Immune-Mediated Inflammatory Diseases and Cancer - a dangerous liaison.

Patients with Immune-Mediated Inflammatory Diseases (IMIDs) are known to have an elevated risk of developing cancer, but the exact causative factors remain subject to ongoing debate. This narrative review aims to present the available evidence concerning the intricate relationship between these two conditions. Environmental influences and genetic predisposition lead to a dysregulated immune response resulting in chronic inflammation, which is crucial in the pathogenesis of IMIDs and oncogenic processes. Mechanisms such as the inflammatory microenvironment, aberrant intercellular communication due to abnormal cytokine levels, excessive reparative responses, and pathological angiogenesis are involved. The chronic immunosuppression resulting from IMIDs treatments further adds to the complexity of the pathogenic scenario. In conclusion, this review highlights critical gaps in the current literature, suggesting potential avenues for future research. The intricate interplay between IMIDs and cancer necessitates more investigation to deepen our understanding and improve patient management.

A key factor in monitoring cannabis consumption trends through wastewater analysis: Partitioning of THCCOOH between the liquid and solid phase of influent wastewater.

Current wastewater-based epidemiology (WBE) studies are predominantly focused on the analysis of urinary biomarkers present in the liquid phase of influent wastewater (IWW). This approach systematically underestimates less polar metabolites, such as cannabis biomarkers. These biomarkers can potentially sorb to and desorb from suspended particulate matter (SPM) present in IWW. This study investigates the bidirectional partitioning of THCCOOH between the liquid phase and SPM of IWW by performing multiple sorption experiments using THCCOOH-D9 as a surrogate due to the unavailability of blank SPM and blank IWW. In addition, this study involves the analysis of IWW collected from eight wastewater treatment plants (WWTP) (n = 56) across four European countries, where raw IWW, the liquid phase and SPM were separately analysed to identify potential trends in the fraction of THCCOOH in the SPM between and withing the examined locations. Based on the performed sorption experiments, bidirectional partitioning of THCCOOH between the liquid phase and SPM was noted, showing partition between both phases when only one of the two phases was spiked. It was illustrated that the concentration of SPM had a notable influence on the THCCOOH partitioning between both phases. In addition to the inter location variability (average THCCOOH present in the SPM ranged 31-59 %), a substantial intra location variation was also observed, e.g., in one location ranged 17-58 %. While the determination of a correction factor for the amount of THCCOOH present in SPM would be ideal, this is challenging, since the amount of SPM is not fixed in all IWW samples. Although SPM has influence on the THCCOOH partition, no correlation (p value Spearman correlation = 0.3160) was observed between the SPM concentration and the fraction of THCCOOH in the solid phase. Moreover, the collection of homogenized samples is difficult, and the time required to reach an equilibration in partitioning of THCCOOH between both IWW phases remains unclear. Due to i) the large inter-and intra-location variation of THCCOOH present in the SPM, ii) the variability in SPM concentration in IWW samples, and iii) the time required to reach a partitioning equilibration, an analytical procedure based on liquid-liquid extraction (LLE) that considers both the liquid phase and SPM of IWW is recommended to reduce the overall uncertainty for THCCOOH measurement in IWW. It was illustrated that this extraction method is capable to recover the total concentration of THCCOOH in both phases.

The central role of magnesium in skeletal muscle: from myogenesis to performance.

A physiological concentration of magnesium (Mg) is essential for optimal skeletal muscle function. Indeed, Mg plays a crucial role during the differentiation process (myogenesis), in muscle fiber composition, muscle contraction and performance. This narrative review describes in detail the relevance of Mg in skeletal muscle, highlighting the importance of adequate Mg intake to ensure optimal skeletal muscle cell function and performance in individuals of all ages.

Placental Bioenergetics and Antioxidant Homeostasis in Maternal Obesity and Gestational Diabetes.

Maternal obesity has been associated with short- and long-term risks of pregnancy-perinatal adverse events, possibly due to alterations of placental mitochondrial bioenergetics. However, several detrimental mechanisms occurring in the placentas of women with obesity still need to be clarified. Here, we analyzed placental mitochondrial features and oxidative environment of 46 pregnancies in relation to pre-pregnancy BMI. Seventeen Caucasian normal-weight (NW) and twenty-nine women who were obese (OB) were enrolled. The protein expression of mitochondrial CypD and electron transfer chain complexes (C) I-V were measured, as well as ATP production and oxygen consumption rates (OCRs). The protein levels of the pro/anti-oxidant enzymes TXNIP, SOD2, and PON2 were also analyzed. Despite no differences in CypD expression, OCRs were significantly lower in OB vs. NW women. Accordingly, ATP synthase (CV) levels and ATP content were decreased in OB women, positively correlating with placental efficiency, suggesting a link between ATP deficiency and placental dysfunction. SOD2 expression negatively correlated with maternal BMI, indicating a possible impairment of antioxidant defenses with increasing BMI. These changes were worsened in 10 OB women presenting with gestational diabetes mellitus. Overall, these results suggest alterations of placental bioenergetics in pregnancies of women with obesity, possibly leading to placental dysfunction and altered fetal development and programming.

Impact of Inducible Nitric Oxide Synthase Activation on Endothelial Behavior under Magnesium Deficiency.

Endothelial dysfunction is a crucial event in the early pathogenesis of cardiovascular diseases and is linked to magnesium (Mg) deficiency. Indeed, in endothelial cells, low Mg levels promote the acquisition of a pro-inflammatory and pro-atherogenic phenotype. This paper investigates the mechanisms by which Mg deficiency promotes oxidative stress and affects endothelial behavior in human umbilical vascular endothelial cells (HUVECs). Our data show that low Mg levels trigger oxidative stress initially by increasing NAPDH oxidase activity and then by upregulating the pro-oxidant thioredoxin-interacting protein TXNIP. The overproduction of reactive oxygen species (ROS) activates NF-κB, leading to its increased binding to the inducible nitric oxide synthase (iNOS) promoter, with the consequent increase in iNOS expression. The increased levels of nitric oxide (NO) generated by upregulated iNOS contribute to disrupting endothelial cell function by inhibiting growth and increasing permeability. In conclusion, we provide evidence that multiple mechanisms contribute to generate a pro-oxidant state under low-Mg conditions, ultimately affecting endothelial physiology. These data add support to the notion that adequate Mg levels play a significant role in preserving cardiovascular health and may suggest new approaches to prevent or manage cardiovascular diseases.

Daratumumab-based regimens for patients with multiple myeloma plus extramedullary plasmacytomas or paraskeletal plasmacytomas: initial follow-up of an Italian multicenter observational clinical experience.

Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients.

How to obtain an integrated picture of the molecular networks involved in adaptation to microgravity in different biological systems?

Periodically, the European Space Agency (ESA) updates scientific roadmaps in consultation with the scientific community. The ESA SciSpacE Science Community White Paper (SSCWP) 9, "Biology in Space and Analogue Environments", focusses in 5 main topic areas, aiming to address key community-identified knowledge gaps in Space Biology. Here we present one of the identified topic areas, which is also an unanswered question of life science research in Space: "How to Obtain an Integrated Picture of the Molecular Networks Involved in Adaptation to Microgravity in Different Biological Systems?" The manuscript reports the main gaps of knowledge which have been identified by the community in the above topic area as well as the approach the community indicates to address the gaps not yet bridged. Moreover, the relevance that these research activities might have for the space exploration programs and also for application in industrial and technological fields on Earth is briefly discussed.

Plastics in biogenic matrices intended for reuse in agriculture and the potential contribution to soil accumulation.

The spread of biogenic matrices for agricultural purposes can lead to plastic input into soils, raising a question on possible consequences for the environment. Nonetheless, the current knowledge concerning the presence of plastics in biogenic matrices is very poor. Therefore, the objective of the present study was a quali-quantitative characterization of plastics in different matrices reused in agriculture as manures, digestate, compost and sewage sludges. Plastics were quantified and characterized using a Fourier Transform Infrared Spectroscopy coupled with an optical microscope (µFT-IR) in Attenuated Total Reflectance mode. Our study showed the presence of plastics in all the investigated samples, albeit with differences in the content among the matrices. We measured a lower presence in animal matrices (0.06-0.08 plastics/g wet weight w.w.), while 3.14-5.07 plastics/g w.w. were measured in sewage sludges. Fibres were the prevalent shape and plastic debris were mostly in the micrometric size. The most abundant polymers were polyester (PEST), polypropylene (PP) and polyethylene (PE). The worst case was observed in the compost sample, where 986 plastics/g w.w. were detected. The majority of these plastics were compostable and biodegradable, with only 8% consisting of fragments of PEST and PE. Our results highlighted the need to thoroughly evaluate the contribution of reused matrices in agriculture to the plastic accumulation in the soil system.

Influent wastewater analysis to investigate emerging trends of new psychoactive substances use in Europe.

Wastewater-based epidemiology (WBE) can provide objective and timely information on the use of new psychoactive substances (NPS), originally designed as legal alternatives of internationally controlled drugs. NPS have rapidly emerged on the global drug market, posing a challenge to drug policy and constituting a risk to public health. In this study, a WBE approach was applied to monitor the use of more than 300 NPS, together with fentanyl and its main metabolite norfentanyl, in influent wastewater collected from 12 European cities during March-June 2021. Quantitative and qualitative analysis of NPS in composite 24 h influent wastewater samples were based on solid phase extraction and liquid chromatography-mass spectrometry. In-sample stability tests demonstrated the suitability of most investigated biomarkers, except for a few synthetic opioids, synthetic cannabinoids and phenetylamines. Fentanyl, norfentanyl and eight NPS were quantified in influent wastewater and at least three substances were found in each city, demonstrating their use in Europe. N,N-dimethyltryptamine and 3-methylmethcathinone (3-MMC) were the most common NPS found, with the latter having the highest mass loads (up to 24.8 mg/day/1000 inhabitants). Seven additional substances, belonging to five categories of NPS, were identified in different cities. Spatial trends of NPS use were observed between cities and countries, and a changing weekly profile of use was observed for 3-MMC. WBE is a useful tool to rapidly evaluate emerging trends of NPS use, complementing common indicators (i.e. population surveys, seizures) and helping to establish measures for public health protection.

To spread or not to spread? Assessing the suitability of sewage sludge and other biogenic wastes for agriculture reuse.

Sewage sludge (biosolids) management represents a worldwide issue. Due to its valuable properties, approximately one half of the EU production is recovered in agriculture. Nevertheless, growing attention is given to potential negative effects deriving from the presence of harmful pollutants. It is recognized that a (even very detailed) chemical characterization is not able to predict ecotoxicity of a mixture. However, this can be directly measured by bioassays. Actually, the choice of the most suitable tests is still under debate. This paper presents a multilevel characterization protocol of sewage sludge and other organic residues, based on bioassays and chemical-physical-microbiological analyses. The detailed description of the experimental procedure includes all the involved steps: the criteria for selecting the organic matrices to be tested and compared; the sample pre-treatment required before the analyses execution; the chemical, physical and microbiological characterisation; the bioassays, grouped in three classes (baseline toxicity; specific mode of action; reactive mode of action); data processing. The novelty of this paper lies in the integrated use of advanced tools, and is based on three pillars:•the direct ecosafety assessment of the matrices to be reused.•the adoption of innovative bioassays and analytical procedures.•the original criteria for data normalization and processing.

How are cell and tissue structure and function influenced by gravity and what are the gravity perception mechanisms?

Progress in mechanobiology allowed us to better understand the important role of mechanical forces in the regulation of biological processes. Space research in the field of life sciences clearly showed that gravity plays a crucial role in biological processes. The space environment offers the unique opportunity to carry out experiments without gravity, helping us not only to understand the effects of gravitational alterations on biological systems but also the mechanisms underlying mechanoperception and cell/tissue response to mechanical and gravitational stresses. Despite the progress made so far, for future space exploration programs it is necessary to increase our knowledge on the mechanotransduction processes as well as on the molecular mechanisms underlying microgravity-induced cell and tissue alterations. This white paper reports the suggestions and recommendations of the SciSpacE Science Community for the elaboration of the section of the European Space Agency roadmap "Biology in Space and Analogue Environments" focusing on "How are cells and tissues influenced by gravity and what are the gravity perception mechanisms?" The knowledge gaps that prevent the Science Community from fully answering this question and the activities proposed to fill them are discussed.

Low extracellular magnesium induces phenotypic and metabolic alterations in C2C12-derived myotubes.

Magnesium (Mg) has a pivotal role in upholding skeletal muscle health and optimizing performance. Its deficiency decreases muscle strength, and an association has been reported between Mg intake and sarcopenia. To gain a comprehensive understanding of the repercussions arising from low Mg concentrations on muscle behavior, we employed an in vitro model utilizing C2C12-derived myotubes. Myotubes cultured in low Mg show a significant reduction of thickness and a concomitant down-regulation of myosin heavy chain (MyHC), Myog and Myomixer. In parallel, myotubes shape their metabolism. Glycolysis is inhibited and beta-oxidation increases. These metabolic changes are consistent with the increase of MyHC I (slow) vs. MyHC II (fast) expression. We identified an essential player in these changes, namely nitric oxide (NO), as the increase in NO production appeared to orchestrate the observed modifications in myotube behavior and metabolism under low Mg conditions. Understanding these underlying mechanisms may pave the way for targeted interventions to ameliorate muscle-related conditions associated with Mg deficiency and contribute to enhancing overall muscle health and function.

How do gravity alterations affect animal and human systems at a cellular/tissue level?

The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: "How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?" This is one of the five major scientific issues of the ESA roadmap "Biology in Space and Analogue Environments". Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects.

Aging and Vascular Disease: A Multidisciplinary Overview.

Vascular aging, i.e., the deterioration of the structure and function of the arteries over the life course, predicts cardiovascular events and mortality. Vascular degeneration can be recognized before becoming clinically symptomatic; therefore, its assessment allows the early identification of individuals at risk. This opens the possibility of minimizing disease progression. To review these issues, a search was completed using PubMed, MEDLINE, and Google Scholar from 2000 to date. As a network of clinicians and scientists involved in vascular medicine, we here describe the structural and functional age-dependent alterations of the arteries, the clinical tools for an early diagnosis of vascular aging, and the cellular and molecular events implicated. It emerges that more studies are necessary to identify the best strategy to quantify vascular aging, and to design proper physical activity programs, nutritional and pharmacological strategies, as well as social interventions to prevent, delay, and eventually revert the disease.

Wastewater-based epidemiology revealed in advance the increase of enterovirus circulation during the Covid-19 pandemic.

Wastewater-based epidemiology (WBE) was conducted to track Enteroviruses (EVs) circulation in the Milan metropolitan area (Northern Italy) during Covid-19 pandemic (March 2020-December 2022). 202 composite 24-hour wastewater samples (WWSs) were collected weekly from March 24, 2020, to December 29, 2022 at the inlet of two wastewater treatment plants (WWTP) in Milan (1.5 million inhabitants). EV-RNA was quantified and molecular characterization of non-polio EVs (NPEV) was performed by Sanger sequence analysis. Data from WWS were matched with virological data collected in the framework of Influenza-Like Illness (ILI) surveillance in the same place and time. EV-RNA was identified in 88.2 % of WWSs. The peak in EVs circulation was observed in late August 2020 (upon conclusion of the first national lockdown), in late August 2021, and in mid-April 2022. EV-RNA concentration in WWS (normalized as copies/d/1000 people) at peak of circulation presented a yearly increase (2020: 2.47 × 1010; 2021: 6.81 × 1010; 2022: 2.14 × 1011). This trend overlapped with trend in EV-positivity rate in ILI cases, expanded from 21.7 % in 2021 to 55.6 % in 2022. EV trends in WWS preceded clinical sample detections in 2021 and 2022 by eight and five weeks, respectively, acting as an early warning of outbreak. Although sequencing of EV-positive WWSs revealed the presence of multiple EV strains, typing remained inconclusive. Molecular characterization of EVs in clinical samples revealed the co-circulation of several genotypes: EV-A accounted for 60 % of EVs, EV-B for 16.7 %, EV-D68 for 23.3 %. EVs were circulating in Milan metropolitan area between March 2020 and December 2022. The epidemiological trends unfolded the progressive accumulation of EV transmission in the population after removal of Covid-19 restrictions. The increased circulation of EVs in 2021-2022 was identified at least 35 days in advance compared to the analysis of clinical data. The inconclusive results of Sanger sequencing lookout for improvement and innovative molecular approaches to deepen track EVs.

Three years of wastewater surveillance for new psychoactive substances from 16 countries.

The proliferation of new psychoactive substances (NPS) over recent years has made their surveillance complex. The analysis of raw municipal influent wastewater can allow a broader insight into community consumption patterns of NPS. This study examines data from an international wastewater surveillance program that collected and analysed influent wastewater samples from up to 47 sites in 16 countries between 2019 and 2022. Influent wastewater samples were collected over the New Year period and analysed using validated liquid chromatography - mass spectrometry methods. Over the three years, a total of 18 NPS were found in at least one site. Synthetic cathinones were the most found class followed by phenethylamines and designer benzodiazepines. Furthermore, two ketamine analogues, one plant based NPS (mitragynine) and methiopropamine were also quantified across the three years. This work demonstrates that NPS are used across different continents and countries with the use of some more evident in particular regions. For example, mitragynine has highest mass loads in sites in the United States, while eutylone and 3-methylmethcathinone increased considerably in New Zealand and in several European countries, respectively. Moreover, 2F-deschloroketamine, an analogue of ketamine, has emerged more recently and could be quantified in several sites, including one in China, where it is considered as one of the drugs of most concern. Finally, some NPS were detected in specific regions during the initial sampling campaigns and spread to additional sites by the third campaign. Hence, wastewater surveillance can provide an insight into temporal and spatial trends of NPS use.

The Interplay between TRPM7 and MagT1 in Maintaining Endothelial Magnesium Homeostasis.

The transient receptor potential cation channel subfamily M member 7 (TRPM7) is an ubiquitous channel fused to an α-kinase domain involved in magnesium (Mg) transport, and its level of expression has been proposed as a marker of endothelial function. To broaden our present knowledge about the role of TRPM7 in endothelial cells, we generated stable transfected Human Endothelial Cells derived from the Umbilical Vein (HUVEC). TRPM7-silencing HUVEC maintain the actin fibers' organization and mitochondrial network. They produce reduced amounts of reactive oxygen species and grow faster than controls. Intracellular Mg concentration does not change in TRPM7-silencing or -expressing HUVEC, while some differences emerged when we analyzed intracellular Mg distribution. While the levels of the plasma membrane Mg transporter Solute Carrier family 41 member 1 (SLC41A1) and the mitochondrial channel Mrs2 remain unchanged, the highly selective Magnesium Transporter 1 (MagT1) is upregulated in TRPM7-silencing HUVEC through transcriptional regulation. We propose that the increased amounts of MagT1 grant the maintenance of intracellular Mg concentrations when TRPM7 is not expressed in endothelial cells.

Cluster-Assembled Zirconia Substrates Accelerate the Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.

Due to their high mechanical strength and good biocompatibility, nanostructured zirconia surfaces (ns-ZrOx) are widely used for bio-applications. Through supersonic cluster beam deposition, we produced ZrOx films with controllable roughness at the nanoscale, mimicking the morphological and topographical properties of the extracellular matrix. We show that a 20 nm ns-ZrOx surface accelerates the osteogenic differentiation of human bone marrow-derived MSCs (bMSCs) by increasing the deposition of calcium in the extracellular matrix and upregulating some osteogenic differentiation markers. bMSCs seeded on 20 nm ns-ZrOx show randomly oriented actin fibers, changes in nuclear morphology, and a reduction in mitochondrial transmembrane potential when compared to the cells cultured on flat zirconia (flat-ZrO2) substrates and glass coverslips used as controls. Additionally, an increase in ROS, known to promote osteogenesis, was detected after 24 h of culture on 20 nm ns-ZrOx. All the modifications induced by the ns-ZrOx surface are rescued after the first hours of culture. We propose that ns-ZrOx-induced cytoskeletal remodeling transmits signals generated by the extracellular environment to the nucleus, with the consequent modulation of the expression of genes controlling cell fate.

Wastewater-based epidemiology for the assessment of population exposure to chemicals: The need for integration with human biomonitoring for global One Health actions.

WBE has now become a complimentary tool in SARS-CoV-2 surveillance. This was preceded by the established application of WBE to assess the consumption of illicit drugs in communities. It is now timely to build on this and take the opportunity to expand WBE to enable comprehensive assessment of community exposure to chemical stressors and their mixtures. The goal of WBE is to quantify community exposure, discover exposure-outcome associations, and trigger policy, technological or societal intervention strategies with the overarching aim of exposure prevention and public health promotion. To achieve WBE's full potential, the following key aspects require further action: (1) Integration of WBE-HBM (human biomonitoring) initiatives that provide comprehensive community-individual multichemical exposure assessment. (2) Global WBE monitoring campaigns to provide much needed data on exposure in low- and middle-income countries (LMICs) and fill in the gaps in knowledge especially in the underrepresented highly urbanised as well as rural settings in LMICs. (3) Combining WBE with One Health actions to enable effective interventions. (4) Advancements in new analytical tools and methodologies for WBE progression to enable biomarker selection for exposure studies, and to provide sensitive and selective multiresidue analysis for trace multi-biomarker quantification in a complex wastewater matrix. Most of all, further developments of WBE needs to be undertaken by co-design with key stakeholder groups: government organisations, health authorities and private sector.

The Effects of Sirolimus and Magnesium on Primary Human Coronary Endothelial Cells: An In Vitro Study.

Drug eluting magnesium (Mg) bioresorbable scaffolds represent a novel paradigm in percutaneous coronary intervention because Mg-based alloys are biocompatible, have adequate mechanical properties and can be resorbed without adverse events. Importantly, Mg is fundamental in many biological processes, mitigates the inflammatory response and is beneficial for the endothelium. Sirolimus is widely used as an antiproliferative agent in drug eluting stents to inhibit the proliferation of smooth muscle cells, thus reducing the occurrence of stent restenosis. Little is known about the potential interplay between sirolimus and Mg in cultured human coronary artery endothelial cells (hCAEC). Therefore, the cells were treated with sirolimus in the presence of different concentrations of extracellular Mg. Cell viability, migration, barrier function, adhesivity and nitric oxide synthesis were assessed. Sirolimus impairs the viability of subconfluent, but not of confluent cells independently from the concentration of Mg in the culture medium. In confluent cells, sirolimus inhibits migration, while it cooperates with Mg in exerting an anti-inflammatory action that might have a role in preventing restenosis and thrombosis.