bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl− efflux signaling pathway
Authors: Zhang Zhen , Xie Shujun , Qian Jin , Gao Fengqiang , Jin Wenjian , Wang Lingqiao , Yan Lili , Chen Hao , Yao Wangxiang , Li Maoqiang , Wang Xuepeng , Zhu Liulong 
Published: July 2023

Abstract
Background
Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease.

Methods
In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice.

Results
The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl− efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model.

Conclusions
Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.
A national assessment of urban forest carbon storage and sequestration in Canada
Authors: Steenberg James W. N. , Ristow Melissa , Duinker Peter N. , Lapointe-Elmrabti Lyna , MacDonald J. Douglas , Nowak David J. , Pasher Jon , Flemming Corey , Samson Cameron 
Published: July 2023

AbstractDuring a time of rapid urban growth and development, it is becoming ever more important to monitor the carbon fluxes of our cities. Unlike Canada’s commercially managed forests that have a long history of inventory and modelling tools, there is both a lack of coordinated data and considerable uncertainty on assessment procedures for urban forest carbon. Nonetheless, independent studies have been carried out across Canada. To improve upon Canada’s federal government reporting on carbon storage and sequestration by urban forests, this study builds on existing data to develop an updated assessment of carbon storage and sequestration for Canada’s urban forests. Using canopy cover estimates derived from ortho-imagery and satellite imagery ranging from 2008 to 2012 and field-based urban forest inventory and assessment data from 16 Canadian cities and one US city, this study found that Canadian urban forests store approximately 27,297.8 kt C (− 37%, + 45%) in above and belowground biomass and sequester approximately 1497.7 kt C year−1 (− 26%, + 28%). In comparison with the previous national assessment of urban forest carbon, this study suggested that in urban areas carbon storage has been overestimated and carbon sequestration has been underestimated. Maximizing urban forest carbon sinks will contribute to Canada’s mitigation efforts and, while being a smaller carbon sink compared to commercial forests, will also provide important ecosystem services and co-benefits to approximately 83% of Canadian people.
A phase 1/2 study of azacitidine, venetoclax and pevonedistat in newly diagnosed secondary AML and in MDS or CMML after failure of hypomethylating agents
Authors: Short Nicholas J. , Muftuoglu Muharrem , Ong Faustine , Nasr Lewis , Macaron Walid , Montalban-Bravo Guillermo , Alvarado Yesid , Basyal Mahesh , Daver Naval , Dinardo Courtney D. , Borthakur Gautam , Jain Nitin , Ohanian Maro , Jabbour Elias , Issa Ghayas C. , Qiao Wei , Huang Xuelin , Kanagal-Shamanna Rashmi , Patel Keyur P. , Bose Prithviraj , Ravandi Farhad , Delumpa Ricardo , Abramova Regina , Garcia-Manero Guillermo , Andreeff Michael , Cortes Jorge , Kantarjian Hagop 
Published: July 2023

Abstract
Background
Pevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.

Methods
This single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m2 IV on days 1–7, venetoclax at maximum dose of 200-400 mg orally on days 1–21 (AML cohort) or days 1–14 (MDS/CMML cohort) and pevonedistat 20 mg/m2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort.

Findings
Forty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61–86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3–4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance.

Conclusions
The triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML.
Trial registration ClinicalTrials.gov (NCT03862157).
Acetylcysteine and budesonide for the treatment of refractory Mycoplasma pneumoniae pneumonia in children: a clinical observation
Authors: Wang Yanli , Liu Kai , Chen Chuangui , Zhang Chengyun 
Published: July 2023

Abstract
Background
To examine the clinical impact of bronchoscope alveolar lavage (BAL) combination with budesonide, ambroxol + budesonide, or acetylcysteine + budesonide in the treatment of refractory Mycoplasma pneumoniae pneumonia (RMPP).

Methods
Eighty-two RMPP patients admitted to Pediatrics at The First People’s Hospital of Zhengzhou were retrospectively evaluated between August 2016 and August 2019. All patients were administered BAL in addition to intravenous Azithromycin, expectoration, and nebulizer inhalation. The medications added to the BLA separated the patients into the Budesonide group, Ambroxol + budesonide group, and acetylcysteine + budesonide group. Analyzed were the variations in laboratory examination indices, improvement in lung imaging, overall effective rate, and adverse responses in the three groups.

Results
The laboratory test indices of patients in all three groups improved significantly relative to pre-treatment levels, and the results were statistically significant. After therapy, there were no significant differences between the three groups in terms of white blood cell (WBC), C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR). Serum lactate dehydrogenase (LDH) and serum ferritin (SF) varied significantly across the three groups (P < 0.05). In the acetylcysteine + budesonide group, the absorption rate of lung imaging lesions and clinical efficacy were superior to those of the other two groups. There were no significant differences between the three groups in the occurrence of adverse events (P > 0.05).

Conclusions
BLA-coupled acetylcysteine + budesonide was superior to the other two groups in enhancing the effectiveness of RMPP in children, which might increase lung opacity absorption and minimize lung inflammation.
Effects of low-dose intravenous heparin therapy in aneurysmal subarachnoid hemorrhage: a randomized controlled clinical trial protocol
Authors: Zhang Yifan , Hu Jiangang 
Published: July 2023

Abstract
Background
Heparin anticoagulation therapy is a widely used method to prevent cerebral vasospasm (CV) and venous thrombosis in patients with subarachnoid hemorrhage caused by ruptured cerebral aneurysms. Subcutaneous heparin injection is considered safe and effective, whereas continuous intravenous heparin infusion is still being debated due to the risk of bleeding. Although most retrospective studies have confirmed the safety and effectiveness of unfractionated heparin (UFH) after aneurysm embolization therapy and its ability to reduce CV, there is still no randomized clinical trial comparing UFH and subcutaneous low-molecular-weight heparin (LMWH) injection in this population. Therefore, this study aims to compare the clinical outcomes associated with these two treatment approaches.

Methods
The study is an open-label, single-center, randomized controlled trial and aims to recruit 456 patients, with 228 patients in each group. The primary outcome was CV; the second outcomes measures are occurrence of bleeding events, ischemic events, heparin-induced thrombocytopenia, deep vein thrombosis, cerebral venous circulation time, brain edema score, and hydrocephalus incidence.

Ethics and dissemination
This study protocol obtained ethical approval from the Ethics Committee of Baoan People’s Hospital, Shenzhen, Guangdong (approval number: BYL20220805). This work will be published in peer-reviewed international medical journals and presented at medical conferences.

Trial registration
ClinicalTrials ID: NCT05696639. Registered on March 30, 2023.
Learnings from clinical trials in patients with connective tissue disease-associated interstitial lung disease
Authors: Higuero Sevilla Jean Paul , Memon Areeka , Hinchcliff Monique 
Published: July 2023

AbstractMany clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD).Herein, we summarize the results of clinical trials, including patient-reported outcome instruments, for the treatment of patients with ILD associated with systemic sclerosis (SSc/scleroderma), rheumatoid arthritis, and idiopathic inflammatory myositis, the diseases with the most available data. For SSc-ILD, the US Food and Drug Administration approved nintedanib (a tyrosine kinase inhibitor) in 2020 and subcutaneous tocilizumab (an IL-6 receptor monoclonal antibody) in 2021. Rituximab was recently shown to have similar efficacy but better tolerability than intravenous cyclophosphamide (CYC) for CTD-ILD therapy. Scleroderma Lung Study II, conducted in patients with SSc-ILD, showed that oral CYC and mycophenolate mofetil (MMF) were comparable in their effects on lung function, but MMF was better tolerated. The increasing treatment armamentarium for patients with CTD-ILD offers physicians new opportunities to improve patient outcomes.
The access route through the anatomical snuffbox in ultrasound-guided synovial biopsy of the wrist allows for a safe and effective collection of tissue samples in inflammatory arthritis
Authors: De Stefano Ludovico , Bugatti Serena , Piccin Veronica , D’Ambrosio Gioacchino , Luvaro Terenzj , Xoxi Blerina , Montecucco Carlomaurizio , Manzo Antonio 
Published: July 2023

Abstract
Background
A proof-of-concept study to evaluate the feasibility and safety of minimally invasive ultrasound (US)-guided synovial biopsy of the radiocarpal (RC) joint using the anatomical snuffbox as an access route.

Methods
Twenty consecutive patients with active chronic arthritis of the wrist underwent minimally invasive US-guided synovial biopsy of the RC joint using the anatomical snuffbox as the access route. Samples were retrieved from 3 predetermined biopsy target sites of the RC synovia (proximal, vault, and distal site), aiming for a minimum of 12 samples. The procedure’s feasibility was evaluated based on the number and histological quality of retrieved tissue fragments tested on pre-defined histometric parameters. The safety and tolerability of the procedure were assessed through 1-week and 1-month follow-up clinical evaluations.

Results
A median number of 17 fragments (≥ 1 mm diameter size at macroscopic evaluation) per procedure was processed for histopathology (range 9–24) and dedicated to the study. At the histopathologic evaluation, a gradable tissue (visible lining layer and ≥ 4 fragments with IST) was recognized in 19/20 biopsies (95%), and all pre-defined histometric parameters were judged applicable and successfully measured in 19/19 gradable biopsies. All three biopsy target sites showed sampling accessibility. The entire procedure was generally well tolerated. At the 1-month follow-up, no patients showed infectious complications.

Conclusions
The access route through the anatomical snuff box in US-guided synovial biopsies of the RC joint allows for a safe and targeted collection of adequate tissue samples. This modification of the traditional access route may allow easier, repeatable, and safer sampling of anatomically distinct areas of the wrist in the course of arthritis.
Horizontal jump asymmetries are associated with reduced range of motion and vertical jump performance in female soccer players
Authors: Roso-Moliner Alberto , Lozano Demetrio , Nobari Hadi , Bishop Chris , Carton-Llorente Antonio , Mainer-Pardos Elena 
Published: July 2023

Abstract
Background
Performance in jumping and change of direction tests are good proxies to reflect the skill level during soccer-specific actions. Greater inter-leg asymmetries have been identified as a risk factor for developing acute and overuse injuries and jeopardizing soccer performance. The aim of this study was to assess the association between asymmetry in the unilateral vertical and horizontal jump tests, ankle range of motion, linear velocity, and change of direction in a sample of highly trained adult female soccer players.

Methods
Thirty-eight highly trained female soccer players underwent a testing protocol including ankle dorsiflexion, single leg jumps for height (CMJ), distance (HJ), 40 m sprint and 180° change of direction tests.

Results
Within-session reliability was acceptable (CV ≤ 7.9%), and relative reliability showed good to excellent (ICC: 0.83 to 0.99). The one-way ANOVA reported higher inter-limb differences for change of direction deficit (10.9 ± 8.04%) and single leg CMJ (5.70 ± 5.22%). Pearson correlations highlighted significant relationships between horizontal jump asymmetries and ankle dorsiflexion (r = -0.41), CMJ (r = -0.36 to -0.49) and HJ (r = -0.28 to -0.56).

Conclusions
Assessing inter-limb asymmetries through different methods can help scientists understand the specificity of their detrimental effects on soccer performance. Practitioners should be aware of these specificities as well as the magnitude and direction of the asymmetries when aiming to improve specific on-field skills.
Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome
Authors: Shang Haitao , Huang Chao , Xiao Zhuanglong , Yang Pengcheng , Zhang Shengyan , Hou Xiaohua , Zhang Lei 
Published: July 2023

Abstract
Background and aims
Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury, such as pyrrolizidine alkaloids, to the liver sinusoidal endothelial cells, and the gut microbiota may be involved. However, the specific role and underlying mechanism of gut microbiota in HSOS is unknown.

Methods
HSOS model was established by gavage of monocrotaline (MCT) in rats. Fecal microbiota transplantation (FMT) with HSOS-derived or healthy gut flora was also conducted to validate the role of gut microflora in MCT-induced liver injury. The microbial 16 s rRNA analysis and untargeted metabolomics analysis in the faeces were performed to identify HSOS-related flora and metabolites. Finally, by supplementation with specific tryptophan metabolites, such as indole-3-acetaldehyde (IAAld) and indole acetic acid (IAA), we further confirmed the role of tryptophan metabolism in HSOS and the role of the AhR/Nrf2 pathway in MCT-induced liver injury.

Results
MCT induced HSOS-like liver injury in rats with significantly altered gut microbiota. Particularly, some tryptophan-metabolizing bacteria reduced in MCT-treated rats, such as Bacteroides, Bifidobacterium, Lactobacillus and Clostridium, and accompanied by a decrease in microbial tryptophan metabolic activity and a series of tryptophan derivatives. Restoring the gut microbiota via FMT improved MCT-induced liver damage, while HSOS-derived gut microbiota aggravated the liver injury induced by MCT. Supplementation with microbial tryptophan derivatives (IAAld or IAA), or 6-formylindolo(3,2-b)carbazole (Ficz, an AhR agonist) could activate the AhR/Nrf2 signaling pathway, thereby attenuating the MCT-induced liver oxidative stress and liver sinusoidal endothelial cells injury.

Conclusions
Gut microbiota plays a critical role in MCT-induced HSOS, with inadequate microbial tryptophan metabolism in the gut and consequently a lower activity of the AhR/Nrf2 signaling pathway in the liver, which should be a potential target for the management of HSOS.
Intermittent body composition analysis as monitoring tool for muscle wasting in critically ill COVID-19 patients
Authors: Kolck Johannes , Rako Zvonimir A. , Beetz Nick L. , Auer Timo A. , Segger Laura K. , Pille Christian , Penzkofer Tobias , Fehrenbach Uli , Geisel Dominik 
Published: July 2023

Abstract
Objectives
SARS-CoV-2 virus infection can lead to acute respiratory distress syndrome (ARDS), which can be complicated by severe muscle wasting. Until now, data on muscle loss of critically ill COVID-19 patients are limited, while computed tomography (CT) scans for clinical follow-up are available. We sought to investigate the parameters of muscle wasting in these patients by being the first to test the clinical application of body composition analysis (BCA) as an intermittent monitoring tool.

Materials
BCA was conducted on 54 patients, with a minimum of three measurements taken during hospitalization, totaling 239 assessments. Changes in psoas- (PMA) and total abdominal muscle area (TAMA) were assessed by linear mixed model analysis. PMA was calculated as relative muscle loss per day for the entire monitoring period, as well as for the interval between each consecutive scan. Cox regression was applied to analyze associations with survival. Receiver operating characteristic (ROC) analysis and Youden index were used to define a decay cut-off.

Results
Intermittent BCA revealed significantly higher long-term PMA loss rates of 2.62% (vs. 1.16%, p < 0.001) and maximum muscle decay of 5.48% (vs. 3.66%, p = 0.039) per day in non-survivors. The first available decay rate did not significantly differ between survival groups but showed significant associations with survival in Cox regression (p = 0.011). In ROC analysis, PMA loss averaged over the stay had the greatest discriminatory power (AUC = 0.777) for survival. A long-term PMA decline per day of 1.84% was defined as a threshold; muscle loss beyond this cut-off proved to be a significant BCA-derived predictor of mortality.

Conclusion
Muscle wasting in critically ill COVID-19 patients is severe and correlates with survival. Intermittent BCA derived from clinically indicated CT scans proved to be a valuable monitoring tool, which allows identification of individuals at risk for adverse outcomes and has great potential to support critical care decision-making.
The relationship between aspirin consumption and hepatocellular carcinoma: a systematic review and meta-analysis
Authors: Wang Shuai , Zuo Lijuan , Lin Zhaojin , Yang Zhiqin , Chen Ran , Xu Yan 
Published: July 2023

AbstractBackgroundRecent studies have shown that aspirin consumption may reduce the risk of hepatocellular carcinoma (HCC), but their correlation is still not fully understood. This meta-analysis aimed to investigate the correlation between aspirin consumption and HCC.MethodsA systematic literature search was conducted on PubMed, Scopus, Cochrane Library, EMBASE, and Web of Science databases. The search period was from the establishment of the database to July 1, 2022 with no language restrictions.ResultsA total of 19 studies including three prospective studies and 16 retrospective ones with 2,217,712 patients were included. Compared with those who did not take aspirin, those who took aspirin had a 30% lower risk of HCC (hazard ratio [HR] = 0.70, 95% confidence interval [CI] 0.63–0.76,I2 = 84.7%,P < 0.001). Subgroup analysis showed that aspirin significantly reduced the risk of HCC by 19% in Asia (HR = 0.81, 95% CI 0.80–0.82,I2 = 85.2%,P < 0.001) and by 33% (HR = 0.67, 95% CI 0.61–0.73,I2 = 43.6%,P = 0.150) in Europe and the U.S with no significant difference. Moreover, in patients with HBV or HCV infection, aspirin reduced 19% and 24% of the risk of HCC, respectively. However, aspirin administration might increase risks of gastrointestinal bleeding in patients with chronic liver disease (HR = 1.14, 95% CI 0.99–1.31,I2 = 0.0%,P = 0.712). Sensitivity analysis showed no significant difference of results after excluding individual studies, suggesting that the results were robust.ConclusionAspirin may reduce the risk of HCC in both healthy population and patients with chronic liver disease. However, attention should be paid to adverse events such as gastrointestinal bleeding in patients with chronic liver disease.