but the weaker test does not reject for cognitive functioning. The necessary condition for vignette equivalence is rejected for both health domains. These results cast some doubt on the validity of the vignettes approach, at least as applied to these health domains

IL-1 and senescence: Friends and foe of EGFR neutralization and immunotherapy

Historically, senescence has been considered a safe program in response to multiple stresses in which cells undergo irreversible growth arrest. This process is characterized by morphological and metabolic changes, heterochromatin formation, and secretion of inflammatory components, known as senescence-associated secretory phenotype (SASP). However, recent reports demonstrated that anti-cancer therapy itself can stimulate a senescence response in tumor cells, the so-called therapy-induced senescence (TIS), which may represent a temporary bypass pathway that promotes drug resistance. In this context, several studies have shown that EGFR blockage, by TKIs or moAbs, promotes TIS by increasing IL-1 cytokine production, thus pushing cells into a "pseudo-senescent" state. Today, senotherapeutic agents are emerging as a potential strategy in cancer treatment thanks to their dual role in annihilating senescent cells and simultaneously preventing their awakening into a resistant and aggressive form. Here, we summarize classic and recent findings about the cellular processes driving senescence and SASP, and we provide a state-of-the-art of the anti-cancer strategies available so far that exploits the activation and/or blockade of senescence-based mechanisms

Does Reporting Heterogeneity Bias The Measurement of Health Disparities?

Heterogeneity in reporting of health by socio-economic and demographic characteristics potentially biases the measurement of health disparities. We use anchoring vignettes to identify reporting heterogeneity in self reports on health for Indonesia, India and China. Correcting for reporting heterogeneity tends to reduce estimated disparities in health by age, sex (not Indonesia), urban/rural and education (not China) and to increase income disparities in health. Overall, while homogeneous reporting by socio-demographic group is significantly rejected, the results suggest that the size of the reporting bias in measures of health disparities is not large

Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies

ERBB4 is a tyrosine kinase receptor reported to exert both oncogenic and tumor suppressor activities. These paradoxical effects were suggested to stem from different ERBB4 homo-/hetero-dimers and/or isoforms. By stratifying breast cancer patients for clinical and molecular subtypes and ERBB4 mRNA abundance, we here report that higher ERBB4 levels correlate with longer relapse-free survival in breast cancer patients of HER2-enriched and luminal A molecular subtypes, proposing a cancer-protecting role for this receptor in these specific subgroups. We also observed that HER2-enriched breast cancers express intermediate ERBB4 mRNA levels compared to luminal and triple-negative/basal-like subgroups, which displayed the highest and the lowest levels, respectively. Inspired by these clinical data, we tested the activation of ERBB4 by Neuregulins as a potential anticancer strategy for HER2+ breast cancers. To this end, we employed two HER2+ breast cancer cellular models (BT474 and SKBR3), which express intermediate/high and low ERBB4 levels, respectively. Cell proliferation and motility were evaluated on these cellular models following treatments with Neuregulin 1 (NRG1), which activates both ERBB3 and ERBB4, or Neuregulin 4 (NRG4), which specifically activates ERBB4. Both NRG1 and NRG4 were used alone or in combination with anti-ERBB2 neutralizing antibodies, namely trastuzumab and pertuzumab. In vitro treatment with NRG1 on BT474 cells restrained cell growth and reduced the anti-proliferative efficacy of trastuzumab. In contrast, treatment with NRG1 on SKBR3 cells increased cell proliferation and migration, and partially or completely impaired the anti-proliferative/anti-migratory action of trastuzumab and/or pertuzumab. Importantly, in both the cell lines, treatment with NRG4 robustly potentiated the anti-proliferative action of trastuzumab and pertuzumab. Collectively, our data in HER2+ breast cancer cells highlight that NRG1 may exert both pro- and anti-proliferative effects, and may reduce the efficacy of anti-HER2 agents, whereas NRG4 may boost the anti-proliferative effects of anti-ERBB2 agents. We propose a provocative paradigm shift in the field of growth factors in cancer progression, suggesting the administration of ERBB4 ligands, such as Neuregulin 4, as a strategy to improve the efficacy of anti-ERBB2 agents

Beta-Catenin/HuR Post-Transcriptional Machinery Governs Cancer Stem Cell Features in Response to Hypoxia

Hypoxia has been long-time acknowledged as major cancer-promoting microenvironment. In such an energy-restrictive condition, post-transcriptional mechanisms gain importance over the energy-expensive gene transcription machinery. Here we show that the onset of hypoxia-induced cancer stem cell features requires the beta-catenin-dependent post-transcriptional up-regulation of CA9 and SNAI2 gene expression. In response to hypoxia, beta-catenin moves from the plasma membrane to the cytoplasm where it binds and stabilizes SNAI2 and CA9 mRNAs, in cooperation with the mRNA stabilizing protein HuR. We also provide evidence that the post-transcriptional activity of cytoplasmic beta-catenin operates under normoxia in basal-like/triple-negative breast cancer cells, where the beta-catenin knockdown suppresses the stem cell phenotype in vitro and tumor growth in vivo. In such cells, we unravel the generalized involvement of the beta-catenin-driven machinery in the stabilization of EGF-induced mRNAs, including the cancer stem cell regulator IL6. Our study highlights the crucial role of post-transcriptional mechanisms in the maintenance/acquisition of cancer stem cell features and suggests that the hindrance of cytoplasmic beta-catenin function may represent an unprecedented strategy for targeting breast cancer stem/basal-like cells

Public support for older disabled people: evidence from the English Longitudinal Study of Ageing on receipt of disability benefits and social care subsidy

In England, state support for older people with disabilities consists of a national system of non-means tested cash disability benefits, and a locally-administered means-tested system of social care. Evidence on how the combination of the two systems targets those in most need is lacking. We estimate a latent factor structural equation model of disability and receipt of one or both forms of support. The model integrates the measurement of disability and its influence on receipt of state support, allowing for the socio-economic gradient in disability, and adopts income and wealth constructs appropriate to each part of the model. We find that receipt of each form of support rises as disability increases, with a strong concentration on the most disabled, especially for LA-funded care. The overlap between the two programmes is confined to the most disabled. Less than half of recipients of local authority-funded care also receive a disability benefit; a third of those in the top 10% of the disability distribution receive neither form of support. Despite being non means-tested, disability benefits display a degree of income and wealth targeting, as a consequence of the socio-economic gradient in disability and likely disability benefit claims behaviour. The scope for improving income/wealth targeting of disability benefits by means testing them, as some have suggested, is thus less than might be expected