Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease.

OBJECTIVES: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD. METHODS: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance. RESULTS: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer. CONCLUSIONS: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events.

BACKGROUND: Rheumatic immune-related adverse events (R-irAEs) occur in 5-15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer and R-irAEs outcomes with particular focus on adverse effects of anti-inflammatory treatment. METHODS: In this prospective, multicenter, long-term, observational study, R-irAEs were comprehensively analyzed in patients with malignant melanoma (MM, n=50) and non-small cell lung cancer (NSCLC, n=41) receiving ICI therapy who were enrolled in the study between August 1, 2018, and December 11, 2022. RESULTS: After a median follow-up of 33 months, progressive disease or death occurred in 66.0% and 30.0% of MM and 63.4% and 39.0% of patients with NSCLC. Male sex (progression-free survival (PFS): p=0.013, and overall survival (OS): p=0.009), flare of a pre-existing condition (vs de novo R-irAE, PFS: p=0.010) and in trend maximum glucocorticoid (GC) doses >10 mg and particularly ≥1 mg/kg prednisolone equivalent (sex-adjusted PFS: p=0.056, OS: p=0.051) were associated with worse cancer outcomes. Patients receiving disease-modifying antirheumatic drugs (DMARDs) showed significantly longer PFS (n=14, p=0.011) and OS (n=20, p=0.018). Effects of these variables on PFS and/or OS persisted in adjusted Cox regression models. Additionally, GC treatment negatively correlated with the time from diagnosis of malignancy and the latency from ICI start until R-irAE onset (all p<0.05). R-irAE features and outcomes were independent of other baseline patient characteristics in both studied cancer entities. CONCLUSION: Male sex, flare of pre-existing rheumatologic conditions and extensive GC treatment appeared to be linked with unfavorable cancer outcomes, while DMARD use had a favorable impact. These findings challenge the current dogma of restrictive DMARD use for R-irAE and thus may pave the way to better strategies and randomized controlled trials for the growing number of patients with R-irAE.

Schools at the Rural-Urban Boundary - Blurring the Divide?

Schools mirror the communities in which they are located. Research on school inequality across the rural-urban spectrum tends to focus on the contrast between urban, suburban, and rural schools and glosses over the variation within these areas as well as the similarities between them. To address this gap and provide a richer description of the spatial distribution of educational inequality, we examine the school composition, achievement, and resources of all U.S. elementary schools in 2010-2011. We apply standard census definitions of what areas fall within central cities, the remainder of metropolitan regions, and in rural America. We then apply spatially explicit methods to reveal blurred boundaries and gradual gradients rather than sharp breaks at the edges of these zones. The results show high levels of variation within the suburbs and substantial commonality between rural and urban areas.

School Segregation and Disparities in Urban, Suburban, and Rural Areas.

Much of the literature on racial and ethnic educational inequality focuses on the contrast between Black and Hispanic students in urban areas and white suburban students. This study extends past research on school segregation and racial/ethnic disparities by highlighting the importance of rural areas and regional variation. Although schools in rural America are disproportionately white, they nevertheless are like urban schools, and disadvantaged relative to suburban schools, in terms of poverty and test performance. The group most affected by rural school disadvantage is Native Americans, who are a small share of students nationally but much more prominent and highly disadvantaged in rural areas, particularly in some parts of the country. These figures suggest a strong case for including rural schools in the continuing conversation about how to deal with unfairness in public education.

School Segregation, Charter Schools, and Access to Quality Education.

Race, class, neighborhood, and school quality are all highly inter-related in the American educational system. In the last decade a new factor has come into play, the option of attending a charter school. We offer a comprehensive analysis of the disparities among public schools attended by white, black, Hispanic, Asian, and Native American children in 2010-2011, including all districts in which charter schools existed. We compare schools in terms of poverty concentration, racial composition, and standardized test scores, and we also examine how attending a charter or non-charter school affects these differences. Black and Hispanic (and to a lesser extent Native American and Asian) students attend elementary and high schools with higher rates of poverty than white students. Especially for whites and Asians, attending a charter school means lower exposure to poverty. Children's own race and the poverty and charter status of their schools affect the test scores and racial isolation of schools that children attend in complex combinations. Most intriguing, attending a charter school means attending a better performing school in high-poverty areas but a lower performing school in low-poverty areas. Yet even in the best case the positive effect of attending a charter school only slightly offsets the disadvantages of black and Hispanic students.

Neighborhood Violent Crime and Academic Growth in Chicago: Lasting Effects of Early Exposure.

A large body of research documents the importance of early experiences for later academic, social, and economic success. Exposure to an unsafe neighborhood is no exception. Living in a violent neighborhood can influence the stress levels, protective behaviors, and community interactions of both parents and children in ways that generate cumulative educational disadvantage. Using nine years (2002-2011) of detailed crime data from the Chicago Police Department and longitudinal administrative data from the Chicago Public Schools, I estimate the influence of early exposure to neighborhood violence on growth in standardized test scores over time. Student fixed-effects are included to remove any bias due to constant differences between students. The results show that children from more violent neighborhoods fall farther behind their peers from safer neighborhoods as they progress through school. These effects are comparable in size to the independent association with socioeconomic disadvantage and an annual measure of more recent neighborhood violence exposure.

Formation and in vitro biocompatibility of biomimetic hydroxyapatite coatings on chemically treated carbon substrates.

Carbon derived materials such as pyrolytic carbon or carbon-carbon composites (CCCs) exhibit excellent mechanical properties making them promising candidates for bone replacement. However, these materials are considered bioinert and not to induce bone formation in vivo. In this study, a two-step chemical surface treatment including etching with HCl/HNO3 solution and subsequent soaking in CaCl2 solution was applied to carbon substrates in order to activate the materials surface towards bioactive behavior. The bioactivity was proven by soaking the samples in simulated body fluid (SBF) and formation of carbonated hydroxyapatite layer (HCA), which indicates the ability of the material to bond to bone in vivo. The materials surface is shown to be functionalized through the chemical etching creating COO(-)Ca(2+) complexes on the surface as confirmed by FTIR and XPS analyses. These ionic complexes provide nucleation sites for HAp precipitation. After similar immersion time in SBF under the condition of local supersaturation the thickness and homogeneity of the HAp layer were found to depend on the chemical pretreatment with HCl/HNO3. Homogenous HAp layers with a thickness ranging from ∼ 6 to ∼ 17 µm were achieved. The proposed bioactivating treatment of carbon stimulates HAp formation in vivo and can be considered an easy biomimetic approach for coating carbon derived materials with bone-like hydroxyapatite. In vitro cell assay with osteosarcoma cells (MG-63) showed increased cell viability (+70%) on HAp coated carbon substrates as compared to uncoated reference while both materials induced ALP expression in MG-63 cells confirming the osteoblastic phenotype.

Reticulated bioactive scaffolds with improved textural properties for bone tissue engineering: nanostructured surfaces and porosity.

Organised nanoporous SBA-15 type silica precursor (SP) particulate material has been processed into three-dimensional macroporous, reticulated structures using a novel strategy consisting of blending increasing percentages of SP with a SiO2 -CaO-P2 O5 (80Si15Ca5P) mesoporous bioactive glass (MBG) sol. The procedure successfully produced consolidated and functionally competent open-cell scaffolds while preserving the nanoporous order of the SP. Scaffolds were prepared using four different (MBG)/(SP) ratios. These structures were then characterized using field emission gun scanning electron microscopy, X-ray diffraction (XRD), nitrogen adsorption-desorption measurements, and compressive strength testing. Open-cell interconnected structures with dual macro (150-500 µm) and nano (4-6 nm)-organised porosity were produced. Both the textural and mechanical properties were found to improve with increasing SBA-15 content. The in vitro bioactive response using simulated body fluid confirmed high reactivity for all prepared scaffolds. In addition, the SBA-15 containing scaffolds exhibited a superior ability to delay the pH-triggered lysozyme release with antibiotic activity.

School Violent Crime and Academic Achievement in Chicago.

Educational outcomes vary dramatically across schools in the United States. Many under-performing schools, especially in Chicago, also deal with high levels of violent crime on school grounds. Exposure to this type of frequent violence may be an important factor shaping already disadvantaged students' educational experiences. However, estimating the effect of school violence on learning is difficult due to potential selection bias and the confounding of other school-level problems. Using detailed crime data from the Chicago Police Department, complete administrative records from the Chicago Public Schools, and school climate surveys conducted by the Consortium on Chicago School Research (2002-10), this study exploits variation in violent crime rates within schools over time to estimate its effect on academic achievement. School and neighborhood fixed-effects models show that violent crime rates have a negative effect on test scores, but not on grades. This effect is more likely related to direct reductions in learning, through cognitive stress and classroom disruptions, than changes in perceived safety, general school climate, or discipline practices.

Bioactive glass-based scaffolds for bone tissue engineering.

Originally developed to fill and restore bone defects, bioactive glasses are currently also being intensively investigated for bone tissue engineering applications. In this chapter, we review and discuss current knowledge on porous bone tissue engineering scaffolds made from bioactive silicate glasses. A brief historical review and the fundamental requirements in the field of bone tissue engineering scaffolds will be presented, followed by a detailed overview of recent developments in bioactive glass-based scaffolds. In addition, the effects of ionic dissolution products of bioactive glasses on osteogenesis and angiogenic properties of scaffolds are briefly addressed. Finally, promising areas of future research and requirements for the advancement of the field are highlighted and discussed.

The role of prenucleation clusters in surface-induced calcium phosphate crystallization.

Unravelling the processes of calcium phosphate formation is important in our understanding of both bone and tooth formation, and also of pathological mineralization, for example in cardiovascular disease. Serum is a metastable solution from which calcium phosphate precipitates in the presence of calcifiable templates such as collagen, elastin and cell debris. A pathological deficiency of inhibitors leads to the uncontrolled deposition of calcium phosphate. In bone and teeth the formation of apatite crystals is preceded by an amorphous calcium phosphate (ACP) precursor phase. ACP formation is thought to proceed through prenucleation clusters--stable clusters that are present in solution already before nucleation--as was recently demonstrated for CaCO(3) (refs 15,16). However, the role of such nanometre-sized clusters as building blocks for ACP has been debated for many years. Here we demonstrate that the surface-induced formation of apatite from simulated body fluid starts with the aggregation of prenucleation clusters leading to the nucleation of ACP before the development of oriented apatite crystals.

Bioactivation of biomorphous silicon carbide bone implants.

Wood-derived silicon carbide (SiC) offers a specific biomorphous microstructure similar to the cellular pore microstructure of bone. Compared with bioactive ceramics such as calcium phosphate, however, silicon carbide is considered not to induce spontaneous interface bonding to living bone. Bioactivation by chemical treatment of biomorphous silicon carbide was investigated in order to accelerate osseointegration and improve bone bonding ability. Biomorphous SiC was processed from sipo (Entrandrophragma utile) wood by heating in an inert atmosphere and infiltrating the resulting carbon replica with liquid silicon melt at 1450°C. After removing excess silicon by leaching in HF/HNO3 the biomorphous preform consisted of ß-SiC with a small amount (approximately 6wt.%) of unreacted carbon. The preform was again leached in HCl/HNO3 and finally exposed to CaCl2 solution. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared analyses proved that oxidation of the residual carbon at the surface induced formation of carboxyl [COO⁻] groups, which triggered adsorption of Ca(2+), as confirmed by XPS and inductively coupled plasma optical emission spectroscopy measurements. A local increase in Ca(2+) concentration stimulated in vitro precipitation of Ca5(PO4)3OH (HAP) on the silicon carbide preform surface during exposure to simulated body fluid, which indicates a significantly increased bone bonding activity compared with SiC.

Biomorphous porous hydroxyapatite-ceramics from rattan (Calamus Rotang).

The three-dimensional, highly oriented pore channel anatomy of native rattan (Calamus rotang) was used as a template to fabricate biomorphous hydroxyapatite (Ca(5)(PO(4))(3)OH) ceramics designed for bone regeneration scaffolds. A low viscous hydroxyapatite-sol was prepared from triethyl phosphite and calcium nitrate tetrahydrate and repeatedly vacuum infiltrated into the native template. The template was subsequently pyrolysed at 800 degrees C to form a biocarbon replica of the native tissue. Heat treatment at 1,300 degrees C in air atmosphere caused oxidation of the carbon skeleton and sintering of the hydroxyapatite. SEM analysis confirmed detailed replication of rattan anatomy. Porosity of the samples measured by mercury porosimetry showed a multimodal pore size distribution in the range of 300 nm to 300 microm. Phase composition was determined by XRD and FT-IR revealing hydroxyapatite as the dominant phase with minimum fractions of CaO and Ca(3)(PO(4))(2). The biomorphous scaffolds with a total porosity of 70-80% obtained a compressive strength of 3-5 MPa in axial direction and 1-2 MPa in radial direction of the pore channel orientation. Bending strength was determined in a coaxial double ring test resulting in a maximum bending strength of approximately 2 MPa.

Porous ceramic bone scaffolds for vascularized bone tissue regeneration.

Hydroxyapatite scaffolds with a multi modal porosity designed for use in tissue engineering of vascularized bone graft substitutes were prepared by three dimensional printing. Depending on the ratio of coarse (mean particle size 50 microm) to fine powder (mean particle size 4 microm) in the powder granulate and the sintering temperature total porosity was varied from 30% to 64%. While macroscopic pore channels with a diameter of 1 mm were created by CAD design, porosity structure in the sintered solid phase was governed by the granulate structure of the printing powder. Scaffolds sintered at 1,250 degrees C were characterized by a bimodal pore structure with intragranular pores of 0.3-0.4 microm and intergranular pores of 20 microm whereas scaffolds sintered at 1,400 degrees C exhibit a monomodal porosity with a maximum of pore size distribution at 10-20 microm. For in-vivo testing, matrices were implanted subcutaneously in four male Lewis rats. Scaffolds with 50% porosity and an average pore size of approximately 18 microm were successfully transferred to rats and vascularized within 4 weeks.