bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclosporine A but Not Corticosteroids Support Efficacy of Ex Vivo Expanded, Adoptively Transferred Human Tregs in GvHD
Authors: Landwehr-Kenzel Sybille , Zobel Anne , Schmitt-Knosalla Isabela , Forke Anne , Hoffmann Henrike , Schmueck-Henneresse Michael , Klopfleisch Robert , Volk Hans-Dieter , Reinke Petra
Published: October 2021

Reshaping the immune balance by adoptive transfer of regulatory T-cells (Tregs) has emerged as a promising strategy to combat undesired immune reactions, including in Graft-versus-Host Disease (GvHD), which is the most lethal non-relapse complication of allogeneic hematopoietic stem cell transplantation. Currently however, little is known about the potentially inhibitory in vivo effects of conventional immunosuppressive drugs, which are routinely used to treat GvHD, on adoptively transferred Tregs. Here we demonstrate drug-specific effects of the conventional immunosuppressive drugs Cyclosporine A, Mycophenolate mofetil and methylprednisolone on adoptively transferred Tregs in a humanized NOD/SCID/IL2Rgamma-/- GvHD mouse model. The clinical course of GvHD and postmortem organ histology, including cellular organ infiltration, showed that co-administration of Cyclosporine A and Tregs is highly beneficial as it enhanced Treg accumulation at inflammatory sites like lung and liver. Similarly, co-administration of Mycophenolate mofetil and Tregs improved clinical signs of GvHD. In contrast, co-administration of methylprednisolone and Tregs resulted in reduced Treg recruitment to inflammatory sites and the fast deterioration of some animals. Consequently, when clinical trials investigating safety and efficacy of adjunctive Treg therapy in GvHD are designed, we suggest co-administering Cyclosporine A, whereas high doses of glucocorticosteroids should be avoided.
Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can
Authors: Tamayo-Velasco Álvaro , Peñarrubia Ponce María Jesús , Álvarez Francisco Javier , Gonzalo-Benito Hugo , de la Fuente Ignacio , Pérez-González Sonia , Rico Lucía , Jiménez García María Teresa , Sánchez Rodríguez Alba , Hijas Villaizan Milagros , Martín-Fernández Marta , Dueñas Carlos , Gómez-Sánchez Esther , Heredia-Rodríguez María , Gorgojo-Galindo Óscar , Fernández Itziar , del Río Lourdes , Carnicero-Frutos Irene , Muñoz-Moreno María Fe , Tamayo Eduardo , Bernardo David , Martínez-Paz Pedro
Published: October 2021

Severe status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.
Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept
Authors: Sato Tomohito , Enoki Toshio , Karasawa Yoko , Someya Hideaki , Taguchi Manzo , Harimoto Kozo , Takayama Kei , Kanda Takayuki , Ito Masataka , Takeuchi Masaru
Published: October 2021

Background

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment.

Methods

Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured.

Results

Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (−) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to −0.09. In receiver operating characteristic analysis and Kaplan–Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group.

Conclusion

Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.
Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood – Interim Analysis of the IMMO-LDRT01 Trial
Authors: Donaubauer Anna-Jasmina , Becker Ina , Weissmann Thomas , Fröhlich Birgitta M. , Muñoz Luis E. , Gryc Thomas , Denzler Manuel , Ott Oliver J. , Fietkau Rainer , Gaipl Udo S. , Frey Benjamin
Published: October 2021

The treatment of chronic inflammatory and degenerative diseases by low dose radiation therapy (LDRT) is promising especially for patients who were refractory for classical therapies. LDRT aims to reduce pain of patients and to increase their mobility. Although LDRT has been applied since the late 19th century, the immunological mechanisms remain elusive. Within the prospective IMMO-LDRT01 trial (NCT02653079) the effects of LDRT on the peripheral blood immune status, as well as on pain and life quality of patients have been analyzed. Blood is taken before and after every serial irradiation with a single dose per fraction of 0.5Gy, as well as during follow-up appointments in order to determine a detailed longitudinal immune status by multicolor flow cytometry. Here, we report the results of an interim analysis of 125 patients, representing half the number of patients to be recruited. LDRT significantly improved patients’ pain levels and induced distinct systemic immune modulations. While the total number of leukocytes remained unchanged in the peripheral blood, LDRT induced a slight reduction of eosinophils, basophils and plasmacytoid dendritic cells and an increase of B cells. Furthermore, activated immune cells were decreased following LDRT. Especially cells of the monocytic lineage correlated to LDRT-induced improvements of clinical symptoms, qualifying these immune cells as predictive biomarkers for the therapeutic success. We conclude that LDRT improves pain of the patients by inducing systemic immune modulations and that immune biomarkers could be defined for prediction by improved patient stratification in the future.
Linking Microstructural Integrity and Motor Cortex Excitability in Multiple Sclerosis
Authors: Radetz Angela , Mladenova Kalina , Ciolac Dumitru , Gonzalez-Escamilla Gabriel , Fleischer Vinzenz , Ellwardt Erik , Krämer Julia , Bittner Stefan , Meuth Sven G. , Muthuraman Muthuraman , Groppa Sergiu
Published: October 2021

Motor skills are frequently impaired in multiple sclerosis (MS) patients following grey and white matter damage with cortical excitability abnormalities. We applied advanced diffusion imaging with 3T magnetic resonance tomography for neurite orientation dispersion and density imaging (NODDI), as well as diffusion tensor imaging (DTI) in 50 MS patients and 49 age-matched healthy controls to quantify microstructural integrity of the motor system. To assess excitability, we determined resting motor thresholds using non-invasive transcranial magnetic stimulation. As measures of cognitive-motor performance, we conducted neuropsychological assessments including the Nine-Hole Peg Test, Trail Making Test part A and B (TMT-A and TMT-B) and the Symbol Digit Modalities Test (SDMT). Patients were evaluated clinically including assessments with the Expanded Disability Status Scale. A hierarchical regression model revealed that lower neurite density index (NDI) in primary motor cortex, suggestive for axonal loss in the grey matter, predicted higher motor thresholds, i.e. reduced excitability in MS patients (p = .009, adjusted r² = 0.117). Furthermore, lower NDI was indicative of decreased cognitive-motor performance (p = .007, adjusted r² = .142 for TMT-A; p = .009, adjusted r² = .129 for TMT-B; p = .006, adjusted r² = .142 for SDMT). Motor WM tracts of patients were characterized by overlapping clusters of lowered NDI (p <.05, Cohen’s d = 0.367) and DTI-based fractional anisotropy (FA) (p <.05, Cohen’s d = 0.300), with NDI exclusively detecting a higher amount of abnormally appearing voxels. Further, orientation dispersion index of motor tracts was increased in patients compared to controls, suggesting a decreased fiber coherence (p <.05, Cohen’s d = 0.232). This study establishes a link between microstructural characteristics and excitability of neural tissue, as well as cognitive-motor performance in multiple sclerosis. We further demonstrate that the NODDI parameters neurite density index and orientation dispersion index detect a larger amount of abnormally appearing voxels in patients compared to healthy controls, as opposed to the classical DTI parameter FA. Our work outlines the potential for microstructure imaging using advanced biophysical models to forecast excitability alterations in neuroinflammation.
Topological Dissection of Proteomic Changes Linked to the Limbic Stage of Alzheimer’s Disease
Authors: Velásquez Erika , Szeitz Beáta , Gil Jeovanis , Rodriguez Jimmy , Palkovits Miklós , Renner Éva , Hortobágyi Tibor , Döme Péter , Nogueira Fábio CS. , Marko-Varga György , Domont Gilberto B. , Rezeli Melinda
Published: October 2021

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available via ProteomeXchange with identifier PXD027173.
Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients
Authors: Wang Danyang , Zhang Hangyu , Xiang Tao , Wang Gang
Published: October 2021

Colorectal cancer (CRC) is one of the most common cancers worldwide. However, the treatment outcomes of immunotherapy in microsatellite-stable (MSS) CRC remain unsatisfactory. As the majority of CRC cases display a molecular MSS/mismatch repair-proficient (pMMR) profile, it is particularly meaningful to explore the clinical applications of adaptive immune therapy in MSS CRC patients. In this review, we summarized the therapeutic approaches of adoptive immune therapies, including cytokines, therapeutic cancer vaccines, adoptive T-cell therapy, and immune checkpoint inhibitors, in the treatment of MSS CRCs.
Oral Pathobiont-Induced Changes in Gut Microbiota Aggravate the Pathology of Nonalcoholic Fatty Liver Disease in Mice
Authors: Yamazaki Kyoko , Kato Tamotsu , Tsuboi Yuuri , Miyauchi Eiji , Suda Wataru , Sato Keisuke , Nakajima Mayuka , Yokoji-Takeuchi Mai , Yamada-Hara Miki , Tsuzuno Takahiro , Matsugishi Aoi , Takahashi Naoki , Tabeta Koichi , Miura Nobuaki , Okuda Shujiro , Kikuchi Jun , Ohno Hiroshi , Yamazaki Kazuhisa
Published: October 2021

Background & Aims

Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology.

Methods

C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction.

Results

CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different.

Conclusions

Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.
Interferon Lambda in the Pathogenesis of Inflammatory Bowel Diseases
Authors: Wallace Jonathan W. , Constant David A. , Nice Timothy J.
Published: October 2021

Interferon λ (IFN-λ) is critical for host viral defense at mucosal surfaces and stimulates immunomodulatory signals, acting on epithelial cells and few other cell types due to restricted IFN-λ receptor expression. Epithelial cells of the intestine play a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD), and the related type II interferons (IFN-γ) have been extensively studied in the context of IBD. However, a role for IFN-λ in IBD onset and progression remains unclear. Recent investigations of IFN-λ in IBD are beginning to uncover complex and sometimes opposing actions, including pro-healing roles in colonic epithelial tissues and potentiation of epithelial cell death in the small intestine. Additionally, IFN-λ has been shown to act through non-epithelial cell types, such as neutrophils, to protect against excessive inflammation. In most cases IFN-λ demonstrates an ability to coordinate the host antiviral response without inducing collateral hyperinflammation, suggesting that IFN-λ signaling pathways could be a therapeutic target in IBD. This mini review discusses existing data on the role of IFN-λ in the pathogenesis of inflammatory bowel disease, current gaps in the research, and therapeutic potential of modulating the IFN-λ-stimulated response.
Where Is More Important Than How in Coastal and Marine Ecosystems Restoration
Authors: Fraschetti Simonetta , McOwen Chris , Papa Loredana , Papadopoulou Nadia , Bilan Meri , Boström Christoffer , Capdevila Pol , Carreiro-Silva Marina , Carugati Laura , Cebrian Emma , Coll Marta , Dailianis Thanos , Danovaro Roberto , De Leo Francesco , Fiorentino Dario , Gagnon Karine , Gambi Cristina , Garrabou Joaquim , Gerovasileiou Vasilis , Hereu Bernat , Kipson Silvija , Kotta Jonne , Ledoux Jean-Baptiste , Linares Cristina , Martin Juliette , Medrano Alba , Montero-Serra I. , Morato Telmo , Pusceddu Antonio , Sevastou Katerina , Smith Christopher J. , Verdura Jana , Guarnieri Giuseppe
Published: October 2021

Restoration is considered an effective strategy to accelerate the recovery of biological communities at local scale. However, the effects of restoration actions in the marine ecosystems are still unpredictable. We performed a global analysis of published literature to identify the factors increasing the probability of restoration success in coastal and marine systems. Our results confirm that the majority of active restoration initiatives are still concentrated in the northern hemisphere and that most of information gathered from restoration efforts derives from a relatively small subset of species. The analysis also indicates that many studies are still experimental in nature, covering small spatial and temporal scales. Despite the limits of assessing restoration effectiveness in absence of a standardized definition of success, the context (degree of human impact, ecosystem type, habitat) of where the restoration activity is undertaken is of greater relevance to a successful outcome than how (method) the restoration is carried out. Contrary to expectations, we found that restoration is not necessarily more successful closer to protected areas (PA) and in areas of moderate human impact. This result can be motivated by the limits in assessing the success of interventions and by the tendency of selecting areas in more obvious need of restoration, where the potential of actively restoring a degraded site is more evident. Restoration sites prioritization considering human uses and conservation status present in the region is of vital importance to obtain the intended outcomes and galvanize further actions.
The Adaptive Evolution and Gigantism Mechanisms of the Hadal “Supergiant” Amphipod Alicella gigantea
Authors: Li Wenhao , Wang Faxiang , Jiang Shouwen , Pan Binbin , Chan Jiulin , Xu Qianghua
Published: October 2021

Hadal trenches are commonly referred to as the deepest areas in the ocean and are characterized by extreme environmental conditions such as high hydrostatic pressures and very limited food supplies. Amphipods are considered the dominant scavengers in the hadal food web. Alicella gigantea is the largest hadal amphipod and, as such, has attracted a lot of attention. However, the adaptive evolution and gigantism mechanisms of the hadal “supergiant” remain unknown. In this study, the whole-body transcriptome analysis was conducted regarding the two hadal amphipods, one being the largest sized species A. gigantea from the New Britain Trench and another the small-sized species Bathycallisoma schellenbergi from the Marceau Trench. The size and weight measurement of the two hadal amphipods revealed that the growth of A. gigantea was comparatively much faster than that of B. schellenbergi. Phylogenetic analyses showed that A. gigantea and B. schellenbergi were clustered into a Lysianassoidea clade, and were distinct from the Gammaroidea consisting of shallow-water Gammarus species. Codon substitution analyses revealed that “response to starvation,” “glycerolipid metabolism,” and “meiosis” pathways were enriched among the positively selected genes (PSGs) of the two hadal amphipods, suggesting that hadal amphipods are subjected to intense food shortage and the pathways are the main adaptation strategies to survive in the hadal environment. To elucidate the mechanisms underlying the gigantism of A. gigantea, small-sized amphipods were used as the background for evolutionary analysis, we found the seven PSGs that were ultimately related to growth and proliferation. In addition, the evolutionary rate of the gene ontology (GO) term “growth regulation” was significantly higher in A. gigantea than in small-sized amphipods. By combining, those points might be the possible gigantism mechanisms of the hadal “supergiant” A. gigantea.
Effects of Vitamin C and E Supplementation on Growth, Fatty Acid Composition, Innate Immunity, and Antioxidant Capacity of Rainbow Trout (Oncorhynchus mykiss) Fed Oxidized Fish Oil
Authors: Rahimnejad Samad , Dabrowski Konrad , Izquierdo Marisol , Hematyar Nima , Imentai Aiman , Steinbach Christoph , Policar Tomas
Published: October 2021

This 10-week feeding experiment examined the effects of supplementing vitamin C (VC) and E (VE) in oxidized oil diets on growth, fatty acid composition, blood physiological indicators, innate immunity, antioxidant capacity, and liver and intestine histology of rainbow trout (Oncorhynchus mykiss). Four diets were produced including a fresh fish oil containing diet (FFO diet), an oxidized fish oil containing diet (OFO diet), and OFO diet supplemented with 500 mg kg–1 VC and 400 mg kg–1 VE (OFO+C500+E400 diet) or 1,000 mg kg–1 VC and 800 mg kg–1 VE (OFO+C1000+E800 diet). Four hundred and twenty fish averaging 46.9 ± 0.32 g were stocked into 12 tanks and fed the diets twice a day to visual satiety. The results showed no significant effect of OFO or vitamins supplementation on growth, feed intake and feed utilization (P > 0.05). The groups that received OFO and OFO+C1000+E800 diets had significantly (P < 0.05) lower hepatosomatic indices than the other groups. Muscle fatty acid composition showed decreased proportion of 15:0, 16:0, 16:1n-7, 16:2n-4, 18:1n-5, 18:2n-6 (linoleic acid) and total saturated fatty acids in OFO group. Whereas higher percentages of 20:3n-6 and 20:3n-3 were found in OFO group. In addition, the highest ratio of docosahexaenoic acid (DHA, 22:6n-3) to eicosapentaenoic acid (EPA, 20:5n-3) was detected in OFO+C500+E400 group. The highest serum triglyceride concentration was recorded in the OFO group. Serum aspartate aminotransferase activity increased in OFO and OFO+C1000+E800 groups compared to OFO+C500+E400 group. Furthermore, significantly higher alkaline phosphatase activity in blood was found in OFO and OFO+C500+E400 groups. Significantly lower serum lysozyme, antiprotease, superoxide dismutase, and catalase activities were recorded in OFO group compared to FFO and OFO+C500+E400 groups, and an opposite trend was observed for malondialdehyde concentration. Muscle VC and VE concentrations, and liver and intestine histology remained unaffected. To conclude, feeding diet containing oxidized oil with peroxide value of 182 meq kg–1 with/without VC and VE supplementation did not influence growth and tissue VC and VE concentrations of rainbow trout. However, supplementing 500 mg kg–1 VC and 400 mg kg–1 VE reversed the adverse effects of OFO on non-specific immune response and antioxidant capacity.
Improving the in vitro Degradation, Mechanical and Biological Properties of AZ91-3Ca Mg Alloy via Hydrothermal Calcium Phosphate Coatings
Authors: Ali Asif , Ikram Fakhera , Iqbal Farasat , Fatima Hira , Mehmood Azra , Kolawole Maruf Yinka , Chaudhry Aqif Anwar , Siddiqi Saadat Anwar , Rehman Ihtesham Ur
Published: October 2021

For many years, calcium phosphate coatings to tailor the degradation behavior of magnesium and magnesium-based alloys for orthopaedic applications have received lots of research attention. However, prolong degradation behavior, its effect on biological and mechanical properties as well as osteoblastic response to single-step hydrothermally deposited calcium phosphate coatings remain poorly documented. In this study, Alamar blue assay, cell attachment, live/dead assay, and qRT-PCR were done to study the biological response of the coatings. Furthermore, immersion testing in SBF for 28 days and compression testing of the degraded samples were carried out to examine the degradation behavior and its effect on mechanical properties. The results indicated that coatings have a significant influence on both the substrate performance and structural integrity of coated AZ91-3Ca alloy. Immersion test revealed that coating deposited at pH 7, 100°C (CP7100) improves the hydrogen evolution rate by 65% and the degradation rate by 60%. As the degradation performance of coated samples improves so does the mechanical strength. CP7100 samples successfully retained 90% of their compressive strength after 14 days of immersion while bare AZ91-3Ca alloy lost its mechanical integrity. Furthermore, biological studies show that cells are happily proliferating, differentiating, and adhering to the coating surfaces, which indicates, improved osteointegration and osteogenesis with no sign of alkaline poisoning. qRT-PCR results showed that calcium phosphate coatings enhanced the mRNA levels for RUNX2, Col1A, and ALP that may exhibit a speedy bone recovery. Thus, calcium phosphate coatings produced via a single-step hydrothermal method improve the degradation behavior, mechanical integrity and stimulate the differentiation of osteoblast lining. This leads toward faster bone regeneration, which shows a great potential of these coatings to be used on degradable implants as a bioactive protective layer.
Efficient Production of High Specific Activity Thulium-167 at Paul Scherrer Institute and CERN-MEDICIS
Authors: Heinke Reinhard , Chevallay Eric , Chrysalidis Katerina , Cocolios Thomas E. , Duchemin Charlotte , Fedosseev Valentin N. , Hurier Sophie , Lambert Laura , Leenders Benji , Marsh Bruce A. , van der Meulen Nicholas P. , Sprung Peter , Stora Thierry , Tosato Marianna , Wilkins Shane G. , Zhang Hui , Talip Zeynep
Published: October 2021

Thulium-167 is a promising radionuclide for nuclear medicine applications with potential use for both diagnosis and therapy (“theragnostics”) in disseminated tumor cells and small metastases, due to suitable gamma-line as well as conversion/Auger electron energies. However, adequate delivery methods are yet to be developed and accompanying radiobiological effects to be investigated, demanding the availability of 167Tm in appropriate activities and quality. We report herein on the production of radionuclidically pure 167Tm from proton-irradiated natural erbium oxide targets at a cyclotron and subsequent ion beam mass separation at the CERN-MEDICIS facility, with a particular focus on the process efficiency. Development of the mass separation process with studies on stable 169Tm yielded 65 and 60% for pure and erbium-excess samples. An enhancement factor of thulium ion beam over that of erbium of up to several 104 was shown by utilizing laser resonance ionization and exploiting differences in their vapor pressures. Three 167Tm samples produced at the IP2 irradiation station, receiving 22.8 MeV protons from Injector II at Paul Scherrer Institute (PSI), were mass separated with collected radionuclide efficiencies between 11 and 20%. Ion beam sputtering from the collection foils was identified as a limiting factor. In-situ gamma-measurements showed that up to 45% separation efficiency could be fully collected if these limits are overcome. Comparative analyses show possible neighboring mass suppression factors of more than 1,000, and overall 167Tm/Er purity increase in the same range. Both the actual achieved collection and separation efficiencies present the highest values for the mass separation of external radionuclide sources at MEDICIS to date.
PET/CT Technology in Adult Zebrafish: A Pilot Study Toward Live Longitudinal Imaging
Authors: Tucker Carl , Collins Richard , Denvir Martin A. , McDougald Wendy A.
Published: October 2021

Decades of research have confirmed the beneficial and advantageous use of zebrafish (Danio rerio) as a model of human disease in biomedical studies. Not only are 71% of human genes shared with the zebrafish many of these genes are linked to human diseases. Currently, numerous transgenic and mutant genetic zebrafish lines are now widely available for use in research. Furthermore, zebrafish are relatively inexpensive to maintain compared to rodents. However, a limiting factor to fully utilising adult zebrafish in research is not the fish but the technological imaging tools available. In order to increase the utilisation of adult zebrafish, which are not naturally transparent, requires new imaging approaches. Therefore, this feasibility study: (1) presents an innovative designed PET/CT adult zebrafish imaging platform, capable of maintaining normal aquatic physiology during scanning; (2) assesses the practical aspects of adult zebrafish imaging; and (3) set basic procedural guidelines for zebrafish imaging during a PET/CT acquisition.

Methods: With computer aided design (CAD) software an imaging platform was developed for 3D printing. A 3D printed zebrafish model was created from a CT acquisition of a zebrafish using the CAD software. This model and subsequently euthanised zebrafish were imaged post-injection using different concentrations of the radiotracer [18F]FDG with CT contrast.

Results: PET/CT imaging was successful, revealing levels as low as 0.01 MBq could be detected in the fish. In the zebrafish imaging post-injection distribution of the radiotracer was observed away from the injection site as well as tissue uptake. Potential preliminary husbandry and welfare guidelines for the fish during and after PET/CT imaging were determined.

Conclusion: Using PET/CT for adult zebrafish imaging as a viable non-invasive technological tool is feasible. Adult zebrafish PET/CT imaging has the potential to be a key imaging technique offering the possibilities of enhanced biomedical understanding and new translational data sets.
Efficiency of Monocyte/High-Density Lipoprotein Cholesterol Ratio Combined With Neutrophil/Lymphocyte Ratio in Predicting 28-Day Mortality in Patients With Sepsis
Authors: Li Jing-yan , Yao Ren-qi , Liu Shuang-qing , Zhang Yun-fei , Yao Yong-ming , Tian Ying-ping
Published: October 2021

Background: Sepsis can cause unpredictable harm, and early identification of risk for mortality may be conducive to clinical diagnosis. The present study proposes to assess the efficacy of the monocyte/high-density lipoprotein cholesterol ratio (MHR) combined with the neutrophil/lymphocyte ratio (NLR) on the day of admission in predictive efficacy in the 28-day mortality risk in critical patients with sepsis.

Material and Methods: We administered observational and retrospective cohort research from a single center. The correlation of the clinical variables, together with the system severity scores of APACHE II and SOFA, are displayed by correlation analysis, and a Cox regression model could be performed to screen the independent risk factors and estimate the capacity of multiple markers in predicting 28-day mortality. The receiver operating characteristic (ROC) curve served as an applied method to output cutoff values for the diagnosis and prognostic risk, and the area under the ROC curve and net reclassification improvement index (NRI), as well as integrated discrimination improvement index (IDI) were employed to assess the feasibility of multiple parameters for predictive value in 28-day mortality of septic patients.

Results: The study enrolled 274 eligible patients with sepsis. The correlation analysis indicated NLR and MHR were related to the sepsis severity. A multivariate Cox regression analysis indicated that NLR together with MHR displayed a close relation to death rate after adjusting for other potential confounders (NLR, HR = 1.404 [95% CI 1.170–1.684], P < 0.001; MHR, HR = 1.217 [95% CI 1.112–1.331], P < 0.001). The AUC of NLR, MHR, NLR_MHR was 0.827, 0.876, and 0.934, respectively. The addition on the biomarker NLR_MHR to the prediction model improved IDI by 18.5% and NRI by 37.8%.

Conclusions: Our findings suggest that NLR and MHR trend to an elevated level in non-surviving patients with sepsis. Evaluation of NLR_MHR, an independent risk factor for increased mortality, might improve the predictive efficacy for 28-day mortality risk in septic patients.
Levosimendan to Facilitate Weaning From Cardiorespiratory Support in Critically Ill Patients: A Meta-Analysis
Authors: Luo Jing-Chao , Zheng Wen-He , Meng Chang , Zhou Hua , Xu Yuan , Tu Guo-Wei , Luo Zhe , Huang Hui-Bin
Published: October 2021

Background: Cardiopulmonary support, as extracorporeal membrane oxygenation (ECMO) or mechanical ventilation (MV), is crucial for ICU patients. However, some of these patients are difficult to wean. Therefore, we aimed to assess the efficacy and safety of levosimendan in facilitating weaning from cardiorespiratory support in this patient population.

Methods: We searched for potentially relevant articles in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database from inception up to Feb 30, 2021. Studies focusing on weaning data in MV/ECMO adult patients who received levosimendan compared to controls were included. We used the Cochrane risk of bias tool or the Newcastle-Ottawa Quality Assessment Scale to evaluate the study quality. The primary outcome was the weaning rate from MV/ECMO. Secondary outcomes were mortality, duration of MV, and ICU stay. Subgroup analysis, sensitivity analysis, and publication bias were also conducted.

Results: Eighteen studies with 2,274 patients were included. The quality of the included studies was low to moderate. Overall, levosimendan effectively improved weaning rates from MV/ECMO [odds ratio (OR) = 2.32; 95%CI, 1.60–3.36; P < 0.00001, I2 = 68%]. Subgroup analyses confirmed the higher successful weaning rates in ventilated patients with low left ventricular ejection fractions (OR = 4.06; 95%CI, 2.16–7.62), patients with ECMO after cardiac surgery (OR = 2.04; 95%CI, 1.25–3.34), and patients with ECMO and cardiogenic shock (OR = 1.98; 95%CI, 1.34–2.91). However, levosimendan showed no beneficial effect on patients with MV weaning difficulty (OR = 2.28; 95%CI, 0.72–7.25). Additionally, no differences were found concerning the secondary outcomes between the groups.

Conclusions: Levosimendan therapy significantly increased successful weaning rates in patients with cardiopulmonary support, especially patients with combined cardiac insufficiency. Large-scale, well-designed RCTs will be needed to define the subgroup of patients most likely to benefit from this strategy.
Management of Progressive Fibrosing Interstitial Lung Diseases (PF-ILD)
Authors: Copeland Carla R. , Lancaster Lisa H.
Published: October 2021

Progressive fibrosing interstitial lung diseases (PF-ILD) consist of a diverse group of interstitial lung diseases (ILD) characterized by a similar clinical phenotype of accelerated respiratory failure, frequent disease exacerbation and earlier mortality. Regardless of underlying disease process, PF-ILD progresses through similar mechanisms of self-sustained dysregulated cell repair, fibroblast proliferation and alveolar dysfunction that can be therapeutically targeted. Antifibrotic therapy with nintedanib or pirfenidone slow lung function decline and are the backbone of treatment for IPF with an expanded indication of PF-ILD for nintedanib. Immunosuppression is utilized for some subtypes of PF-ILD, including connective tissue disease ILD and hypersensitivity pneumonitis. Inhaled treprostinil is a novel therapy that improves exercise tolerance in individuals with PF-ILD and concomitant World Health Organization (WHO) group 3 pulmonary hypertension. Lung transplantation is the only curative therapy and can be considered in an appropriate and interested patient. Supportive care, oxygen therapy when appropriate, and treatment of comorbid conditions are important aspects of PF-ILD management. This review summarizes the current data and recommendations for management of PF-ILD.
COVID-19 and Hemoglobinopathies: A Systematic Review of Clinical Presentations, Investigations, and Outcomes
Authors: Lee Jun Xin , Chieng Wei Keong , Lau Sie Chong Doris , Tan Chai Eng
Published: October 2021

This systematic review aimed to provide an overview of the clinical profile and outcome of COVID-19 infection in patients with hemoglobinopathy. The rate of COVID-19 mortality and its predictors were also identified. A systematic search was conducted in accordance with PRISMA guidelines in five electronic databases (PubMed, Scopus, Web of Science, Embase, WHO COVID-19 database) for articles published between 1st December 2019 to 31st October 2020. All articles with laboratory-confirmed COVID-19 cases with underlying hemoglobinopathy were included. Methodological quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklists. Thirty-one articles with data on 246 patients with hemoglobinopathy were included in this review. In general, clinical manifestations of COVID-19 infection among patients with hemoglobinopathy were similar to the general population. Vaso-occlusive crisis occurred in 55.6% of sickle cell disease patients with COVID-19 infection. Mortality from COVID-19 infection among patients with hemoglobinopathy was 6.9%. After adjusting for age, gender, types of hemoglobinopathy and oxygen supplementation, respiratory (adj OR = 89.63, 95% CI 2.514–3195.537, p = 0.014) and cardiovascular (adj OR = 35.20, 95% CI 1.291–959.526, p = 0.035) comorbidities were significant predictors of mortality. Patients with hemoglobinopathy had a higher mortality rate from COVID-19 infection compared to the general population. Those with coexisting cardiovascular or respiratory comorbidities require closer monitoring during the course of illness. More data are needed to allow a better understanding on the clinical impact of COVID-19 infections among patients with hemoglobinopathy.

Clinical Trial Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020218200.
New Endothelial Mechanisms in Glomerular (Patho)biology and Proteinuria Development Captured by Intravital Multiphoton Imaging
Authors: Gyarmati Georgina , Jacob Chaim O. , Peti-Peterdi János
Published: October 2021

In the past two decades, intravital imaging using multiphoton microscopy has provided numerous new visual and mechanistic insights into glomerular biology and disease processes including the function of glomerular endothelial cells (GEnC), podocytes, and the development of proteinuria. Although glomerular endothelial injury is known to precede podocyte damage in several renal diseases, the primary role of GEnCs in proteinuria development received much less attention compared to the vast field of podocyte pathobiology. Consequently, our knowledge of GEnC mechanisms in glomerular diseases is still emerging. This review highlights new visual clues on molecular and cellular mechanisms of GEnCs and their crosstalk with podocytes and immune cells that were acquired recently by the application of multiphoton imaging of the intact glomerular microenvironment in various proteinuric disease models. New mechanisms of glomerular tissue remodeling and regeneration are discussed based on results of tracking the fate and function of individual GEnCs using serial intravital multiphoton imaging over several days and weeks. The three main topics of this review include (i) the role of endothelial injury and microthrombi in podocyte detachment and albumin leakage via hemodynamic and mechanical forces, (ii) the alterations of the endothelial surface layer (glycocalyx) and its interactions with circulating immune cells in lupus nephritis, and (iii) the structural and functional remodeling and regeneration of GEnCs in hypertension, diabetes, and other experimental injury conditions. By the comprehensive visual portrayal of GEnCs and the many other contributing glomerular cell types, this review emphasizes the complexity of pathogenic mechanisms that result in proteinuria development.
An Investigation of Stability and Species and Strain-Level Specificity in Bacterial Volatilomes
Authors: Fitzgerald Shane , Holland Linda , Morrin Aoife
Published: October 2021

Microbial volatilomics is a rapidly growing field of study and has shown great potential for applications in food, farming, and clinical sectors in the future. Due to the varying experimental methods and growth conditions employed in microbial volatilomic studies as well as strain-dependent volatilomic differences, there is limited knowledge regarding the stability of microbial volatilomes. Consequently, cross-study comparisons and validation of results and data can be challenging. In this study, we investigated the stability of the volatilomes of multiple strains of Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli across three frequently used nutrient-rich growth media. Volatilomic stability was assessed based on media-, time- and strain-dependent variation across the examined bacterial volatilomes. Strain-level specificity of the observed volatilomes of E. coli and P. aeruginosa strains was further investigated by comparing the emission of selected compounds at varying stages of cell growth. Headspace solid phase microextraction (HS-SPME) sampling coupled with gas chromatography mass spectrometry (GC-MS) was used to analyze the volatilome of each strain. The whole volatilomes of the examined strains demonstrate a high degree of stability across the three examined growth media. At the compound-level, media dependent differences were observed particularly when comparing the volatilomes obtained in glucose-containing brain heart infusion (BHI) and tryptone soy broth (TSB) growth media with the volatilomes obtained in glucose-free Lysogeny broth (LB) media. These glucose-dependent volatilomic differences were primarily seen in the emission of primary metabolites such as alcohols, ketones, and acids. Strain-level differences in the emission of specific compounds in E. coli and P. aeruginosa samples were also observed across the media. These strain-level volatilomic differences were also observed across varying phases of growth of each strain, therefore confirming that these strains had varying core and accessory volatilomes. Our results demonstrate that, at the species-level, the examined bacteria have a core volatilome that exhibits a high-degree of stability across frequently-used growth media. Media-dependent differences in microbial volatilomes offer valuable insights into identifying the cellular origin of individual metabolites. The observed differences in the core and accessory volatilomes of the examined strains illustrate the complexity of microbial volatilomics as a study while also highlighting the need for more strain-level investigations to ultimately elucidate the whole volatilomic capabilities of microbial species in the future.
Development of Nitrogen Recycling Strategies for Bioregenerative Life Support Systems in Space
Authors: Verbeelen Tom , Leys Natalie , Ganigué Ramon , Mastroleo Felice
Published: October 2021

To enable long-distance space travel, the development of a highly efficient and robust system to recover nutrients from waste streams is imperative. The inability of the current physicochemical-based environmental control and life support system (ECLSS) on the ISS to produce food in situ and to recover water and oxygen at high enough efficiencies results in the need for frequent resupply missions from Earth. Therefore, alternative strategies like biologically-based technologies called bioregenerative life support systems (BLSSs) are in development. These systems aim to combine biological and physicochemical processes, which enable in situ water, oxygen, and food production (through the highly efficient recovery of minerals from waste streams). Hence, minimalizing the need for external consumables. One of the BLSS initiatives is the European Space Agency’s (ESA) Micro-Ecological Life Support System Alternative (MELiSSA). It has been designed as a five-compartment bioengineered system able to produce fresh food and oxygen and to recycle water. As such, it could sustain the needs of a human crew for long-term space exploration missions. A prerequisite for the self-sufficient nature of MELiSSA is the highly efficient recovery of valuable minerals from waste streams. The produced nutrients can be used as a fertilizer for food production. In this review, we discuss the need to shift from the ECLSS to a BLSS, provide a summary of past and current BLSS programs and their unique approaches to nitrogen recovery and processing of urine waste streams. In addition, compartment III of the MELiSSA loop, which is responsible for nitrogen recovery, is reviewed in-depth. Finally, past, current, and future related ground and space demonstration and the space-related challenges for this technology are considered.