MCP-1 and MIP-3α Secreted from Necrotic Cell-Treated Glioblastoma Cells Promote Migration/Infiltration of Microglia

Background/Aims: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The defining characteristics of GBM are diffuse infiltration of tumor cells into normal brain parenchyma, rapid growth, a high degree of infiltration of microglia and macrophages, and the presence of necrosis. Microglia/macrophages are frequently found in gliomas and they extensively infiltrate GBM tissue, up to 30% of total tumor mass. However, little is known about the effect of necrotic cells (NCs) on microglia infiltration in GBM and the tumor-infiltrating microglia-induced factors in GBMs. Methods: In this study, to address whether necrosis or necrosis-exposed GBM cells affect the degree of microglia/macrophage infiltration, migration and invasion/infiltration assays were performed. Culture supernatants and nuclear extracts of CRT-MG cells treated or untreated with necrotic cells were analyzed using a chemokine array and electrophoretic mobility shift assay, respectively. Results: The presence of NCs promoted the migration/infiltration of microglia, and GBM cell line CRT-MG cells exposed to NCs further enhanced the migration and infiltration of HMO6 microglial cells. Treatment with NCs induced mRNA and protein expression of chemokines such as Monocyte Chemoattractant Protein-1 (CCL2/MCP-1) and Macrophage Inflammatory Protein-3α (CCL20/MIP-3α) in CRT-MG cells. In particular, CCL2/MCP-1 and CCL20/MIP-3α were significantly increased in NC-treated CRT-MG cells. NCs induced DNA binding of the transcription factors Nuclear Factor (NF)-κB and Activator Protein 1 (AP-1) to the CCL2/MCP-1 and CCL20/MIP-3α promoters, leading to increased CCL2/MCP-1 and CCL20/MIP-3α mRNA and protein expression in CRT-MG cells. Conclusion: These results provide evidence that NCs induce the expression of CCL2/MCP-1 and CCL20/MIP-3α in glioblastoma cells through activation of NF-κB and AP-1 and facilitate the infiltration of microglia into tumor tissues

Uncertainty, evidence and irrecoverable costs: informing approval, pricing and research decisions for health technologies

The general issue of balancing the value of evidence about the performance of a technology and the value of access to a technology can be seen as central to a number of policy questions. Establishing the key principles of what assessments are needed, as well as how they should be made, will enable them to be addressed in an explicit and transparent manner. This report presents the key finding from MRC and NHIR funded research which aimed to: i) Establish the key principles of what assessments are needed to inform an only in research (OIR) or Approval with Research (AWR) recommendation. ii) Evaluate previous NICE guidance where OIR or AWR recommendations were made or considered. iii) Evaluate a range of alternative options to establish the criteria, additional information and/or analysis which could be made available to help the assessment needed to inform an OIR or AWR recommendation. iv) Provide a series of final recommendations, with the involvement of key stakeholders, establishing both the key principles and associated criteria that might guide OIR and AWR recommendations, identifying what, if any, additional information or analysis might be included in the Technology Appraisal process and how such recommendations might be more likely to be implemented through publicly funded and sponsored research. The key principles and the assessments and judgments required are discussed in Section 2. The sequence of assessment and judgment is represented as an algorithm, which can also be summarised as a simple set of explicit criteria or a seven point checklist of assessments. The application of the check list of assessment to a series of four case studies in Section 3 can inform considerations of whether such assessments can be made based on existing information and analysis in current NICE appraisal and in what circumstances could additional information and/or analysis be useful. In Section 4, some of the implications that this more explicit assessment of OIR and AWR might have for policy (e.g., NICE guidance and drug pricing), the process of appraisal (e.g., greater involvement of research commissioners) and methods of appraisal (e.g., should additional information, evidence and analysis be required) are drawn together

When does NICE recommend the use of health technologies within a programme of evidence development?

This article is made available through the Brunel Open Access Publishing Fund. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background: There is growing interest internationally in linking reimbursement decisions with recommendations for further research. In the UK, the National Institute for Health and Clinical Excellence (NICE) can issue guidance to approve the routine use of a health intervention, reject routine use or recommend use within a research programme. These latter recommendations have restricted use to ‘only in research’ (OIR) or have recommended further research alongside routine use (‘approval with research’ or AWR). However, it is not currently clear when such recommendations are likely to be made. Objectives: This study aims to identify NICE technology appraisals where OIR or AWR recommendations were made and to examine the key considerations that led to those decisions. Methods: Draft and final guidance including OIR/AWR recommendations were identified. The documents were reviewed to establish the characteristics of the technology appraisal, the cost effectiveness of the technologies, the key considerations that led to the recommendations and the types of research required. Results: In total, 29 final and 31 draft guidance documents included OIR/AWR recommendations up to January 2010. Overall, 86 % of final guidance included OIR recommendations. Of these, the majority were for technologies considered to be cost ineffective (83 %) and the majority of final guidance (66 %) specified the need for further evidence on relative effectiveness. The use of OIR/AWR recommendations is decreasing over time and they have rarely been used in appraisals conducted through the single technology appraisal process. Conclusion: NICE has used its ability to recommend technologies within research programmes, although predominantly within the multiple technology appraisal process. OIR recommendations have been most frequently issued for technologies considered cost ineffective and the most frequently cited consideration is uncertainty related to relative effectiveness. Key considerations cited for most AWR recommendations and some OIR recommendations included a need for further evidence on long-term outcomes and adverse effects of treatment.Medical Research Counci

Population health outcomes in South Korea 1990-2019, and projections up to 2040: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: South Korea has one of the longest operating universal health coverage (UHC) systems. A comprehensive analysis of long-term trajectories of morbidity and mortality in the South Korean population after the inception of UHC is needed to inform health-care policy and practice. METHODS: We used data from the Global Burden of Disease Study (GBD) 2019 to present estimates of cause-specific mortality, incidence, prevalence, years of life lost (YLLs), years of life lived with disability, and disability-adjusted life-years (DALYs) in South Korea from 1990 to 2019. We also examined forecasted estimates of YLLs up to 2040 to investigate likely future changes in disease burden. Finally, we evaluated GBD estimates from seven comparator countries to place disease burden in South Korea within a broader context. FINDINGS: Age-standardised DALYs related to non-communicable diseases (NCDs) decreased by 43·6% (95% uncertainty interval [UI] 39·4-47·9) and mortality by 58·8% (55·9-60·5) from 1990 to 2019. In 2019, the ratio of male to female age-standardised rates of YLLs in South Korea was higher than the global average for 75·9% (22 of 29 diseases) of leading causes, indicating a disproportional disease burden on males in South Korea. Among risk factors, tobacco use accounted for the highest number of 2019 deaths (44 470 [95% UI 37 432-53 989]) in males and high systolic blood pressure for the highest number (21 014 [15 553-26 723]) in females. Among the top ten leading causes of YLLs forecast in South Korea in 2040, nine were NCDs, for both males and females. INTERPRETATION: Our report shows a positive landscape of population health outcomes in South Korea following the establishment of UHC. However, due in part to the effects of population ageing driving up medical expenditures for NCDs, financial pressures and sustainability challenges associated with UHC are pressing concerns. Policy makers should work to tackle population ageing and allocate resources efficiently by prioritising interventions that address the leading causes of death and disability identified in this study. FUNDING: Bill & Melinda Gates Foundation

Loss of the Promyelocytic Leukemia Protein in Gastric Cancer: Implications for IP-10 Expression and Tumor-Infiltrating Lymphocytes

Gastric cancer is one of the most common causes of cancer-related mortality worldwide. Expression of the tumor suppressor, promyelocytic leukemia (PML) protein, is reduced or abolished in gastric carcinomas, in association with an increased level of lymphatic invasion, development of higher pTNM staging, and unfavorable prognosis. Herein, we investigated the relationship between the extent of tumor-infiltrating lymphocytes and the status of PML protein expression in advanced gastric carcinoma. We observed higher numbers of infiltrating T-cells in gastric carcinoma tissues in which PML expression was reduced or abolished, compared to tissues positive for PML. The extent of T-cell migration toward culture supernatants obtained from interferon-gamma (IFN-γ-stimulated gastric carcinoma cell lines was additionally affected by expression of PML in vitro. Interferon-gamma-inducible protein 10 (IP-10/CXCL10) expression was increased in gastric carcinoma tissues displaying reduced PML levels. Moreover, both Pml knockout and knockdown cells displayed enhanced IP-10 mRNA and protein expression in the presence of IFN-γ. PML knockdown increased IFN-γ-mediated Signal Transducer and Activator of Transcription-1 (STAT-1) binding to the IP-10 promoter, resulting in elevated transcription of the IP-10 gene. Conversely, PML IV protein expression suppressed IP-10 promoter activation. Based on these results, we propose that loss of PML protein expression in gastric cancer cells contributes to increased IP-10 transcription via enhancement of STAT-1 activity, which, in turn, promotes lymphocyte trafficking within tumor regions

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Interaction of Apoptotic Cells with Macrophages Upregulates COX-2/PGE2 and HGF Expression via a Positive Feedback Loop

Recognition of apoptotic cells by macrophages is crucial for resolution of inflammation, immune tolerance, and tissue repair. Cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and hepatocyte growth factor (HGF) play important roles in the tissue repair process. We investigated the characteristics of macrophage COX-2 and PGE2 expression mediated by apoptotic cells and then determined how macrophages exposed to apoptotic cells in vitro and in vivo orchestrate the interaction between COX-2/PGE2 and HGF signaling pathways. Exposure of RAW 264.7 cells and primary peritoneal macrophages to apoptotic cells resulted in induction of COX-2 and PGE2. The COX-2 inhibitor NS-398 suppressed apoptotic cell-induced PGE2 production. Both NS-398 and COX-2-siRNA, as well as the PGE2 receptor EP2 antagonist, blocked HGF expression in response to apoptotic cells. In addition, the HGF receptor antagonist suppressed increases in COX-2 and PGE2 induction. The in vivo relevance of the interaction between the COX-2/PGE2 and HGF pathways through a positive feedback loop was shown in cultured alveolar macrophages following in vivo exposure of bleomycin-stimulated lungs to apoptotic cells. Our results demonstrate that upregulation of the COX-2/PGE2 and HGF in macrophages following exposure to apoptotic cells represents a mechanism for mediating the anti-inflammatory and antifibrotic consequences of apoptotic cell recognition

Intercalation of Transition Metals into Stacked Benzene Rings: A Model Study of the Intercalation of Transition Metals into Bilayered Graphene

Structures of neutral metal-dibenzene complexes, M(C6H6)(2) (M = Sc-Zn), are investigated by using Moller-Plesset second order perturbation theory (MP2). The benzene molecules change their conformation and shape upon complexation with the transition metals. We find two types of structures: (i) stacked forms for early transition metal complexes and (ii) distorted forms for late transition metal ones. The benzene molecules and the metal atom are bound together by delta bonds which originate from the interaction of pi-MOs and d orbitals. The binding energy shows a maximum for Cr(C6H6)(2), which obeys the 18-electron rule. It is noticeable that Mn(C6H6)(2), a 19-electron complex, manages to have a stacked structure with an excess electron delocalized. For other late transition metal complexes having more than 19 electrons, the benzene molecules are bent or stray away from each other to reduce the electron density around a metal atom. For the early transition metals, the M(C6H6) complexes are found to be more weakly bound than M(C6H6)(2). This is because the M(C6H6) complexes do not have enough electrons to satisfy the 18-electron rule, and so the M(C6H6)(2) complexes generally tend to have tighter binding with a shorter benzene-metal length than the M(C6H6) complexes, which is quite unusual. The present results could provide a possible explanation of why on the Ni surface graphene tends to grow in a few layers, while on the Cu surface the weak interaction between the copper surface and graphene allows for the formation of a single layer of graphene, in agreement with chemical vapor deposition experiments.X112729sciescopu

Gas6 Prevents Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells via Production of PGE2, PGD2 and Their Receptors

The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-β1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-β1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors