bluuebunny/crossref_metadata_2025 huggingface dataset:
Acute-to-chronic glycemic ratio as an outcome predictor in ischemic stroke in patients with and without diabetes mellitus
Authors: Climent Elisenda , Rodriguez-Campello Ana , Jiménez-Balado Joan , Fernández-Miró Mercè , Jiménez-Conde Jordi , Llauradó Gemma , Ois Ángel , Flores Juana A. , Cuadrado-Godia Elisa , Steinhauer Eva Giralt , Chillarón Juan J. ,   Neurovascular Research Group (NEUVAS), Perez Isabel Fernandez , Gomez Adrià Macías , Perez Antoni Suarez , Alonso Daniel Guisado , Prats Marta Vallverdú
Published: June 2024

Objective

Elevated plasma glucose levels are common in patients suffering acute ischemic stroke (AIS), and acute hyperglycemia has been defined as an independent determinant of adverse outcomes. The impact of acute-to-chronic glycemic ratio (ACR) has been analyzed in other diseases, but its impact on AIS prognosis remains unclear. The main aim of this study was to assess whether the ACR was associated with a 3-month poor prognosis in patients with AIS.

Research, design and methods

Retrospective analysis of patients admitted for AIS in Hospital del Mar, Barcelona. To estimate the chronic glucose levels (CGL) we used the formula eCGL= [28.7xHbA1c (%)]-46.7. The ACR (glycemic at admission / eCGL) was calculated for all subjects. Tertile 1 was defined as: 0.28–0.92, tertile 2: 0.92–1.13 and tertile 3: > 1.13. Poor prognosis at 3 months after stroke was defined as mRS score 3–6.

Results

2.774 subjects with AIS diagnosis were included. Age, presence of diabetes, previous disability (mRS), initial severity (NIHSS) and revascularization therapy were associated with poor prognosis (p values < 0.05). For each 0.1 increase in ACR, there was a 7% increase in the risk of presenting a poor outcome. The 3rd ACR tertile was independently associated with a poor prognosis and mortality. In the ROC curves, adding the ACR variable to the classical clinical model did not increase the prediction of AIS prognosis (0.786 vs. 0.781).

Conclusions

ACR was positively associated with a poor prognosis and mortality at 3-months follow-up after AIS. Subjects included in the 3rd ACR tertile presented a higher risk of poor prognosis and mortality. Baseline glucose or ACR did not add predictive value in comparison to only using classical clinical variables.
Integrated profiling identifies DXS253E as a potential prognostic marker in colorectal cancer
Authors: Xing Pu , Hao Hao , Chen Jiangbo , Qiao Xiaowen , Song Tongkun , Yang Xinying , Weng Kai , Hou Yifan , Chen Jie , Wang Zaozao , Di Jiabo , Jiang Beihai , Xing Jiadi , Su Xiangqian
Published: June 2024

Background

Increasing evidence suggests that DXS253E is critical for cancer development and progression, but the function and potential mechanism of DXS253E in colorectal cancer (CRC) remain largely unknown. In this study, we evaluated the clinical significance and explored the underlying mechanism of DXS253E in CRC.

Methods

DXS253E expression in cancer tissues was investigated using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The Kaplan-Meier plot was used to assess the prognosis of DXS253E. The cBioPortal, MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were employed to analyze the mutation profile, methylation, and immune infiltration associated with DXS253E. The biological functions of DXS253E in CRC cells were determined by CCK-8 assay, plate cloning assay, Transwell assay, flow cytometry, lactate assay, western blot, and qRT-PCR.

Results

DXS253E was upregulated in CRC tissues and high DXS253E expression levels were correlated with poor survival in CRC patients. Our bioinformatics analyses showed that high DXS253E gene methylation levels were associated with the favorable prognosis of CRC patients. Furthermore, DXS253E levels were linked to the expression levels of several immunomodulatory genes and an abundance of immune cells. Mechanistically, the overexpression of DXS253E enhanced proliferation, migration, invasion, and the aerobic glycolysis of CRC cells through the AKT/mTOR pathway.

Conclusions

We demonstrated that DXS253E functions as a potential role in CRC progression and may serve as an indicator of outcomes and a therapeutic target for regulating the AKT/mTOR pathway in CRC.
Circ6834 suppresses non-small cell lung cancer progression by destabilizing ANHAK and regulating miR-873-5p/TXNIP axis
Authors: Wang Maoye , Ding Xiaoge , Fang Xinjian , Xu Jing , Chen Yanke , Qian Yu , Zhang Jiahui , Yu Dan , Zhang Xiaoxin , Ma Xiuqin , Zhu Taofeng , Gu Jianmei , Zhang Xu
Published: June 2024

Background

Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear.

Methods

In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments.

Results

Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells.

Conclusion

In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.
Targeting SUMOylation with an injectable nanocomposite hydrogel to optimize radiofrequency ablation therapy for hepatocellular carcinoma
Authors: Liu Junfeng , Li Xi , Chen Jiawen , Guo Jingpei , Guo Hui , Zhang Xiaoting , Fan Jinming , Zhang Ke , Mao Junjie , Zhou Bin
Published: June 2024

Background

Incomplete radiofrequency ablation (iRFA) in hepatocellular carcinoma (HCC) often leads to local recurrence and distant metastasis of the residual tumor. This is closely linked to the development of a tumor immunosuppressive environment (TIME). In this study, underlying mechanisms and potential therapeutic targets involved in the formation of TIME in residual tumors following iRFA were explored. Then, TAK-981-loaded nanocomposite hydrogel was constructed, and its therapeutic effects on residual tumors were investigated.

Results

This study reveals that the upregulation of small ubiquitin-like modifier 2 (Sumo2) and activated SUMOylation is intricately tied to immunosuppression in residual tumors post-iRFA. Both knockdown of Sumo2 and inhibiting SUMOylation with TAK-981 activate IFN-1 signaling in HCC cells, thereby promoting dendritic cell maturation. Herein, we propose an injectable PDLLA-PEG-PDLLA (PLEL) nanocomposite hydrogel which incorporates self-assembled TAK-981 and BSA nanoparticles for complementary localized treatment of residual tumor after iRFA. The sustained release of TAK-981 from this hydrogel curbs the expansion of residual tumors and notably stimulates the dendritic cell and cytotoxic lymphocyte-mediated antitumor immune response in residual tumors while maintaining biosafety. Furthermore, the treatment with TAK-981 nanocomposite hydrogel resulted in a widespread elevation in PD-L1 levels. Combining TAK-981 nanocomposite hydrogel with PD-L1 blockade therapy synergistically eradicates residual tumors and suppresses distant tumors.

Conclusions

These findings underscore the potential of the TAK-981-based strategy as an effective therapy to enhance RFA therapy for HCC.

Graphic Abstract
Exosomes as drug delivery systems in glioma immunotherapy
Authors: Hao Xinqing , Wang Shiming , Wang Liang , Li Jiaqi , Li Ying , Liu Jing
Published: June 2024

Recently, the significant benefits of cancer immunotherapy for most cancers have been demonstrated in clinical and preclinical studies. However, the efficacy of these immunotherapies for gliomas is limited, owing to restricted drug delivery and insufficient immune activation. As drug carriers, exosomes offer the advantages of low toxicity, good biocompatibility, and intrinsic cell targeting, which could enhance glioma immunotherapy efficacy. However, a review of exosome-based drug delivery systems for glioma immunotherapy has not been presented. This review introduces the current problems in glioma immunotherapy and the role of exosomes in addressing these issues. Meanwhile, preparation and application strategies of exosome-based drug delivery systems for glioma immunotherapy are discussed, especially for enhancing immunogenicity and reversing the immunosuppressive tumor microenvironment. Finally, we briefly describe the challenges of exosome-based drug delivery systems in clinical translation. We anticipate that this review will guide the use of exosomes as drug carriers for glioma immunotherapy.

Graphical Abstract
Single-cell RNA transcriptomic reveal the mechanism of MSC derived small extracellular vesicles against DKD fibrosis
Authors: Ji Cheng , Zhang Jiahui , Shi Hui , Chen Binghai , Xu Wenrong , Jin Jianhua , Qian Hui
Published: June 2024

Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-β1+Arg1+macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-β1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/β-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.
3D stem-like spheroids-on-a-chip for personalized combinatorial drug testing in oral cancer
Authors: Mehta Viraj , Vilikkathala Sudhakaran Sukanya , Nellore Vijaykumar , Madduri Srinivas , Rath Subha Narayan
Published: June 2024

Background

Functional drug testing (FDT) with patient-derived tumor cells in microfluidic devices is gaining popularity. However, the majority of previously reported microfluidic devices for FDT were limited by at least one of these factors: lengthy fabrication procedures, absence of tumor progenitor cells, lack of clinical correlation, and mono-drug therapy testing. Furthermore, personalized microfluidic models based on spheroids derived from oral cancer patients remain to be thoroughly validated. Overcoming the limitations, we develop 3D printed mold-based, dynamic, and personalized oral stem-like spheroids-on-a-chip, featuring unique serpentine loops and flat-bottom microwells arrangement.

Results

This unique arrangement enables the screening of seven combinations of three drugs on chemoresistive cancer stem-like cells. Oral cancer patients-derived stem-like spheroids (CD 44+) remains highly viable (> 90%) for 5 days. Treatment with a well-known oral cancer chemotherapy regimen (paclitaxel, 5 fluorouracil, and cisplatin) at clinically relevant dosages results in heterogeneous drug responses in spheroids. These spheroids are derived from three oral cancer patients, each diagnosed with either well-differentiated or moderately-differentiated squamous cell carcinoma. Oral spheroids exhibit dissimilar morphology, size, and oral tumor-relevant oxygen levels (< 5% O2). These features correlate with the drug responses and clinical diagnosis from each patient’s histopathological report.

Conclusions

Overall, we demonstrate the influence of tumor differentiation status on treatment responses, which has been rarely carried out in the previous reports. To the best of our knowledge, this is the first report demonstrating extensive work on development of microfluidic based oral cancer spheroid model for personalized combinatorial drug screening. Furthermore, the obtained clinical correlation of drug screening data represents a significant advancement over previously reported personalized spheroid-based microfluidic devices. Finally, the maintenance of patient-derived spheroids with high viability under oral cancer relevant oxygen levels of less than 5% O2 is a more realistic representation of solid tumor microenvironment in our developed device.

Graphical Abstract
Neoadjuvant PD-(L)1 blockade plus platinum-based chemotherapy for potentially resectable oncogene-positive non-small cell lung cancer
Authors: Zhang Xuchen , Zhang Hefeng , Hou Feng , Fang Tao , Zhang Chuantao , Wang Huiyun , Song Shanai , Lan Hongwei , Wang Yongjie , Hou Helei
Published: June 2024

Background

Whether programmed cell death-1/ligand-1 (PD-1/PD-L1) blockade-based neoadjuvant treatment may benefit locally advanced oncogene-mutant non–small cell lung cancer (NSCLC) patients remains controversial. This retrospective study was designed to observe the efficacy and safety of neoadjuvant PD-1/PD-L1 blockade plus chemotherapy versus chemotherapy and corresponding tyrosine kinase inhibitors (TKIs) in patients with resectable oncogene-positive NSCLC.

Methods

Patients with potential resectable NSCLC harbouring oncogene alterations who had received neoadjuvant treatment were retrospectively recruited, and an oncogene-negative cohort of patients who received neoadjuvant PD-(L)1 blockade-based neoadjuvant treatment was reviewed for comparison during the same period. The primary aim was to observe the treatment efficacy and event-free survival (EFS) of these agents. Safety profile, molecular target, and immunologic factor data, including PD-L1 expression and tumour mutational burden (TMB), were also obtained.

Results

A total of 46 patients were recruited. Thirty-one of them harboured oncogene alterations, includingEGFR,KRAS,ERBB2,ROS1,MET,RET,ALK, andFGFR3alterations. Among the oncogene-positive patients, 18 patients received neoadjuvant PD-(L)1 blockade immunotherapy plus chemotherapy (oncogene-positive IO group), 13 patients were treated with neoadjuvant chemotherapy and/or corresponding TKIs or TKIs alone (oncogene-positive chemo/TKIs group), and the other 15 patients were oncogene negative and received neoadjuvant PD-(L)1 blockade plus chemotherapy (oncogene-negative IO group). The pathological complete response (pCR) and major pathological response (MPR) rates were 22.2% (4 of 18) and 44.4% (8 of 18) in the oncogene-positive IO group, 0% (P = 0.120) and 23.1% (3 of 13) (P = 0.276) in the oncogene-positive chemo/TKIs group, and 46.7% (7 of 15) (P = 0.163) and 80.0% (12 of 15) (P = 0.072) in the oncogene-negative IO group, respectively. By the last follow-up, the median EFS time had not reached in the oncogene-positive IO group, and was 29.5 months in the oncogene-positive chemo/TKIs group and 38.4 months in the oncogene-negative IO group.

Conclusion

Compared with chemotherapy/TKIs treatment, neoadjuvant treatment with PD-(L)1 blockade plus platinum-based chemotherapy was associated with higher pCR/MPR rates in patients with partially resectable oncogene-mutant NSCLC, while the pCR/MPR rates were lower than their oncogene-negative counterparts treated with PD-(L)1 blockade-based treatment. Specifically, oncogene alteration types and other predictors of response to immunotherapy should be taken into account in clinical practice.
Physician assistants/associates in psychiatry: a workforce analysis
Authors: Bruza-Augatis Mirela , Kozikowski Andrzej , Hooker Roderick S. , Puckett Kasey
Published: June 2024

Background

Physician assistants/associates (PAs) provide services in diverse medical specialties globally, including psychiatry. While health professionals in psychiatry have been described for many years, little is known about PAs practicing in this discipline.

Methods

We describe US PAs practicing in psychiatry using robust national data from the National Commission on Certification of Physician Assistants (NCCPA). Analyses included descriptive and inferential statistics comparing PAs in psychiatry to PAs in all other medical and surgical specialties.

Results

The percentage of PAs practicing in psychiatry has increased from 1.1% (n = 630) in 2013 to 2.0% (n = 2 262) in 2021. PAs in psychiatry differed from PAs practicing in all other specialties in the following: they identified predominately as female (71.4% vs. 69.1%; p = 0.016), were more racially diverse (Asian [6.6% vs. 6.0%], Black/African American [5.5% vs. 3.4%], multi-race [2.8% vs. 2.1%], and other races [Native Hawaiian/Pacific Islander, American Indian/Alaska Native, or other; 3.7% vs. 3.6%]; p < 0.001), and resided in the South (43.8% vs. 34.1%; p < 0.001). PAs in psychiatry vs. all other specialties were more likely to work in office-based private practice settings (41.6% vs. 37.3%; p < 0.001) and nearly twice as likely to provide telemedicine services for their patients (62.7% vs. 32.9%; p < 0.001). While one-third (31.9%) of PAs in psychiatry experienced one or more burnout symptoms, and 8.1% considered changing their current position, the vast majority of PAs in psychiatry (86.0%) were satisfied with their position.

Conclusions

Understanding the attributes of PAs in psychiatry is essential in medical labor supply and demand research. Our findings suggest that the number of PAs working in psychiatry is steadily increasing. These PAs were predominantly female, exhibited greater racial diversity, and were primarily located in the South and Midwest regions of the US. A striking difference was that PAs in psychiatry were almost twice as likely to provide telemedicine services for their patients. Although nearly a third of PAs in psychiatry acknowledged having one or more symptoms of burnout, few were considering changing their employment, and the vast majority reported high job satisfaction.
A novel approach to alleviate acetaminophen-induced hepatotoxicity with hybrid balloon flower root-derived exosome-like nanoparticles (BDEs) with silymarin via inhibition of hepatocyte MAPK pathway and apoptosis
Authors: Kim Jisu , Gao Chao , Guo Pengcheng , Sheng Jianyong , Wang Jianxin
Published: June 2024

Introduction

Balloon flower root-derived exosome-like nanoparticles (BDEs) have recently been proposed as physiologically active molecules with no cytotoxicity. However, the therapeutic effects of drug-induced hepatotoxicity of BDEs have not been elucidated. BDEs contain a large amount of platycodin D, which is widely known to be effective in regulating inflammation and ameliorating systemic toxicity. Thus, the main therapeutic activity of BDEs is attributed to inhibiting the inflammatory response and alleviating toxicity. In this study, we fabricated the hybrid BDEs fused with liposomes containing silymarin (SM) to enhance the synergistic effect on inhibition of acetaminophen-induced hepatotoxicity (APAP).

Objective

Considering the potential therapeutic effects of BDEs, and the potential to achieve synergistic effects to improve therapeutic outcomes, we constructed hybrid BDEs with a soy lecithin-based liposome loaded with SM. Since liposomes can provide higher thermal stability and have greater structural integrity, these might be more resistant to clearance and enzymatic degradation of drug molecules.

Methods

Hybrid BDEs with liposome-loaded SM (BDEs@lipo-SM) were fabricated by thin-film hydration and extrusion. BDEs@lipo-SM were characterized using dynamic light scattering and high-performance liquid chromatography. After confirmation of the physical properties of BDEs@lipo-SM, various therapeutic properties were evaluated.

Results

BDEs@lipo-SM were internalized by hepatocytes and immune cells and significantly decreased mRNA expression of apoptosis and inflammation-relevant cytokines by inhibiting the hepatocyte MAPK pathway. BDEs@lipo-SM significantly induced an increase in glutathione levels and inhibited APAP-induced hepatotoxicity.

Conclusion

From this study, we know that BDEs are reliable and safe nanovesicles containing natural metabolites derived from balloon flower, and they can facilitate intercellular communication. BDEs are also easily modified to enhance drug loading capacity, targeting effects, and long-term accumulation in vivo. BDEs@lipo-SM have therapeutic benefits for acute liver injury and can alleviate cell death and toxicity. They can be efficiently delivered to the liver and effectively inhibit APAP-induced hepatotoxicity by inhibiting the MAPK signaling pathway and apoptosis, which accelerates liver recovery in the APAP-induced acute liver injury model. These findings highlight that BDEs represent an attractive delivery vehicle for drug delivery.

Graphical abstract
CT-based delta-radiomics nomogram to predict pathological complete response after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma patients
Authors: Fan Liyuan , Yang Zhe , Chang Minghui , Chen Zheng , Wen Qiang
Published: June 2024

Background

This study developed a nomogram model using CT-based delta-radiomics features and clinical factors to predict pathological complete response (pCR) in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT).

Methods

The study retrospectively analyzed 232 ESCC patients who underwent pretreatment and post-treatment CT scans. Patients were divided into training (n = 186) and validation (n = 46) sets through fivefold cross-validation. 837 radiomics features were extracted from regions of interest (ROIs) delineations on CT images before and after nCRT to calculate delta values. The LASSO algorithm selected delta-radiomics features (DRF) based on classification performance. Logistic regression constructed a nomogram incorporating DRFs and clinical factors. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses evaluated nomogram performance for predicting pCR.

Results

No significant differences existed between the training and validation datasets. The 4-feature delta-radiomics signature (DRS) demonstrated good predictive accuracy for pCR, with α-binormal-based and empirical AUCs of 0.871 and 0.869. T-stage (p = 0.001) and differentiation degree (p = 0.018) were independent predictors of pCR. The nomogram combined the DRS and clinical factors improved the classification performance in the training dataset (AUCαbin = 0.933 and AUCemp = 0.941). The validation set showed similar performance with AUCs of 0.958 and 0.962.

Conclusions

The CT-based delta-radiomics nomogram model with clinical factors provided high predictive accuracy for pCR in ESCC patients after nCRT.
Mutational variant allele frequency profile as a biomarker of response to immune checkpoint blockade in non-small cell lung Cancer
Authors: Gao Ruyun , Lou Ning , Li Lin , Xie Tongji , Xing Puyuan , Tang Le , Yao Jiarui , Han Xiaohong , Shi Yuankai
Published: June 2024

Introduction

Identifying new biomarkers for predicting immune checkpoint inhibitors (ICIs) response in non-small cell lung cancer (NSCLC) is crucial. We aimed to assess the variant allele frequency (VAF)-related profile as a novel biomarker for NSCLC personalized therapy.

Methods

We utilized genomic data of 915 NSCLC patients via cBioPortal and a local cohort of 23 patients for model construction and mutational analysis. Genomic, transcriptomic data from 952 TCGA NSCLC patients, and immunofluorescence (IF) assessment with the local cohort supported mechanism analysis.

Results

Utilizing the random forest algorithm, a 15-gene VAF-related model was established, differentiating patients with durable clinical benefit (DCB) from no durable benefit (NDB). The model demonstrated robust performance, with ROC-AUC values of 0.905, 0.737, and 0.711 across training (n = 313), internal validation (n = 133), and external validation (n = 157) cohorts. Stratification by the model into high- and low-score groups correlated significantly with both progression-free survival (PFS) (training: P < 0.0001, internal validation: P < 0.0001, external validation: P = 0.0066) and overall survival (OS) (n = 341) (P < 0.0001). Notably, the stratification system was independent of PD-L1 (P < 0.0001) and TMB (P < 0.0001). High-score patients exhibited an increased DCB ratio and longer PFS across both PD-L1 and TMB subgroups. Additionally, the high-score group appeared influenced by tobacco exposure, with activated DNA damage response pathways. Whereas, immune/inflammation-related pathways were enriched in the low-score group. Tumor immune microenvironment analyses revealed higher proportions of exhausted/effector memory CD8 + T cells in the high-score group.

Conclusions

The mutational VAF profile is a promising biomarker for ICI therapy in NSCLC, with enhanced therapeutic stratification and management as a supplement to PD-L1 or TMB.
The effect of different preventive strategies during total joint arthroplasty on periprosthetic joint infection: a network meta-analysis
Authors: Wu Yongtao , Xiang Xinni , Ma Yimei
Published: June 2024

Background

Periprosthetic joint infection after total joint arthroplasty has a large incidence, and it may often require two or more stages of revision, placing an additional burden on clinicians and patients. The purpose of this network meta-analysis is to evaluate the effect of four different preventive strategies during total joint arthroplasty on the prevention of periprosthetic joint infection.

Methods

The study protocol was registered at PROSPERO (CRD: 42,023,448,868), and the literature search databases included Web of Science, PubMed, OVID Cochrane Central Register of Controlled Trials, OVID EMBASE, and OVID MEDLINE (R) ALL that met the requirements. The network meta-analysis included randomized controlled trials, retrospective cohort studies and prospective cohort studies with the outcome of periprosthetic joint infection. The gemtc R package was applied to perform the network meta-analysis to evaluate the relative results of different preventive strategies.

Results

This network meta-analysis study included a total of 38 articles with 4 preventive strategies and negative controls. No improvement was observed in antibiotic-loaded bone cement compared with negative controls. Chlorhexidine showed the highest probability of delivering the best preventive effect, and povidone iodine had the second highest probability. Although vancomycin ranked after chlorhexidine and povidone iodine, it still showed a significant difference compared with negative controls. In addition, the incidence after applying chlorhexidine was significantly lower than that after applying negative controls and vancomycin. In the heterogeneity test between direct and indirect evidence, there was no apparent heterogeneity between them.

Conclusion

The study indicated that chlorhexidine, povidone iodine and vancomycin showed significant efficacy in preventing periprosthetic joint infection after total joint arthroplasty, while antibiotic-loaded bone cement did not. Therefore, more high-quality randomized controlled trials are needed to verify the results above.
Central imaging based on near-infrared functional imaging technology can be useful to plan management in patients with chronic lateral ankle instability
Authors: Luo Xiaoming , Huang Ben , Huang Yonglei , Li Ming , Niu Wenxin , Wang Taoli
Published: June 2024

Background

Near infrared brain functional imaging (FNIRS) has been used for the evaluation of brain functional areas, the imaging differences of central activation of cognitive-motor dual tasks between patients with chronic lateral ankle instability (CLAI) and healthy population remain unclear. This study aimed to evaluated the role of central imaging based on FNIRS technology on the plan management in patients with CLAI, to provide insights to the clinical treatment of CLAI.

Methods

CLAI patients treated in our hospital from January 1, 2021 to June 31, 2022 were selected. Both CLAI patients and health controls were intervened with simple task and cognitive-motor dual task under sitting and walking conditions, and the changes of oxygenated hemoglobin concentration in bilateral prefrontal cortex (PFC), premotor cortex (PMC) and auxiliary motor area (SMA) were collected and compared.

Results

A total of 23 participants were enrolled. There were significant differences in the fNIRS ΔHbO2of barefoot subtractive walking PFC-R and barefoot subtractive walking SMA-R between experimental and control group (allP < 0.05). There was no significant difference in ΔHbO2between the experimental group and the control group in other states (P > 0.05). There was no significant difference in ΔHbO2between the experimental group and the control group in each state of the brain PMC region.

Conclusion

Adaptive alterations may occur within the relevant brain functional regions of individuals with CLAI. The differential activation observed between the PFC and the SMA could represent a compensatory mechanism emerging from proprioceptive afferent disruptions following an initial ankle sprain.
Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging
Authors: Roy Ethan R. , Li Sanming , Saroukhani Sepideh , Wang Yanyu , Cao Wei
Published: June 2024

Background

Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.

Methods

To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters.

Results

We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain.

Conclusions

Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.
Proof of mechanism investigation of Transcutaneous auricular vagus nerve stimulation through simultaneous measurement of autonomic functions: a randomized controlled trial protocol
Authors: Katsunuma Ruri , Takamura Tsunehiko , Yamada Mitsuhiko , Sekiguchi Atsushi
Published: June 2024

Background

The autonomic nervous system plays a vital role in regulating physiological functions. Transcutaneous auricular vagus nerve stimulation (taVNS) is a method that provides insights into autonomic nerve modulation. This paper presents a research protocol investigating proof of mechanism for the impact of taVNS on autonomic functions and aims to both deepen theoretical understanding and pave the way for clinically relevant applications.

Methods

This protocol employs a single-blind, randomized cross-over design involving 10 healthy male participants. Simultaneous assessment of both the afferent and efferent aspects of the vagus nerve will be performed by integrating physiological measures, magnetic resonance imaging, and a questionnaire survey. Electrocardiogram will be measured to assess changes in heart rate, as a primary outcome, and heart rate variability. Active taVNS and sham stimulation will be compared, which ensures precision and blinding. Electrical stimulation will be applied to the leftconcha cymbaand the leftlobulefor the active and sham conditions, respectively. The specific parameters of taVNS involve a pulse width of 250 µs, a frequency of 25 Hz, and a current adjusted to the perception threshold (0.1 mA ≤ 5 mA), delivered in cycles of 32 s on and 28 s off.

Conclusions

This research investigates proof of mechanism for taVNS to elucidate its modulatory effects on the central and peripheral components of the autonomic nervous system. Beyond theoretical insights, the findings will provide a foundation for designing targeted neuromodulation strategies, potentially benefiting diverse patient populations experiencing autonomic dysregulation. By elucidating the neural mechanisms, this study contributes to the evolution of personalized and effective clinical interventions in the field of neuromodulation.

Trial Registration

JRCT, jRCTs032220332, Registered 13 September 2022;https://jrct.niph.go.jp/latest-detail/jRCTs032220332.
C-MYC-activated lncRNA SNHG20 accelerates the proliferation of diffuse large B cell lymphoma via USP14-mediated deubiquitination of β-catenin
Authors: Wang Chaoyu , Fu Wen , Zhang Youju , Hu Xiaoge , Xu Qiuran , Tong Xiangmin
Published: June 2024

Background

Long noncoding RNAs (lncRNAs) are implicated in the initiation and progression of diffuse large B-cell lymphoma (DLBCL). Small nucleolar RNA host gene 20 (SNHG20) has been recognized as a critical lncRNA in multiple human cancers. However, the role of SNHG20 and its underlying mechanism in DLBCL are still unclear.

Methods

The expression levels of SNHG20, c-MYC, β-catenin, and ubiquitin-specific peptidase 14 (USP14) were measured by reverse transcription-quantitative polymerase chain reaction (RT‒qPCR) and immunoblotting. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2′-deoxyuridine (EdU) incorporation, and flow cytometry assays were used to assess the proliferation and apoptosis of DLBCL cells. The transcriptional regulation of SNHG20 by c-MYC was confirmed by a luciferase reporter assay and RNA immunoprecipitation. The interaction between USP14 and β-catenin was demonstrated using coimmunoprecipitation. A subcutaneous xenograft model was constructed to determine the role of SNHG20 in vivo.

Results

In the present study, we found that SNHG20 expression was upregulated in DLBCL cell lines and tissues compared to their normal counterparts. SNHG20 knockdown prominently reduced the proliferation and induced the apoptosis of U2932 and OCI-LY3 cells. However, SNHG20 overexpression increased the proliferation and apoptosis resistance of DLBCL cells. Mechanistically, the expression of SNHG20 was positively regulated by c-MYC in DLBCL cells. C-MYC directly bound to the promoter of SNHG20 to activate its transcription. SNHG20 was expressed mainly in the cytosol in DLBCL cells. SNHG20 silencing did not impact USP14 expression but markedly decreased the level of β-catenin, the substrate of USP14, in DLBCL cells. USP14 overexpression increased the β-catenin level, and this increase was attenuated by SNHG20 knockdown. Treatment with the proteasome inhibitor MG132 abolished SNHG20 knockdown-induced β-catenin downregulation. Moreover, SNHG20 silencing reduced the half-life but increased the ubiquitination of β-catenin in DLBCL cells. SNHG20 knockdown weakened the interaction between both endogenous and exogenous USP14 and β-catenin. In turn, SNHG20 overexpression increased the c-MYC level, and this increase was attenuated by β-catenin knockdown. Importantly, β-catenin knockdown attenuated the SNHG20-mediated increase in DLBCL cell proliferation in vitro and tumour growth in vivo.

Conclusions

Taken together, our results suggested that c-MYC-activated SNHG20 accelerated the proliferation and increased the apoptosis resistance of DLBCL cells via USP14-mediated deubiquitination of β-catenin. The c-MYC/SNHG20 positive feedback loop may be a new target for anti-DLBCL treatment.
Gossypiboma larynx: a rare cause of post-tracheostomy stridor—case report and review of literature
Authors: Prakash Gagan S. , Satish Vikyath , Raju Bharath , Onkaramurthy Neema Jayachamarajapura , Prakash Sathya
Published: June 2024

Background

Gossypiboma, a retained surgical sponge with a foreign body reaction, is an unusual but serious complication seen in open abdominal surgeries. It is exceptionally rare following head and neck surgeries. Here, we present a case of Gossypiboma of the upper airway following tracheostomy.

Case presentation

A 32-year-old male presented with stridor and difficulty breathing one-month post-tracheostomy after a severe head injury following a road traffic accident. A neck radiograph was unremarkable, and a computed tomography (CT) scan of the neck showed a well-defined homogenous curvilinear membrane extending from the hypopharynx to the upper trachea. Bronchoscopic evaluation of the larynx and upper trachea revealed a retained surgical sponge, which was retrieved. The patient’s breathing improved drastically post intervention.

Conclusion

Gossypiboma may go undetected in radiographs and may also present atypically as a homogenous membrane on a CT scan of the neck. Though rare, retained surgical items can have profound medicolegal and professional consequences on physicians. Hence, a strong clinical suspicion and vigilance for gossypiboma is necessary for patients presenting with respiratory distress post-tracheostomy.
Extracellular matrices of stromal cell subtypes regulate phenotype and contribute to the stromal microenvironment in vivo
Authors: Stone Andrew P. , Rand Emma , Thornes Gabriel , Kay Alasdair G. , Barnes Amanda L. , Hitchcock Ian S. , Genever Paul G.
Published: June 2024

Background

Bone marrow stromal cells (BMSCs) are highly heterogeneous, which may reflect their diverse biological functions, including tissue maintenance, haematopoietic support and immune control. The current understanding of the mechanisms that drive the onset and resolution of heterogeneity, and how BMSCs influence other cells in their environment is limited. Here, we determined how the secretome and importantly the extracellular matrix of BMSCs can influence cellular phenotype.

Methods

We used two immortalised clonal BMSC lines isolated from the same heterogeneous culture as model stromal subtypes with distinct phenotypic traits; a multipotent stem-cell-like stromal line (Y201) and a nullipotent non-stem cell stromal line (Y202), isolated from the same donor BMSC pool. Label-free quantitative phase imaging was used to track cell morphology and migration of the BMSC lines over 96 h in colony-forming assays. We quantified the secreted factors of each cell line by mass spectrometry and confirmed presence of proteins in human bone marrow by immunofluorescence.

Results

Transfer of secreted signals from a stem cell to a non-stem cell resulted in a change in morphology and enhanced migration to more closely match stem cell-like features. Mass spectrometry analysis revealed a significant enrichment of extracellular matrix (ECM) proteins in the Y201 stem cell secretome compared to Y202 stromal cells. We confirmed that Y201 produced a more robust ECM in culture compared to Y202. Growth of Y202 on ECM produced by Y201 or Y202 restored migration and fibroblastic morphology, suggesting that it is the deficiency of ECM production that contributes to its phenotype. The proteins periostin and aggrecan, were detected at 71- and 104-fold higher levels in the Y201 versus Y202 secretome and were subsequently identified by immunofluorescence at rare sites on the endosteal surfaces of mouse and human bone, underlying CD271-positive stromal cells. These proteins may represent key non-cellular components of the microenvironment for bona-fide stem cells important for cell maintenance and phenotype in vivo.

Conclusions

We identified plasticity in BMSC morphology and migratory characteristics that can be modified through secreted proteins, particularly from multipotent stem cells. Overall, we demonstrate the importance of specific ECM proteins in co-ordination of cellular phenotype and highlight how non-cellular components of the BMSC microenvironment may provide insights into cell population heterogeneity and the role of BMSCs in health and disease.
Reprogramming of 3D genome structure underlying HSPC development in zebrafish
Authors: He Min , Li Xiaoli , Xu Bingxiang , Lu Yinbo , Lai Jingyi , Ling Yiming , Liu Huakai , An Ziyang , Zhang Wenqing , Li Feifei
Published: June 2024

Background

Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals. Understanding the mechanism underlying HSPC development is a holy grail of hematopoietic biology, which is helpful for HSPC clinical application. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision; however, its dynamic and role in HSPC development is poorly investigated.

Methods

We performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish for the first time, including Hi-C, RNA-seq, ATAC-seq, H3K4me3 and H3K27ac ChIP-seq.

Results

The chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure. We revealed the multi-scale reorganization of chromatin structure and its influence on transcriptional regulation and transition of cell fate during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression of HSPC.

Conclusions

Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factors involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.
Stereochemically-aware bioactivity descriptors for uncharacterized chemical compounds
Authors: Comajuncosa-Creus Arnau , Lenes Aksel , Sánchez-Palomino Miguel , Dalton Dylan , Aloy Patrick
Published: June 2024

Stereochemistry plays a fundamental role in pharmacology. Here, we systematically investigate the relationship between stereoisomerism and bioactivity on over 1 M compounds, finding that a very significant fraction (~ 40%) of spatial isomer pairs show, to some extent, distinct bioactivities. We then use the 3D representation of these molecules to train a collection of deep neural networks (Signaturizers3D) to generate bioactivity descriptors associated to small molecules, that capture their effects at increasing levels of biological complexity (i.e. from protein targets to clinical outcomes). Further, we assess the ability of the descriptors to distinguish between stereoisomers and to recapitulate their different target binding profiles. Overall, we show how these new stereochemically-aware descriptors provide an even more faithful description of complex small molecule bioactivity properties, capturing key differences in the activity of stereoisomers.

Scientific contribution

We systematically assess the relationship between stereoisomerism and bioactivity on a large scale, focusing on compound-target binding events, and use our findings to train novel deep learning models to generate stereochemically-aware bioactivity signatures for any compound of interest.
MIRACLE—a microphone array impulse response dataset for acoustic learning
Authors: Kujawski Adam , Pelling Art J. R. , Sarradj Ennes
Published: June 2024

This work introduces a large dataset comprising impulse responses of spatially distributed sources within a plane parallel to a planar microphone array. The dataset, named MIRACLE, encompasses 856,128 single-channel impulse responses and includes four different measurement scenarios. Three measurement scenarios were conducted under anechoic conditions. The fourth scenario includes an additional specular reflection from a reflective panel. The source positions were obtained by uniformly discretizing a rectangular source plane parallel to the microphone for each scenario. The dataset contains three scenarios with a spatial resolution of $$23\,\textrm{mm}$$

23

mm

at two different source-plane-to-array distances, as well as a scenario with a resolution of $$5\,\textrm{mm}$$

5

mm

for the shorter distance. In contrast to existing room impulse response datasets, the accuracy of the provided source location labels is assessed and additional metadata, such as the directivity of the loudspeaker used for excitation, is provided. The MIRACLE dataset can be used as a benchmark for data-driven modelling and interpolation methods as well as for various acoustic machine learning tasks, such as source separation, localization, and characterization. Two timely applications of the dataset are presented in this work: the generation of microphone array data for data-driven source localization and characterization tasks and data-driven model order reduction.
A comparative study between aqueous and methanol solutions of barium hydroxide: implications for applying barium protectants in gypsification calcareous relics
Authors: Yan Jingchen , Huang Guang , Li Xiangnan , Liu Qing , Liu Yan , Yang Fuwei , Zhang Kun , Sun Yichen
Published: June 2024

Gypsification is a common problem in weathered calcareous relics. In previous studies, the solutions of barium hydroxide in water and methanol were used as protectants for gypsification calcareous relics and showed significant differences in permeability. In this study, the underlying reasons for permeability differences between these two solutions were investigated using optical microscopy, ultraviolet–visible spectrophotometry, X-ray diffractometry, Fourier transform infrared spectroscopy, the phenolphthalein test and physical property characterizations. The results indicated that the permeability differences were primarily caused by the solutions’ reactivity. Specifically, owing to the high reactivity of barium hydroxide in water, it reacted rapidly with atmospheric CO2 and gypsum (the weathering product) to generate barium carbonate, barium sulfate and calcium hydroxide precipitates. These precipitates hindered the penetration of solution into weathered relics. In contrast, barium hydroxide in methanol did not react with atmospheric CO2 or weathered relics, which also kept the solution in a liquid state during the infiltration process. Therefore, the solution of barium hydroxide in methanol exhibited high permeability. Based on the above findings, this study is meaningful for applying barium protectants in the conservation of gypsification calcareous relics.