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We monitored the burden of cancer in Italy and its trends over the last three decades, providing estimates of cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs), for cancer overall and 30 cancer sites using data from the Global Burden of Disease study 2017. An overview of mortality trends between 1990 and 2017 was also provided. In 2017, there were 254,336 new cancer cases in men and 214,994 in women, corresponding to an age-standardized incidence rate (ASIR) of 438 and 330/100,000, respectively. Between 1990 and 2017, incident cancer cases, and, to a lesser extent, ASIRs significantly increased overall and for almost all cancer sites, but ASIRs significantly declined for lung and other tobacco-related neoplasms. In 2017, there were 101,659 cancer deaths in men (age-standardized death rate, ASDR, 158.5/100,000) and 78,918 in women (ASDR 93.9/100,000). Cancer deaths significantly increased between 1990 and 2017 (+ 18%), but ASDR significantly decreased (− 28%). Deaths significantly increased for many cancer sites, but decreased for stomach, esophageal, laryngeal, Hodgkin lymphoma, and testicular cancer. ASDRs significantly decreased for most neoplasms, with the main exceptions of cancer of the pancreas and uterus, and multiple myeloma. In 2017, cancer caused 3,204,000 DALYs. Between 1990 and 2017, DALYs and age-standardized DALY rates significantly declined (-3.4% and -33%, respectively). Age-standardized mortality rates in Italy showed favorable patterns over the last few decades. However, the absolute number of cancer cases and, to a lower extent, of cancer deaths increased likely due to the progressive ageing of the population, this calling for a continuous effort in cancer prevention, early diagnosis, and treatment.

Brain and CNS cancers (collectively referred to as CNS cancers) are a source of mortality and morbidity for which diagnosis and treatment require extensive resource allocation and sophisticated diagnostic and therapeutic technology. Previous epidemiological studies are limited to specific geographical regions or time periods, making them difficult to compare on a global scale. In this analysis, we aimed to provide a comparable and comprehensive estimation of the global burden of brain cancer between 1990 and 2016. We report means and 95% uncertainty intervals (UIs) for incidence, mortality, and disability-adjusted life-years (DALYs) estimates for CNS cancers (according to the International Classification of Diseases tenth revision: malignant neoplasm of meninges, malignant neoplasm of brain, and malignant neoplasm of spinal cord, cranial nerves, and other parts of CNS) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016. Data sources include vital registration and cancer registry data. Mortality was modelled using an ensemble model approach. Incidence was estimated by dividing the final mortality estimates by mortality to incidence ratios. DALYs were estimated by summing years of life lost and years lived with disability. Locations were grouped into quintiles based on the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. In 2016, there were 330 000 (95% UI 299 000 to 349 000) incident cases of CNS cancer and 227 000 (205 000 to 241 000) deaths globally, and age-standardised incidence rates of CNS cancer increased globally by 17·3% (95% UI 11·4 to 26·9) between 1990 and 2016 (2016 age-standardised incidence rate 4·63 per 100 000 person-years [4·17 to 4·90]). The highest age-standardised incidence rate was in the highest quintile of SDI (6·91 [5·71 to 7·53]). Age-standardised incidence rates increased with each SDI quintile. East Asia was the region with the most incident cases of CNS cancer for both sexes in 2016 (108 000 [95% UI 98 000 to 122 000]), followed by western Europe (49 000 [37 000 to 54 000]), and south Asia (31 000 [29 000 to 37 000]). The top three countries with the highest number of incident cases were China, the USA, and India. CNS cancer was responsible for 7·7 million (95% UI 6·9 to 8·3) DALYs globally, a non-significant change in age-standardised DALY rate of −10·0% (−16·4 to 2·6) between 1990 and 2016. The age-standardised DALY rate decreased in the high SDI quintile (−10·0% [–27·1 to −0·1]) and high-middle SDI quintile (−10·5% [–18·4 to −1·4]) over time but increased in the low SDI quintile (22·5% [11·2 to 50·5]). CNS cancer is responsible for substantial morbidity and mortality worldwide, and incidence increased between 1990 and 2016. Significant geographical and regional variation in the incidence of CNS cancer might be reflective of differences in diagnoses and reporting practices or unknown environmental and genetic risk factors. Future efforts are needed to analyse CNS cancer burden by subtype. Bill & Melinda Gates Foundation.

We have developed an automated die-scale process for the attachment of X-ray absorbers onto microcalorimeters. Here, we describe the process for the production of absorber tiles on a handle wafer, their attachment to the microcalorimeter, and the removal of the supporting handle wafer. The process is shown to be a robust path to large format arrays of microcalorimeters.

The Backshort-Under-Grid (BUG) superconducting bolometer array architecture is intended to be highly versatile, operating over a large range of wavelengths and background conditions. To validate the basic array design and to demonstrate its applicability for future kilopixel arrays, we will demonstrate a 128-element bolometer array optimized for 2 mm wavelength using a new Goddard Space Flight Center instrument, GISMO (Goddard IRAM Superconducting 2-Millimeter Observer). The design considerations unique to GISMO and laboratory experimental results will be discussed.

To investigate the objective sleep influencers behind older adult responses to subjective sleep measures, in this case, the Pittsburgh Sleep Quality Index (PSQI). Based on previous literature, we hypothesized that SE would be associated with PSQI reported sleep disruption. Furthermore, because SOL increases progressively with age and it tends to be easily remembered by the patients, we also expected it to be one of the main predictors of the perceived sleep quality in the elderly. We studied 32 cognitively healthy community-dwelling older adults (age 74 ± 0.3 years) who completed an at-home sleep assessment (Zeo, Inc.) and the PSQI. Linear mixed models were used to analyze the association of the objective sleep parameters (measured by the Zeo) with the PSQI total score and sub-scores, adjusting for age, gender, years of education and likelihood of sleep apnea. Objective sleep parameters did not show any association with the PSQI total score. We found that objective measures of Wake after sleep onset (WASO, % and min) were positively associated with the PSQI sleep disturbance component, while SE and Total Sleep Time (TST) were negatively associated with PSQI sleep disturbance. Lastly, objective SE was positively associated with PSQI SE. Our findings showed that WASO, SE and TST, are associated with PSQI sleep disturbance, where the greater WASO, overall lower SE and less TST, were associated with increased subjective report of sleep disturbance. As expected, subjective (PSQI) and objective measures of SE were related. However, PSQI total score did not relate to any of the objective measures. These results suggest that by focusing on the PSQI total score we may miss the insight this easily administered self-report tool can provide. If interpreted in the right way, the PSQI can provide further insight into cognitively healthy older adults that have the likelihood of objective sleep disturbance.

Nanomedicines have created a paradigm shift in healthcare. Yet fundamental barriers still exist that prevent or delay the clinical translation of nanomedicines. Critical hurdles inhibiting clinical success include poor understanding of nanomedicines’ physicochemical properties, limited exposure in the cell or tissue of interest, poor reproducibility of preclinical outcomes in clinical trials, and biocompatibility concerns. Barriers that delay translation include industrial scale-up or scale-down and good manufacturing practices, funding and navigating the regulatory environment. Here we propose the DELIVER framework comprising the core principles to be realized during preclinical development to promote clinical investigation of nanomedicines. The proposed framework comes with design, experimental, manufacturing, preclinical, clinical, regulatory and business considerations, which we recommend investigators to carefully review during early-stage nanomedicine design and development to mitigate risk and enable timely clinical success. By reducing development time and clinical trial failure, it is envisaged that this framework will help accelerate the clinical translation and maximize the impact of nanomedicines. The authors propose a framework to be followed during preclinical investigation of nanomedicines to increase their translatability potential.

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters—preferably in vivo—plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. Good–bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.

Long-acting injectables are considered one of the most promising therapeutic strategies for the treatment of chronic diseases as they can afford improved therapeutic efficacy, safety, and patient compliance. The use of polymer materials in such a drug formulation strategy can offer unparalleled diversity owing to the ability to synthesize materials with a wide range of properties. However, the interplay between multiple parameters, including the physicochemical properties of the drug and polymer, make it very difficult to intuitively predict the performance of these systems. This necessitates the development and characterization of a wide array of formulation candidates through extensive and time-consuming in vitro experimentation. Machine learning is enabling leap-step advances in a number of fields including drug discovery and materials science. The current study takes a critical step towards data-driven drug formulation development with an emphasis on long-acting injectables. Here we show that machine learning algorithms can be used to predict experimental drug release from these advanced drug delivery systems. We also demonstrate that these trained models can be used to guide the design of new long acting injectables. The implementation of the described data-driven approach has the potential to reduce the time and cost associated with drug formulation development. Polymer-based long-acting injectable drugs are a promising therapeutic strategy for chronic diseases. Here the authors use machine learning to inform the data-driven development of advanced drug formulations.

Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745 Renal cell cancers with mutations in a specific chromatin regulator have a better clinical response to immunotherapy. Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti–PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene ( P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti–CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1 -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase–signal transducers and activators of transcription), hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.

The role of IL-6 in obesity-associated inflammation remains controversial. Bruening and colleagues identify signaling by IL-6 as an important determinant for the alternative activation of macrophages during inflammation. Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells ( Il6ra Δmyel mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra Δmyel mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.