bluuebunny/crossref_metadata_2025 huggingface dataset:
Bone Engineering Scaffolds With Exosomes: A Promising Strategy for Bone Defects Repair
Authors: Zhang Mingming , Li Yi , Feng Taojin , Li Ran , Wang Zhongqi , Zhang Licheng , Yin Pengbin , Tang Peifu
Published: June 2022

The treatment of bone defects is still an intractable clinical problem, despite the fact that numerous treatments are currently available. In recent decades, bone engineering scaffolds have become a promising tool to fill in the defect sites and remedy the deficiencies of bone grafts. By virtue of bone formation, vascular growth, and inflammation modulation, the combination of bone engineering scaffolds with cell-based and cell-free therapy is widely used in bone defect repair. As a key element of cell-free therapy, exosomes with bioactive molecules overcome the deficiencies of cell-based therapy and promote bone tissue regeneration via the potential of osteogenesis, angiogenesis, and inflammation modulation. Hence, this review aimed at overviewing the bone defect microenvironment and healing mechanism, summarizing current advances in bone engineering scaffolds and exosomes in bone defects to probe for future applications.
Temporal Whole-Transcriptomic Analysis of Characterized In Vitro and Ex Vivo Primary Nasal Epithelia
Authors: Legebeke Jelmer , Horton Katie L. , Jackson Claire L. , Coles Janice , Harris Amanda , Wai Htoo A. , Holloway John W. , Wheway Gabrielle , Baralle Diana , Lucas Jane S.
Published: June 2022

Air-liquid interface (ALI) cell culture of primary airway progenitors enables the differentiation and recapitulation of a pseudostratified epithelium in vitro, providing a highly useful tool for researching respiratory health and disease. Previous studies into gene expression in ALI-cultures compared to ex vivo nasal brushings have been limited in the number of time-points and/or the number of genes studied. In this study physiological and global transcriptomic changes were assessed in an extended in vitro 63-day human healthy nasal epithelium ALI-culture period and compared to ex vivo nasal brushing samples. Ex vivo nasal brushing samples formed distinct transcriptome clusters to in vitro ALI-cultured nasal epithelia, with from day 14 onwards ALI samples best matching the ex vivo samples. Immune response regulation genes were not expressed in the in vitro ALI-culture compared to the ex vivo nasal brushing samples, likely because the in vitro cultures lack an airway microbiome, lack airborne particles stimulation, or did not host an immune cell component. This highlights the need for more advanced co-cultures with immune cell representation to better reflect the physiological state. During the first week of ALI-culture genes related to metabolism and proliferation were increased. By the end of week 1 epithelial cell barrier function plateaued and multiciliated cell differentiation started, although widespread ciliation was not complete until day 28. These results highlight that time-points at which ALI-cultures are harvested for research studies needs to be carefully considered to suit the purpose of investigation (transcriptomic and/or functional analysis).
Design, Synthesis, and Quorum Quenching Potential of Novel Catechol–Zingerone Conjugate to Find an Elixir to Tackle Pseudomonas aeruginosa Through the Trojan Horse Strategy
Authors: Mangal Surabhi , Dua Tamanna , Chauhan Monika , Dhingra Neelima , Chhibber Sanjay , Singh Vasundhara , Harjai Kusum
Published: June 2022

To address the issue of multidrug resistance in Pseudomonas aeruginosa, a novel catechol–zingerone conjugate (1) linked via a non-hydrolyzable 1,2,3-triazole linker was synthesized and subjected to biological evaluation based on the Trojan horse strategy. To enhance the efficacy, catechol, a xenosiderophore, utilized by P. aeruginosa for iron assimilation, and the dietary phytochemical zingerone, known for its anti-virulent activity against Pseudomonas aeruginosa, were exploited in the present study. Theoretical validation of conjugate (1) was conducted by in silico molecular docking analysis to determine the interaction with outer membrane transport receptor PirA and quorum sensing signal receptors. In addition, nine-fold binding affinity of Conjugate (1) toward PirA (5FP2) in comparison to its natural ligand catechol with D-score −1.13 Å authenticated the designed Trojan horse drug. Conjugate (1) showed stronger anti-virulent activity than zingerone; hence, it exhibited a promising anti-biofilm efficacy as assessed by crystal violet assay and visualized by FESEM toward P. aeruginosa. Encouraging results against P. aeruginosa in terms of quorum sensing regulated virulence factors, motility phenotypes, and biofilm formation with no cell cytotoxicity and could help open hitherto unexplored possibilities of establishing Trojan horse drugs as a successful approach against multidrug resistance in P. aeruginosa.
Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection
Authors: Urso Andreacarola , Prince Alice
Published: June 2022

Host and pathogen metabolism have a major impact on the outcome of infection. The microenvironment consisting of immune and stromal cells drives bacterial proliferation and adaptation, while also shaping the activity of the immune system. The abundant metabolites itaconate and adenosine are classified as anti-inflammatory, as they help to contain the local damage associated with inflammation, oxidants and proteases. A growing literature details the many roles of these immunometabolites in the pathogenesis of infection and their diverse functions in specific tissues. Some bacteria, notably P. aeruginosa, actively metabolize these compounds, others, such as S. aureus respond by altering their own metabolic programs selecting for optimal fitness. For most of the model systems studied to date, these immunometabolites promote a milieu of tolerance, limiting local immune clearance mechanisms, along with promoting bacterial adaptation. The generation of metabolites such as adenosine and itaconate can be host protective. In the setting of acute inflammation, these compounds also represent potential therapeutic targets to prevent infection.
Clinical Insights to Complete and Incomplete Surgical Revascularization in Atrial Fibrillation and Multivessel Coronary Disease
Authors: Pasierski Michal , Staromłyński Jakub , Finke Janina , Litwinowicz Radoslaw , Filip Grzegorz , Kowalówka Adam , Wańha Wojciech , Kołodziejczak Michalina , Piekuś-Słomka Natalia , Łoś Andrzej , Stefaniak Sebastian , Wojakowski Wojciech , Jemielity Marek , Rogowski Jan , Deja Marek , Jagielak Dariusz , Bartus Krzysztof , Mariani Silvia , Li Tong , Matteucci Matteo , Ronco Daniele , Jiritano Federica , Fina Dario , Martucci Gennaro , Meani Paolo , Raffa Giuseppe Maria , Słomka Artur , Malvidni Pietro Giorgio , Lorusso Roberto , Zembala Michal , Suwalski Piotr , Kowalewski Mariusz
Published: June 2022

Objectives

Although endorsed by international guidelines, complete revascularization (CR) with Coronary Artery Bypass Grafting (CABG) remains underused. In higher-risk patients such as those with pre-operative atrial fibrillation (AF), the effects of CR are not well studied.

Methods

We analyzed patients’ data from the HEIST (HEart surgery In AF and Supraventricular Tachycardia) registry. Between 2012 and 2020 we identified 4770 patients with pre-operative AF and multivessel coronary artery disease who underwent isolated CABG. We divided the cohort according to the completeness of the revascularization and used propensity score matching (PSM) to minimize differences between baseline characteristics. The primary endpoint was all-cause mortality.

Results

Median follow-up was 4.7 years [interquartile range (IQR) 2.3–6.9]. PSM resulted in 1,009 pairs of complete and incomplete revascularization. Number of distal anastomoses varied, accounting for 3.0 + –0.6 vs. 1.7 + –0.6, respectively. Although early (< 24 h) and 30-day post-operative mortalities were not statistically different between non-CR and CR patients [Odds Ratio (OR) and 95% Confidence Intervals (CIs): 1.34 (0.46–3.86); P = 0.593, Hazard Ratio (HR) and 95% CIs: 0.88 (0.59–1.32); P = 0.542, respectively] the long term mortality was nearly 20% lower in the CR cohort [HR (95% CIs) 0.83 (0.71–0.96); P = 0.011]. This benefit was sustained throughout subgroup analyses, yet most accentuated in low-risk patients (younger i.e., < 70 year old, with a EuroSCORE II < 2%, non-diabetic) and when off-pump CABG was performed.

Conclusion

Complete revascularization in patients with pre-operative AF is safe and associated with improved survival. Particular survival benefit with CR was observed in low-risk patients undergoing off-pump CABG.
Therapeutic Response of miR-145 Micelles on Patient-Derived Vascular Smooth Muscle Cells
Authors: Patel Neil , Chin Deborah D. , Magee Gregory A. , Chung Eun Ji
Published: June 2022

During atherosclerosis, vascular smooth muscle cells (VSMCs) undergo a phenotypic transition from a healthy contractile state into pathological phenotypes including a proliferative and migratory, synthetic phenotype and osteochondrogenic-like phenotype that exacerbate plaques. Thus, inhibiting the transition of healthy, quiescent VSMCs to atherogenic cell types has the potential to mitigate atherosclerosis. To that end, previously, we reported that delivery of microRNA-145 (miR-145, a potent gatekeeper of the contractile VSMC phenotype) using nanoparticle micelles limited atherosclerotic plaque growth in murine models of atherosclerosis. Building on this preclinical data and toward clinical application, in this study, we tested the therapeutic viability of miR-145 micelles on patient-derived VSMCs and evaluated their effects based on disease severity. We collected vascular tissues from 11 patients with healthy, moderate, or severe stages of atherosclerosis that were discarded following vascular surgery or organ transplant, and isolated VSMCs from these tissues. We found that with increasing disease severity, patient-derived VSMCs had decreasing levels of contractile markers (miR-145, ACTA2, MYH11) and increasing levels of synthetic markers (KLF4, KLF5, and ELK1). Treatment with miR-145 micelles showed that an increase in disease severity correlated with a more robust response to therapy in VSMCs. Notably, miR-145 micelle therapy rescued contractile marker expression to baseline contractile levels in VSMCs derived from the most severely diseased tissues. As such, we demonstrate the use of miR-145 micelles across different stages of atherosclerosis disease and present further evidence of the translatability of miR-145 micelle treatment for atherosclerosis.
Contributions of Sediment From the Slate Canyon Alluvial Fan to the Formation and Morphogenesis of the Keeler Dunes, CA
Authors: Blanton Stephen G. , Kolesar Katheryn R. , Jaffe David A.
Published: June 2022

The Keeler Dunes Complex is an active dunefield located adjacent to Owens (dry) Lake, California. The source of sediment to the Keeler Dunes area is often assumed to be from the Owens Lake playa; however, the dunes lie at the toe of the Slate Canyon alluvial fan (the Fan). Here hydrologic and hydraulic modeling was conducted for the Fan to assess the contribution of fan sediment to the Keeler Dunes. Assessment of the potential for sediment deposition was conducted for two scenarios based on the relocation of State Highway 136 from the Owens Lake playa upgradient on the Fan and the subsequent construction of flow diversion berms. The berm construction (1954 and 1967) coincided with observations of the destabilization and migration of the Keeler Dunes. Runoff from Slate Canyon watershed was estimated using a Hydrological Simulation Program–Fortran (HSPF) model based on hourly precipitation records. The resulting hydrology output served as inputs to FLO-2D models of the Fan. With the model of hydraulic output, it was estimated that approximately one million tons of sediment were moved from the Fan hydrographic apex toward the Keeler Dunes area during the peak streamflow event of record. This represents a significant volume with respect to the total volume of the Keeler Dunes. Our modeling of the peak flow event indicates the construction of the highway diversion berms resulted in the partial redirection of fan flows and therefore sediment deposition in relation to the Keeler Dunes. This localized change in sediment availability and spatial distribution is a likely factor in the subsequent morphogenesis of the dunes.
Global Trends and Current Status in Osteonecrosis of the Femoral Head: A Bibliometric Analysis of Publications in the Last 30 Years
Authors: Wen Zeqin , Li Yusheng , Cai Zijun , Fan Meng , Wang Jian , Ding Ran , Huang Cheng , Xiao Wenfeng
Published: June 2022

Introduction

Osteonecrosis of the femoral head (ONFH) is a progressive and disabling disease with severe socioeconomic burdens. In the last 30 years, a growing number of publications have reported significant advances in understanding ONFH. However, only a few studies have clarified its global trends and current status. Thus, the purpose of our study was to summarize the global trends and current status in ONFH through bibliometrics.

Materials and Methods

Publications related to ONFH from 1991 to 2020 were searched from the Web of Science (WOS) core collection database. The data were analyzed with bibliometric methods. Microsoft Excel was used for statistical analysis and to draw bar charts. SPSS was applied to perform linear regression analysis. VOSviewer was used to conduct bibliographic coupling analysis, co-authorship analysis, co-citation analysis and co-occurrence analysis.

Results

A total of 5,523 publications were covered. The United States consistently ranked first in total publications, sum of times cited, average citations per item and H-index. Kyushu University was the main contributor to ONFH. Clinical Orthopaedics and Related Research was the major publishing channels for ONFH-related articles. Takuaki Yamamoto published the most ONFH-related articles. Studies regarding ONFH could be divided into five clusters: 1) mechanism study, 2) treatment study, 3) complication study, 4) radiological study and 5) etiological study. Mechanism study might become a hot spot in the future.

Conclusions

The total number of publications in ONFH has generally increased over the last three decades. The United States was the leading country in ONFH research. Transplantation, engineering, cell and molecular biology, pharmacology and endocrinology have gradually increased and become hot topics in ONFH research. Mechanism study in ONFH including mesenchymal stem cells, apoptosis, oxidative stress, adipogenesis, osteogenic differentiation and endothelial progenitor cells, have attracted more attention and will become a hot spot in the future.
Reactive Voltage Control of Wind Farm Based on Tabu Algorithm
Authors: Ren Xin , Wang Hua , Wang Zhongchao , Wang Qijiang , Li Bangxing , Wu Hao , Yang Jian , Wang Wei
Published: June 2022

In view of the fact that current wind farms are mostly multi-wind turbines and it is difficult to accurately control a single wind turbine because of its high dimension in the optimization solution process, the article proposes a reactive power and voltage coordinated control strategy suitable for doubly-fed wind farms. The strategy is mainly divided into three layers. The first is the group layer, which can obtain the reactive power compensation task of the entire group according to the current voltage and voltage indicators of the group collection station. The second is the field layer, in which according to the reactive power compensation tasks issued by the group layer, the reactive power tasks are allocated to each field area based on the tabu search algorithm or the equal margin method. The third is the equipment layer, which allocates equal margins in the area according to the reactive power compensation tasks assigned by the field layer. At the field layer, this article divides 66 wind turbines into five different field areas to solve the reactive power compensation distribution task according to the voltage sensitivity characteristics of the wind turbines on different feeders.
Can Carbon Emissions Trading Scheme Make Power Plants Greener? Firm-Level Evidence From China
Authors: Shi Mingxia , Zou Tingting , Xu Jingxuan , Wang Jie
Published: June 2022

The green energy structure transition is an effective means to achieve carbon emission reduction and sustainable energy development in the long term. Whether the carbon emissions trading scheme, a typical market-oriented environmental regulation, can realize a green energy structure transition has attracted widespread attention. Rather than focusing on the macro-effects of the carbon emissions trading scheme, this paper explores its effect on green energy structural transition in the power sector, which is a major carbon emitter by consuming non-renewable energy. With the multi-period difference-in-differences method, this study manually collects a panel data set of 103 listed power plants from 2011 to 2020 for a total of 1,030 samples and investigates the effect of the carbon emissions trading scheme on the proportion of clean energy power generation. The corresponding mechanism and heterogeneous effects are also examined. The results reveal: 1) The carbon emissions trading scheme increases the proportion of clean energy power generation significantly. This improvement is achieved by increasing clean energy power generation and decreasing thermal power generation. 2) Power companies to which power plants belong are private-owned and have lower debt-to-asset ratios and higher fixed asset ratios, or in regions with a high development level or strong environmental law enforcement, they are found to be more responsive to carbon emissions trading schemes. 3) Green technological innovation is the primary path for transitioning to a green energy structure, but it is not the only path.
Phylogeography of a Typical Forest Heliothermic Lizard Reveals the Combined Influence of Rivers and Climate Dynamics on Diversification in Eastern Amazonia
Authors: Cronemberger Áurea A. , Werneck Fernanda P. , Ávila-Pires Teresa C. S.
Published: June 2022

The formation of the Amazon drainage basin has been considered an important driver of speciation of several taxa, promoting vicariant events or reinforcement of barriers that restrict gene flow between opposite river margins. Several recent studies reported a set of miscellaneous events involving climatic fluctuations, geomorphological changes, and dispersal mechanisms as propellers of diversification of Amazonian rainforest taxa. Here, we show the results of dated phylogenetic, biogeographic, and populational analyses to investigate which events could better explain the current distribution of a heliothermic, active foraging lizard in the central and eastern portions of the Amazonian rainforest (besides a disjunct distribution in part of the Atlantic Forest). We sampled Kentropyx calcarata from most of its area of occurrence in Amazonia and used mitochondrial and nuclear markers to evaluate if the genetic structure agrees with evolutionary scenarios previously proposed for Amazonia. We performed phylogenetic and populational analyses to better understand the dynamics of this species in the Amazonia rainforest over time. Phylogenetic inference recovered ten K. calcarata structured lineages in eastern Amazonia, some of them limited by the Amazon River and its southern tributaries (Tapajós, Xingu, and Tocantins), although we detected occasional haplotype sharing across some of the river banks. According to molecular dating, K. calcarata diversified since Miocene–Pliocene, and some of the lineages presented signs of demographic expansion during the Pleistocene, supposedly triggered by climatic dynamics. The putative ancestral lineage of K. calcarata was distributed on the Guiana Shield, later spreading south and southeastward by dispersion. Our results indicate that Amazonian rivers acted as barriers to the dispersal of Kentropyx calcarata, but they were not the sole drivers of diversification.
Natural and Engineered Sex Ratio Distortion in Insects
Authors: Compton Austin , Tu Zhijian
Published: June 2022

Insects have evolved highly diverse genetic sex-determination mechanisms and a relatively balanced male to female sex ratio is generally expected. However, selection may shift the optimal sex ratio while meiotic drive and endosymbiont manipulation can result in sex ratio distortion (SRD). Recent advances in sex chromosome genomics and CRISPR/Cas9-mediated genome editing brought significant insights into the molecular regulators of sex determination in an increasing number of insects and provided new ways to engineer SRD. We review these advances and discuss both naturally occurring and engineered SRD in the context of the Anthropocene. We emphasize SRD-mediated biological control of insects to help improve One Health, sustain agriculture, and conserve endangered species.
A Vicious Cycle: In Severe and Critically Ill COVID-19 Patients
Authors: Huang Peifeng , Zuo Qingwei , Li Yue , Oduro Patrick Kwabena , Tan Fengxian , Wang Yuanyuan , Liu Xiaohui , Li Jing , Wang Qilong , Guo Fei , Li Yue , Yang Long
Published: June 2022

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is one of the fastest-evolving viral diseases that has instigated a worldwide pandemic. Severe inflammatory syndrome and venous thrombosis are commonly noted in COVID-19 patients with severe and critical illness, contributing to the poor prognosis. Interleukin (IL)-6, a major complex inflammatory cytokine, is an independent factor in predicting the severity of COVID-19 disease in patients. IL-6 and tumor necrosis factor (TNF)-α participate in COVID-19-induced cytokine storm, causing endothelial cell damage and upregulation of plasminogen activator inhibitor-1 (PAI-1) levels. In addition, IL-6 and PAI-1 form a vicious cycle of inflammation and thrombosis, which may contribute to the poor prognosis of patients with severe COVID-19. Targeted inhibition of IL-6 and PAI-1 signal transduction appears to improve treatment outcomes in severely and critically ill COVID-19 patients suffering from cytokine storms and venous thrombosis. Motivated by studies highlighting the relationship between inflammatory cytokines and thrombosis in viral immunology, we provide an overview of the immunothrombosis and immunoinflammation vicious loop between IL-6 and PAI-1. Our goal is that understanding this ferocious circle will benefit critically ill patients with COVID-19 worldwide.
Diagnostic Value of Spectral-Domain Optical Coherence Tomography for Polypoidal Choroidal Vasculopathy: A Systematic Review and Meta-Analysis
Authors: Jiang Yang , Qi Shixin
Published: June 2022

Purpose

To evaluate the diagnostic value of spectral-domain optical coherence tomography (SD-OCT) for polypoidal choroidal vasculopathy (PCV).

Methods

A search of electronic databases was conducted from 2010 to 2021 to review the relevant literature on SD-OCT to identify PCV and other lesions causing serious or serosanguinous retinal pigment epithelial detachment (PED), specifically neovascular age-related macular degeneration (nvAMD). The QUADAS-2 scale was used to evaluate the quality of the literature. We performed a meta-analysis, including heterogeneity tests, analyze and synthesize the study data, meta-regression analysis, subgroup analysis, Fagan's plot, sensitivity analysis and publication bias tests.

Results

A total of 12 related studies involving 1,348 eyes were included in this study, and the random-effects model was used for meta-analysis. The results showed that the pooled sensitivity of SD-OCT in the diagnosis of PCV was 0.87 (95% CI: 0.84–0.89), the pooled specificity was 0.83 (95% CI: 0.80–0.86), and the pooled positive/negative likelihood ratios were 5.38 (95% CI: 3.28–8.80) and 0.16 (95% CI: 0.10–0.25), respectively. The diagnostic odds ratio (DOR) was 36.07 (95% CI: 15.98–81.40), and the area under the sROC curve (AUC) was 0.9429. When the pre–test probability was set at 20%, the post-test positive and negative probabilities were 58% and 4%, respectively. Meta-regression indicated that race was the primary source of heterogeneity (P <0.05). The Deeks' funnel plot showed no significant publication bias in this study (P>0.05).

Conclusion

SD-OCT has high sensitivity and specificity for the diagnosis of PCV, as well as significant clinical applicability. Since color fundus photography (CFP) is more clinically available and can improve the diagnostic efficacy, we recommend SD-OCT combined with CFP to diagnose PCV, especially without indocyanine green angiography (ICGA).

Systematic Review Registration

https://inplasy.com/inplasy-2021-12-0048/, identifier: INPLASY2021120048.
Clinical Patterns and Follow-Up of Inflammatory Arthritis and Other Immune-Related Adverse Events Induced by Checkpoint Inhibitors. A Multicenter Study
Authors: Gómez-Puerta José A. , Lobo-Prat David , Perez-García Carolina , Ponce Andrés , Frade-sosa Beatriz , Millán Arciniegas Ana Milena , Ojeda Fabiola , Ruiz-Esquide Virginia , Corominas Hector
Published: June 2022

Objectives

To describe different clinical patterns of rheumatic immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICI) and their rheumatic and oncologic outcomes.

Methods

We classified clinical syndromes according to five different categories: non-inflammatory arthralgias (NIA), rheumatoid arthritis (RA)-like, psoriatic arthritis (PsA)-like, polymyalgia rheumatica (PMR)-like, and a miscellaneous group of patients with other syndromes. We conducted a baseline visit and then follow-up in order to determine their clinical pattern, treatment response, and outcome.

Results

We included 73 patients (64% male) with a mean age of 66.1 ± 11.6 years. Main underlying diagnosis was lung carcinoma in 29 (39%) patients, melanoma in 20 (27%), and renal-urothelial cancer in 11 (15%). Main ICI included Pembrolizumab in 24 (32%), Nivolumab 17 (23%), and Atezolizumab 7 (9 %). Seventeen out of seventy-three patients had an underlying rheumatic disease before ICI treatment. Fourteen patients developed other irAEs before or simultaneously with rheumatic syndromes. Main rheumatic irAEs included: RA-like in 31 (42.4%), NIA in 19 (26.0%), PMR-like in 10 (13.7%), and PsA-like in 5 (6.8%), among others. Median time from ICI to irAEs was 5 months (IQR 3–9). Those patients who received combined therapy, had a trend for an earlier presentation than those who received monotherapy (4.3 months IQR 1.85–17 vs. 6 months IQR 3–9.25, p = NS). Mean follow-up time was 14.0 ± 10.8 (SD, months). At the last visit, 47 % were taking glucocorticoids and 11% DMARD therapy. At the last visit, 13 (17.8%) patients remained with persistent arthritis, 19 (26%) had intermittent flares, and 39 (53.4%) had a self-limited pattern. Only in 15.1% of patients ICI therapy was discontinued.

Conclusions

We described different patterns according to treatment and irAEs. Combined ICI therapy had an earlier onset of symptoms. Patients who presented as RA-like, had a higher risk of persistent arthritis. After a mean follow-up of more than 1 year, one-fifth of the patients remained with persistent arthritis and 11% required DMARD therapy.
Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease
Authors: Marsal Jan , Barreiro-de Acosta Manuel , Blumenstein Irina , Cappello Maria , Bazin Thomas , Sebastian Shaji
Published: June 2022

Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both “step-up” and “top-down” approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.
The Microbiological Drivers of Temporally Dynamic Dimethylsulfoniopropionate Cycling Processes in Australian Coastal Shelf Waters
Authors: O’Brien James , McParland Erin L. , Bramucci Anna R. , Ostrowski Martin , Siboni Nachshon , Ingleton Timothy , Brown Mark V. , Levine Naomi M. , Laverock Bonnie , Petrou Katherina , Seymour Justin
Published: June 2022

The organic sulfur compounds dimethylsulfoniopropionate (DMSP) and dimethyl sulfoxide (DMSO) play major roles in the marine microbial food web and have substantial climatic importance as sources and sinks of dimethyl sulfide (DMS). Seasonal shifts in the abundance and diversity of the phytoplankton and bacteria that cycle DMSP are likely to impact marine DMS (O) (P) concentrations, but the dynamic nature of these microbial interactions is still poorly resolved. Here, we examined the relationships between microbial community dynamics with DMS (O) (P) concentrations during a 2-year oceanographic time series conducted on the east Australian coast. Heterogenous temporal patterns were apparent in chlorophyll a (chl a) and DMSP concentrations, but the relationship between these parameters varied over time, suggesting the phytoplankton and bacterial community composition were affecting the net DMSP concentrations through differential DMSP production and degradation. Significant increases in DMSP were regularly measured in spring blooms dominated by predicted high DMSP-producing lineages of phytoplankton (Heterocapsa, Prorocentrum, Alexandrium, and Micromonas), while spring blooms that were dominated by predicted low DMSP-producing phytoplankton (Thalassiosira) demonstrated negligible increases in DMSP concentrations. During elevated DMSP concentrations, a significant increase in the relative abundance of the key copiotrophic bacterial lineage Rhodobacterales was accompanied by a three-fold increase in the gene, encoding the first step of DMSP demethylation (dmdA). Significant temporal shifts in DMS concentrations were measured and were significantly correlated with both fractions (0.2–2 μm and >2 μm) of microbial DMSP lyase activity. Seasonal increases of the bacterial DMSP biosynthesis gene (dsyB) and the bacterial DMS oxidation gene (tmm) occurred during the spring-summer and coincided with peaks in DMSP and DMSO concentration, respectively. These findings, along with significant positive relationships between dsyB gene abundance and DMSP, and tmm gene abundance with DMSO, reinforce the significant role planktonic bacteria play in producing DMSP and DMSO in ocean surface waters. Our results highlight the highly dynamic nature and myriad of microbial interactions that govern sulfur cycling in coastal shelf waters and further underpin the importance of microbial ecology in mediating important marine biogeochemical processes.
MicroRNA-124/Death-Associated Protein Kinase 1 Signaling Regulates Neuronal Apoptosis in Traumatic Brain Injury via Phosphorylating NR2B
Authors: Shi Yingwu , Cui Wenxing , Wang Qiang , Zhou Jinpeng , Wu Xun , Wang Jin , Zhang Shenghao , Hu Qing , Han Liying , Du Yong , Ge Shunnan , Liu Haixiao , Qu Yan
Published: June 2022

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine-protein kinase, promotes neurons apoptosis in ischemic stroke and Alzheimer’s disease (AD). We hypothesized that knockdown DAPK1 may play a protective role in traumatic brain injury (TBI) and explore underlying molecular mechanisms. ELISA, Western blotting, immunofluorescence, dual-luciferase assay, and Reverse Transcription and quantitative Polymerase Chain Reaction (RT-qPCR) were used to determine the mechanism for the role of DAPK1 in TBI. Open field and novel objective recognition tests examined motor and memory functions. The morphology and number of synapses were observed by transmission electron microscopy and Golgi staining. DAPK1 was mainly found in neurons and significantly increased in TBI patients and TBI mice. The dual-luciferase assay showed that DAPK1 was upregulated by miR-124 loss. The number of TUNEL+ cells, expression levels of cleaved caspase3 and p-NR2B/NR2B were significantly reduced after knocking-down DAPK1 or overexpressing miR-124 in TBI mice; and motor and memory dysfunction was recovered. After Tat-NR2B were injected in TBI mice, pathological and behavioral changes were mitigated while the morphology while the number of synapses were not affected. Overall, DAPK1 is a downstream target gene of miR-124 that regulates neuronal apoptosis in TBI mice via NR2B. What’s more, DAPK1 restores motor and memory dysfunctions without affecting the number and morphology of synapses.
Renal Health Benefits of Rural City Planning in Japan
Authors: Nagai Kei , Koo Yuk Cheong Daniel , Ueda Atsushi
Published: June 2022

Progression of chronic kidney disease (CKD) is a substantial threat because it is associated with reduced healthy life expectancy and quality of life, and increase in economic burden. Research indicates people with nondialysis CKD often have lower physical functioning and that improvement of physical activity may contribute to maintaining renal health. Another issue with the current treatment of CKD is that the synergistic effects of rural depopulation due to aging and uncontrolled rural city sprawling will increase the number of under-served healthcare areas. To ensure the quality of renal health care, hospital integration is desirable, under the condition of reconstruction of the public transport system for physically and socially vulnerable people. Recently, medical and non-medical scientists advocate the challenge of city planning for population health. The links between city design and health such as cardiovascular disease, obesity, type 2 diabetes and mental disorders, have been widely studied, except for renal health. Based on our experience in a Kidney and Lifestyle-related Disease Center, we propose the idea that city planning be prioritized to improve renal health through two main streams: 1) Improve physical status by use of public and active transportation including daily walking and cycling; and 2) Equal accessibility to renal health services. Many countries, including Japan, have enacted plans and public policy initiatives that encourage increased levels of physical activity. We should focus on the impact of such movement on renal as well as general health.
Correlation Between the Prognosis of Sudden Total Deafness and the Peripheral Blood Inflammation Markers
Authors: Diao Tongxiang , Ke Yujie , Zhang Junbo , Jing Yuanyuan , Ma Xin
Published: June 2022

Objective

To analyze the correlation between prognosis of sudden total deafness (STD) and peripheral blood inflammation markers including white blood cell count (WBC), monocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), fibrinogen (FIB).

Methods

125 patients with STD who were hospitalized in our department from 2014 to 2019 were enrolled. The general physical conditions, clinical manifestations, pure tone audiometry, imaging examination, and peripheral blood inflammation markers were collected, and all patients were divided into effective and ineffective two groups according to the degree of hearing recovery at the time of discharge. Then binary logistic regression was used to analyze the correlation between multiple factors and prognosis, meanwhile the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of the above prognostic factors.

Results

Compared with the ineffective group, patients in the effective group were younger and have higher PLR level and lower FIB levels. Age and PLR are independent prognostic factors. Taking age ≤ 56 years old, PLR >142.6 as the standard to predict the prognosis of patients with STD has the largest AUC with the potential effective rate reaching 78.1%.

Conclusions

Age and PLR are independent prognostic factors for patients with STD. The younger the age and the higher the PLR, the better the prognosis. Clinically, the prognosis of patients with STD can be evaluated by the patient's age and PLR level, which is of great significance to predict the prognosis of patients with STD.
Retroauricular/Transcranial Color-Coded Doppler Ultrasound Approach in Junction With Ipsilateral Neck Compression on Real-Time Hydroacoustic Variation of Venous Pulsatile Tinnitus
Authors: Gao Xiuli , Hsieh Yue-Lin , Wang Xing , Wang Wuqing
Published: June 2022

Alterations in dural venous sinus hemodynamics have recently been suggested as the major contributing factors in venous pulsatile tinnitus (PT). Nevertheless, little is known about the association between real-time alterations in hemodynamics and the subjective perception of venous PT. This study aimed to investigate the hydroacoustic correlations among diverticular vortices, mainstream sinus flow, and PT using various Doppler ultrasound techniques. Nineteen venous PT patients with protrusive diverticulum were recruited. The mainstream sinus and diverticular hemodynamics before and after ipsilateral internal jugular vein (IJV) compression were investigated using an innovative retroauricular color-coded Doppler (RCCD) method to examine the correlation between the disappearance of PT and hemodynamic alterations. To reveal the hydroacoustic characteristics of disparate segments of venous return, a computational fluid dynamics (CFD) technique combined with the transcranial color-coded Doppler method was performed. When the ipsilateral IJV was compressed, PT disappeared, as the mean velocity of mainstream sinus flow and diverticular vortex decreased by 51.2 and 50.6%, respectively. The vortex inside the diverticulum persisted in 18 of 19 subjects. The CFD simulation showed that the flow amplitude generated inside the transverse–sigmoid sinus was segmental, and the largest flow amplitude difference was 20.5 dB. The difference in flow amplitude between the mainstream sinus flow and the diverticular flow was less than 1 dB. In conclusion, the sensation of PT is closely associated with the flow of kinetic energy rather than the formation of a vortex, whereby the amplitude of PT is correlated to the magnitude of the flow velocity and pressure gradient. Additionally, the range of velocity reduction revealed by the RCCD method may serve as a presurgical individual baseline curative marker that may potentially optimize the surgical outcomes.
Defibrotide Prophylaxis of Sinusoidal Obstruction Syndrome in Adults Treated With Inotuzumab Ozogamicin Prior to Hematopoietic Stem Cell Transplantation
Authors: Giglio Fabio , Xue Elisabetta , Greco Raffaella , Lazzari Lorenzo , Clerici Daniela Teresa , Lorentino Francesca , Mastaglio Sara , Marktel Sarah , Lupo-Stanghellini Maria Teresa , Marcatti Magda , Corti Consuelo , Bernardi Massimo , Piemontese Simona , Ciceri Fabio , Peccatori Jacopo
Published: June 2022

Sinusoidal Obstruction Syndrome (SOS) is a life threatening HSCT complication and it can rapidly evolve in Multiple Organ Dysfunction Syndrome, with a mortality exceeding 80%. Early treatment with defibrotide is the leading factor for efficacy. Its prophylactic use is recommended in the pediatric setting, but its value isn’t validated for adults, although factors for individual risk assessment are debated. We here present a real-world experience of Defibrotide prophylaxis in adults at very high risk of SOS. We treated with prophylactic Defibrotide and Ursodeoxycholic Acid seven patients receiving allogeneic HSCT for high risk B-ALL, previously treated with single agent Inotuzomab-Ozogamicin. They all had other high risk factors for SOS such as previous hepatotoxicity, previous allo-HSCT, double alkylating conditioning. All patients received Treosulfan-Fludarabine conditioning, Thiotepa was added in 4 patients and 4GyTBI in 2 patients. GvHD prophylaxis included post-transplant cyclophosphamide, rapamycin and mycophenolate. Donor source was PBSC. Five patients received family MMRD transplant, 1 patient a MRD transplant and 1 patient a MUD transplant. Non-severe gastrointestinal bleeding occurred in two patients requiring defibrotide temporarily discontinuation. SOS occurred in 3/7 cases within 21 days after HSCT and no late-onset SOS were diagnosed. SOS caused death in all cases. All three patients were characterized by a common pattern of very high risk factors by prior HSCT, they all received a myeloablative conditioning with Treosulfan-Thiotepa and a MMRD transplant. Defibrotide prophylaxis apparently failed to protect against the development of SOS in those patients treated with a double alkylator-based conditioning regimen, while a possible efficacy for the other high-risk patients is debatable.
A Randomized Controlled Dose-Escalation Study of LY06006, a Recombinant Humanized Monoclonal Antibody to RANKL, in Chinese Healthy Adults
Authors: Niu Suping , Chen Min , Yan Diqin , Liu Xiangxing , Guo Shuren , Ou Lun , Fan Huaying , Lv Jie , Wang Qian , Dong Wenliang , Xia Lin , Wang Simin , Liu Gang , Gu Qun , Guo Danjie , Liu Hongxia , Rao Huiying , Zheng Qingshan , Nie Xiaoyan , Song Haifeng , Fang Yi
Published: June 2022

Background: This study was conducted to explore the safety, tolerance, pharmacokinetics, pharmacodynamics, and immunogenicity of LY06006, a recombinant humanized monoclonal antibody to RANKL, when administrated subcutaneously in Chinese healthy adults.

Research design and methods: This was a randomized, double-blinded, placebo-controlled, single ascending dose study performed in 32 healthy Chinese adults, who were randomly assigned to receive a single injection dose of 18, 60, 120 mg study drug or placebo with a follow-up of 140–252 days.

Results: No deaths or drug-related serious adverse events occurred. LY06006 was rapidly absorbed in the 60 mg group with a Tmax range of 120–480 h and serum LY06006 concentrations decreased slowly 11–13 days after dosing with a long mean (SD) half-life of 389.58 (63.44) h. The most frequent AEs were elevated serum parathyroid hormone (PTH) level (83.3%), hypocalcemia (54.2%), and hypophosphatemia (45.8%). None of the 32 subjects tested positive for anti-drug antibody during the trial.

Conclusion: Single-dose subcutaneous administration of LY06006 was safe and well-tolerated in healthy Chinese adults. Cmax showed linear pharmacokinetic characteristics in the dose range of 18–120 mg based on dose-exposure proportionality analysis.
UTP Regulates the Cardioprotective Action of Transplanted Stem Cells Derived From Mouse Cardiac Adipose Tissue
Authors: Diaz Villamil Esteban , De Roeck Lucas , Vanorlé Marion , Communi Didier
Published: June 2022

Adipose tissue is a source of stem cells with a high potential of differentiation for cell-based regenerative therapies. We previously identified mouse P2Y2, an ATP and UTP nucleotide receptor, as a regulator of adipogenic and endothelial differentiation of cardiac adipose-derived stem cells (cADSC). We investigated here the potential involvement of P2Y2 receptor in the cardioprotective action of undifferentiated cADSC transplantation in mouse ischemic heart. Transplantation of cADSC was realized in the periphery of the infarcted zone of ischemic heart, 3 days after left anterior descending artery ligation. A strong reduction of collagen stained area was observed 14 days after cADSC injection, compared to PBS injection. Interestingly, loss of P2Y2 expression totally inhibits the ability of transplanted cADSC to reduce cardiac fibrosis. A detailed gene ontology enrichment analysis was realized by comparing RNA-sequencing data obtained for UTP-treated wild type cASDC and UTP-treated P2Y2-null cASDC. We identified UTP target genes linked to extracellular matrix organization such as matrix metalloproteinases and various collagen types, UTP target genes related to macrophage chemotaxis and differentiation into pro-fibrotic foam cells, and a significant number of UTP target genes linked to angiogenesis regulation. More particularly, we showed that UTP regulated the secretion of CCL5, CXCL5, and CCL12 chemokines and serum amyloid apolipoprotein 3, in the supernatants of UTP-treated cADSC. Interestingly, CCL5 is reported as a key factor in post-infarction heart failure and in the reparative and angiogenic action of transplanted ADSC on ischemic tissue. We investigated then if a UTP-pretreatment of cADSC amplifies their effect on cardiac revascularization in mouse ischemic heart. Transplantation of cADSC was able to increase peri-infarct capillary density, 14 days after their injection. This beneficial effect on cardiac revascularization was enhanced by a UTP-pretreatment of cADSC before their transplantation, and not observed using P2Y2-null cADSC. Our data support that the efficacy of transplanted cADSC can be regulated by the release of inflammatory mediators such as extracellular nucleotides in the ischemic site. The present study highlights the P2Y2 receptor as a regulator of cADSC cardioprotective action, and as a potential target for the therapeutic use of undifferentiated cADSC in post-ischemic cardiac ischemia.
Urolithin A Attenuates Hyperuricemic Nephropathy in Fructose-Fed Mice by Impairing STING-NLRP3 Axis-Mediated Inflammatory Response via Restoration of Parkin-Dependent Mitophagy
Authors: Zhang Cong , Song Yingying , Chen Liang , Chen Peng , Yuan Ming , Meng Yan , Wang Qi , Zheng Guohua , Qiu Zhenpeng
Published: June 2022

Urolithin A (UroA) is one of the primary intestinal metabolites of ellagitannins, showing translational potential as a nutritional intervention in humans. Mounting evidence suggests that fructose consumption contributes to the progression of chronic kidney disease (CKD) that manifests in hyperuricemic nephropathy, renal inflammation, and tubulointerstitial injury. Here, we investigated the efficacy of UroA in alleviating fructose-induced hyperuricemic nephropathy in mice. Uric acid-exposed human kidney-2 (HK-2) cells were utilized for in vitro mechanism validation. Histopathological staining, immunoblotting, and transmission electron microscope were performed for the mechanistic investigations. Our results revealed that UroA ameliorated fructose-induced hyperuricemic nephropathy in mice. The histopathologic assessment showed that UroA attenuated tubular hypertrophy and dilation, glomerular basement membrane thickening, and collagen deposition in the kidney of fructose-fed mice. Mechanistically, UroA treatment impaired STING-NLRP3 activation, resulting in reduced production of proinflammatory cytokines IL-1β, IL-6, and TNF-α. Notably, UroA exhibited a scavenging effect against reactive oxygen species (ROS) and restored fructose-impaired PINK1/Parkin-mediated mitophagy in nephropathic mice. Furthermore, the inhibitory effect of UroA in STING-NLRP3 activation was impaired after Parkin gene silencing in HK-2 cells. Together, this study suggests that UroA alleviates fructose-induced hyperuricemic nephropathy by promoting Parkin-dependent mitophagy, thereby suppressing STING-NLRP3 axis-mediated inflammatory response. Thus, dietary supplementation with UroA or ellagitannins-rich foods may serve as a promising intervention to prevent CKD progression.