bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening of key genes in the pathogenesis of muscle atrophy in CKD-PEW children based on RNA sequencing
Authors: Ying Liang , Yeping Jiang , Hui Wang , Nan Zhou , FuQian  , Ying Shen
Published: November 2023

Background

In children with CKD, Protein Energy Wasting (PEW) is common, which affects the outcome of children and is an important cause of poor prognosis. We are aiming to explore the pathogenesis of muscle wasting in CKD-PEW children.

Methods

Blood samples of 32 children diagnosed with chronic kidney disease (CKD) and protein energy wasting (PEW) in our hospital from January 2016 to June 2021 were collected. RNA sequencing and bioinformatics analysis were performed.

Results

Based on GO (Gene Ontology) functional enrichment analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis and differential gene expression analysis, a total of 25 CKD-PEW related genes were obtained including CRP, IL6, TNF, IL1B, CXCL8, IL12B, IL12A, IL18, IL1A, IL4, IL10, TGFB2, TGFB1, TGFB3, ADIPOQ, NAMPT, RETN, RETNLB, LEP, CD163, ICAM1, VCAM1, SELE, NF-κB1, NF-κB2. The most significantly differentially expressed gene was NF-κB2 (adjusted P = 2.81 × 10–16), and its expression was up-regulated by 3.92 times (corresponding log2FoldChange value was 1.979). Followed by RETN (adjusted P = 1.63 × 10–7), and its expression was up-regulated by 8.306 times (corresponding log2FoldChange value was 2.882). SELE gene were secondly significant (adjusted P = 5.81 × 10–7), and its expression was down-regulated by 22.05 times (corresponding log2FoldChange value was -4.696).

Conclusions

A variety of inflammatory factors are involved in the pathogenesis of CKD-PEW in children, and chronic inflammation may lead to the development of muscle atrophy in CKD-PEW. It is suggested for the first time that NF-κB is a key gene in the pathogenesis of muscle wasting in CKD-PEW children, and its increased expression may play an important role in the pathogenesis of muscle wasting in children with CKD-PEW.
Safety and efficacy of bempedoic acid: a systematic review and meta-analysis of randomised controlled trials
Authors: De Filippo Ovidio , D’Ascenzo Fabrizio , Iannaccone Mario , Bertaina Maurizio , Leone Attilio , Borzillo Irene , Ravetti Emanuele , Solano Andrea , Pagliassotto Ilaria , Nebiolo Marco , Bruno Francesco , Giacobbe Federico , Muscoli Saverio , Monticone Silvia , Brizzi Maria Felice , Biondi Zoccai Giuseppe , De Ferrari Gaetano Maria
Published: November 2023

Background and aims

Bempedoic Acid (BA) is a novel Lipid-Lowering Therapy (LLT). We performed a systematic review and meta-analysis to assess the efficacy and safety of BA in patients with hypercholesterolemia.

Methods

PubMed, Scopus, and Cochrane library databases were searched for randomised controlled trials evaluating the efficacy and/or safety of BA compared with placebo. Trials investigating dosages other than 180 mg/die were excluded. Major adverse cardiovascular events (MACE) were the primary efficacy endpoint. LDL-cholesterol reduction was the primary laboratory endpoint. Pre-specified safety endpoints included muscle-related adverse events, new-onset diabetes, and gout. The protocol was registered on PROSPERO (temporary ID:399,867).

Results

Study search identified 275 deduplicated results. 11 studies, encompassing 18,315 patients (9854 on BA vs 8461 on placebo/no treatment) were included. BA was associated with a reduced risk of MACE (OR 0.86, 95% CI 0.79–0.95), myocardial infarction (OR 0.76, 95% CI 0.64–0.88) and unstable angina (OR 0.69, 95% CI 0.54–0.88) compared to control, over a median follow up of 87 (15–162) weeks. BA was associated with a reduction of LDL-Cholesterol (mean difference [MD]–22.42,95% CI − 24.02% to − 20.82%), total cholesterol (− 16.50%,95% − 19.21% to − 13.79%), Apo-B lipoprotein (− 19.55%, − 22.68% to − 16.42%) and high-sensitivity CRP (− 27.83%, − 31.71% to − 23.96%) at 12 weeks. BA was associated with a higher risk of gout (OR 1.55, 95% CI 1.27–1.90) as compared with placebo. Efficacy on laboratory endpoints was confirmed, with a variable extent, across patients on statin or ezetimibe background therapy.

Conclusions

The improved cholesterol control achieved with BA translates into a reduced risk of MACE, including myocardial infarction and coronary revascularisation. The drug has a satisfactory safety profile except for an increased risk of gout.
Triglyceride-glucose index, renal function and cardiovascular disease: a national cohort study
Authors: Cui Cancan , Liu Lin , zhang Te , Fang Ling , Mo Zhanhao , Qi Yitian , Zheng Jia , Wang Zhijia , Xu Haikun , Yan Han , Yue Siqi , Wang Xuekui , Wu Zhiyuan
Published: November 2023

Background

The triglyceride-glucose (TyG) index is a predictor of cardiovascular diseases; however, to what extent the TyG index is associated with cardiovascular diseases through renal function is unclear. This study aimed to evaluate the complex association of the TyG index and renal function with cardiovascular diseases using a cohort design.

Methods

This study included participants from the China Health and Retirement Longitudinal Study (CHARLS) free of cardiovascular diseases at baseline. We performed adjusted regression analyses and mediation analyses using Cox models. The TyG index was calculated as Ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Renal function was defined by the estimated glomerular filtration rate (eGFR).

Results

A total of 6 496 participants were included in this study. The mean age of the participants was 59.6 ± 9.5 years, and 2996 (46.1%) were females. During a maximum follow-up of 7.0 years, 1 996 (30.7%) people developed cardiovascular diseases, including 1 541 (23.7%) cases of heart diseases and 651 (10.0%) cases of stroke. Both the TyG index and eGFR level were significantly associated with cardiovascular diseases. Compared with people with a lower TyG index (median level) and eGFR ≥ 60 ml/minute/1.73 m2, those with a higher TyG index and decreased eGFR had the highest risk of cardiovascular diseases (HR, 1.870; 95% CI 1.131–3.069). Decreased eGFR significantly mediated 29.6% of the associations between the TyG index and cardiovascular diseases.

Conclusions

The combination of a higher TyG index and lower eGFR level was associated with the highest risk of cardiovascular diseases. Renal function could mediate the association between the TyG index and cardiovascular risk.
Temporal relationship between triglyceride-glucose index and blood pressure and their joint cumulative effect on cardiovascular disease risk: a longitudinal cohort study
Authors: Wu Kuangyi , Zheng Huancong , Wu Weiqiang , Chen Guanzhi , Cai Zefeng , Cai Zhiwei , Lan Yulong , Wu Dan , Wu Shouling , Chen Youren
Published: November 2023

Background

Concurrent insulin resistance and elevated blood pressure are commonly observed in cardiovascular disease (CVD) and have long been proposed to contribute to CVD. However, the temporal relationship between them and the effect of their cumulative co-exposure on future incident CVD remains unclear.

Methods

Longitudinal analysis of data on 57,192 participants from a real-world, prospective cohort study (Kailuan Study) was performed to address the temporal relationship between Triglyceride-Glucose Index (TyG, calculated as ln [TG (mg/dL) × FBG (mg/dL)/2]) and blood pressure (BP) assessed by cross-lagged analyses in an approximately 4-year exposure period (2006/2007 to 2010/2011). After excluding 879 participants with known diabetes, 56,313 nonCVD participants were included for further analysis of the CVD outcome. Cox regression models were used to examine the hazard ratios (HRs) upon the cumulative TyG (CumTyG) and BP(CumBP) in the exposure period.

Results

The standard regression coefficient from baseline TyG to follow-up systolic BP was 0.0142 (95% CI 0.0059–0.0226), which was greater than the standard regression coefficient from baseline systolic BP to follow-up TyG (− 0.0390; 95% CI − 0.0469 to − 0.0311). The same results were observed in the cross-lag between TyG and diastolic blood pressure [0.0271 (0.0185 to 0.0356) vs. − 0.0372 (− 0.0451 to − 0.0293)]. During a median follow-up of 9.98 years, 3981 CVD cases occurred. Significant interactions were observed between the median CumTyG (8.61) and CumSBP thresholds (130, 140 mmHg) (P = 0.0149), the median CumTyG (8.61) and CumDBP thresholds (80, 90 mmHg) (P = 0.0441). Compared to CumTyG < 8.61 and CumSBP < 130 mmHg, after adjusting for potential confounding factors, the HR gradually increased in the high co-exposure groups. The hazard ratios (HRs) and 95% confidence intervals (CIs) for Q2–Q6 were 1.39 (1.24, 1.57), 1.94 (1.69, 2.22), 2.40 (2.12, 2.71), 2.74 (2.43, 3.10), and 3.07 (2.74, 3.45). Additionally, the CVD risks in the co-exposure were more prominent in younger participants.

Conclusions

These findings suggest that elevated TyG has a greater impact on future blood pressure changes than vice versa. Dual assessment and management of insulin resistance and blood pressure contribute to the prevention of CVD, especially in younger individuals.
miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability
Authors: Liu Ying , Jin Aihua , Quan Xianglan , Shen Xionghu , Zhou Houkun , Zhao Xingyu , Lin Zhenhua
Published: November 2023

Background

T lymphoma invasion and metastasis 1 (Tiam1) is a tumor related gene that specifically activates Rho-like GTPases Rac1 and plays a critical role in the progression of various malignancies. Glycolysis plays an important role in cancer progression, it is crucial for supplying energy and producing metabolic end products, which can maintain the survival of tumor cells. As yet, however, the mechanism of Tiam1 in glycolysis reprogramming of pancreatic cancer (PC) remains to be clarified. Here, we investigated the functional role of Tiam1 in PC cell proliferation, metastasis and glycolysis reprogramming. It is expected to provide a new direction for clinical treatment.

Methods

The clinical relevance of Tiam1 was evaluated in 66 patients with PC, the effect of Tiam1 on cell proliferation was detected via 5-Ethynyl-2′-deoxyuridine (EdU) and colony formation. The ability of cell migration was detected by the wound healing and Transwell. Quantitative real time polymerase chain reaction (qRT-PCR) and luciferase reporter gene experiments clarify the regulatory relationship of miR-590-5p inhibiting Tiam1. Detection of the molecular mechanism of Tiam1 regulating glucose metabolism reprogramming in PC by glucose metabolism kit. RNA sequencing and Co-Immunoprecipitation (CoIP) have identified glucose transporter protein 3 (SLC2A3) as a key downstream target gene for miR-590-5p/Tiam1.

Results

We found that Tiam1 expression increased in PC tissues and was associated with lymph node metastasis. The silencing or exogenous overexpression of Tiam1 significantly altered the proliferation, invasion, and angiogenesis of PC cells through glucose metabolism pathway. In addition, Tiam1 could interact with the crucial SLC2A3 and promote the evolution of PC in a SLC2A3-dependent manner. Moreover, miR-590-5p was found to exacerbate the PC cell proliferation, migration and invasion by targeting Tiam1. Furthermore, the reversing effects on proliferation, migration and invasion were found in PC cells with miR-590-5p/Tiam1 overexpression after applying glucose metabolism inhibition.

Conclusions

Our findings demonstrate the critical role of Tiam1 in PC development and the miR-590-5p/Tiam1/SLC2A3 signaling pathway may serve as a target for new PC therapeutic strategies.

Graphical Abstract
Identifying prognostic characteristics of m6A-related glycolysis gene and predicting the immune infiltration landscape in bladder cancer
Authors: Zhou Guanwen , Li Yi , Ren Xiangguo , Qin Guoliang , Zhang Zhaocun , Zhao Haifeng , Gao Lijian , Jiang Xianzhou
Published: November 2023

Backgrounds

Glucose metabolism is associated with the development of cancers, and m6A RNA methylation regulator-related genes play vital roles in bladder urothelial carcinoma (BLCA). However, the role of m6A-related glucose metabolism genes in BLCA occurrence and development has not yet been reported. Our study aims to integrate m6A- and glycolysis-related genes and find potential gene targets for clinical diagnosis and prognosis of BLCA patients.

Methods

Sequencing data and clinical information on BLCA were extracted from common databases. Univariate Cox analysis was used to screen prognosis-related m6A glucose metabolism genes; BLCA subtypes were distinguished using consensus clustering analysis. Subsequently, genes associated with BLCA occurrence and development were identified using the “limma” R package. The risk score was then calculated, and a nomogram was constructed to predict survival rate of BLCA patients. Functional and immune microenvironment analyses were performed to explore potential functions and mechanisms of the different risk groups.

Results

Based on 70 prognosis-related m6A glucose metabolism genes, BLCA was classified into two subtypes, and 34 genes associated with its occurrence and development were identified. Enrichment analysis revealed an association of genes in high-risk groups with tricarboxylic acid cycle function and glycolysis. Moreover, significantly higher levels of seven immune checkpoints, 14 immune checkpoint inhibitors, and 32 immune factors were found in high-risk score groups.

Conclusions

This study identified two biomarkers associated with BLCA prognosis; these findings may deepen our understanding of the role of m6A-related glucose metabolism genes in BLCA development. We constructed a m6A-related glucose metabolism- and immune-related gene risk model, which could effectively predict patient prognosis and immunotherapy response and guide individualized immunotherapy.
Long-term exposure to exogenous phthalate, masculinity and femininity trait, and gender identity in children: a Chinese 3-year longitudinal cohort study
Authors: Liu Jieyu , Gao Di , Wang Huan , Li Yanhui , Chen Manman , Ma Qi , Wang Xinxin , Cui Mengjie , Chen Li , Zhang Yi , Guo Tongjun , Yuan Wen , Ma Tao , Jiang Jianuo , Dong Yanhui , Zou Zhiyong , Ma Jun
Published: November 2023

Background

Phthalate esters (PAEs) are known to have hormone-like properties, and there is a growing trend of children expressing a gender identity different from assigned sex. However, there has been limited research in the potential links between PAEs exposure and gender identity.

Methods

A total of 571 children (278 boys) completed the follow-up from Oct 2017 to Oct 2020 in Childhood Blood Pressure and Environmental Factors (CBPEF) cohort in Xiamen, China. Urinary PAE metabolites were measured at three time of visits using ultraperformance liquid chromatography-tandem mass spectrometry. The Children’s Sex Role Inventory scale was used to assess gender identity (masculinity, femininity, androgyny and undifferentiated), and Tanner definition was used to define puberty timing. Generalized linear models and log-binomial regression were used to assess the relationships between PAEs exposure, gender trait scores and gender identity.

Results

Overall, the concentration of most PAEs in more than 90% of participants was above the limit of detection values. In visit 1, there were 10.1% boys with femininity and 11.3% girls with masculinity; while these figures increased to 10.8% and 12.3% during follow-up, respectively. Early puberty onset accounted for 24.8% and 25.6% among boys and girls. Long-term exposure to mono-2-ethylhexyl phthalate (MEHP) (β = 1.20, 95%CI = 0.13, 2.28), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (β = 1.25, 95%CI = 0.22, 2.28) and mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 1.40, 95%CI = 0.24, 2.56) was associated with the increased differences of femininity trait scores in boys who enter puberty earlier, prolonged exposure to di(2-ethylhexyl) phthalate (DEHP) might also have such a positive impact (β = 1.38, 95%CI = 0.36, 2.41). For gender identity, persistent exposure to low molecular weight phthalates (LMWP) was negatively associated with undifferentiated type among boys entering puberty earlier (RR = 0.18, 95%CI = 0.05, 0.75, P < 0.05), and most of the PAE metabolites exposures showed risk ratios > 1 for their femininity.

Conclusion

Long-term exposure to PAEs increase the femininity trait scores in boys with early onset of puberty. Although the mechanisms remain to be determined, environmental pollution might have subtle, yet measurable effects on childhood gender identity. Reducing these chemicals exposure has important public implications on gender development.
Correlation between dietary inflammation and mortality among hyperlipidemics
Authors: Wang Lili , Liu Tao , Zhang Qingdui , Wang Lele , Zhou Qiang , Wang Jing , Miao Hao , Hao Ji , Qi Chunmei
Published: November 2023

Background and objective

Although the the Dietary Inflammatory Index (DII) serves to be one of the reliable indicator for hyperlipidaemia, there is still uncertainty about its relationship to prognosis in the hyperlipidaemic population. In current study, the DII levels were analyzed in relation to the mortality risk among among the hyperlipidaemic individuals with the aim of determining any prospective correlation.

Methods

14,460 subjects with hyperlipidaemia from the 10-year (2001–2010) National Health and Nutrition Examination Survey (NHANES) were chosen for this study. The endpoint event for follow-up was all-cause mortality, and subjects were tracked for up to December 31, 2019, or death, whichever occurred first. The tertiles of the DII levels were utilized for categorizing the study population into three groups. Survival curves, Cox proportional hazards regression models, restricted cubic spline (RCS), subgroup and interaction analyses, and sensitivity analyses were employed sequentially for the purpose of evaluating the association of the DII with mortality.

Results

3170 (21.92%) all-cause deaths were recorded during an average 148-month follow-up period. Kaplan-Meier survival curves indicated that the survival rate of participants divided into the low DII group was substantially improved compared to that of those in the higher DII group (log-rank P < 0.001). After controlling for confounders, higher levels of DII were observed to be meaningfully linked to an elevated risk of death, no matter whether DII was specified for the continuous (hazard ratio (HR): 1.06; 95% confidence interval (CI): 1.04–1.08) or the categorical variable (HR: 1.22; 95% CI: 1.11–1.33). The DII and mortality displayed a linear association, according to the RCS. Stratified and sensitivity analyses reinforced the proof that these findings were reliable.

Conclusion

Among patients with hyperlipidaemia, the risk of death was positively and linearly linked with DII levels.
Recent advances in melittin-based nanoparticles for antitumor treatment: from mechanisms to targeted delivery strategies
Authors: Yu Xiang , Jia Siyu , Yu Shi , Chen Yaohui , Zhang Chengwei , Chen Haidan , Dai Yanfeng
Published: November 2023

As a naturally occurring cytolytic peptide, melittin (MLT) not only exhibits a potent direct tumor cell-killing effect but also possesses various immunomodulatory functions. MLT shows minimal chances for developing resistance and has been recognized as a promising broad-spectrum antitumor drug because of this unique dual mechanism of action. However, MLT still displays obvious toxic side effects during treatment, such as nonspecific cytolytic activity, hemolytic toxicity, coagulation disorders, and allergic reactions, seriously hampering its broad clinical applications. With thorough research on antitumor mechanisms and the rapid development of nanotechnology, significant effort has been devoted to shielding against toxicity and achieving tumor-directed drug delivery to improve the therapeutic efficacy of MLT. Herein, we mainly summarize the potential antitumor mechanisms of MLT and recent progress in the targeted delivery strategies for tumor therapy, such as passive targeting, active targeting and stimulus-responsive targeting. Additionally, we also highlight the prospects and challenges of realizing the full potential of MLT in the field of tumor therapy. By exploring the antitumor molecular mechanisms and delivery strategies of MLT, this comprehensive review may inspire new ideas for tumor multimechanism synergistic therapy.
Transplantation of active nucleus pulposus cells with a keep-charging hydrogel microsphere system to rescue intervertebral disc degeneration
Authors: Tang Yingchuang , Zhang Kai , Zhou Hongyou , Zhang Chenchen , Liu Zixiang , Chen Hao , Li Hanwen , Chen Kangwu
Published: November 2023

Background

Cell transplantation has been demonstrated as a promising approach in tissue regeneration. However, the reactive oxygen species (ROS) accumulation and inflammation condition establish a harsh microenvironment in degenerated tissue, which makes the transplanted cells difficult to survive.

Methods

In this study, we constructed a keep-charging hydrogel microsphere system to enable cells actively proliferate and function in the degenerated intervertebral disc. Specifically, we combined Mg2+ to histidine-functionalized hyaluronic acid (HA-His-Mg2+) through coordination reaction, which was further intercrossed with GelMA to construct a double-network hydrogel microsphere (GelMA/HA-His-Mg2+, GHHM) with microfluidic methods. In vitro, the GHHM loaded with nucleus pulposus cells (GHHM@NPCs) was further tested for its ability to promote NPCs proliferation and anti-inflammatory properties. In vivo, the ability of GHHM@NPCs to promote regeneration of NP tissue and rescue intervertebral disc degeneration (IVDD) was evaluated by the rat intervertebral disc acupuncture model.

Results

The GHHM significantly enhanced NPCs adhesion and proliferation, providing an ideal platform for the NPCs to grow on. The loaded NPCs were kept active in the degenerative intervertebral disc microenvironment as charged by the Mg2+ in GHHM microspheres to effectively support the loaded NPCs to reply against the ROS-induced inflammation and senescence. Moreover, we observed that GHHM@NPCs effectively alleviated nucleus pulposus degeneration and promoted its regeneration in the rat IVDD model.

Conclusion

In conclusion, we constructed a keep charging system with a double-network hydrogel microsphere as a framework and Mg2+ as a cell activity enhancer, which effectively maintains NPCs active to fight against the harsh microenvironment in the degenerative intervertebral disc. The GHHM@NPCs system provides a promising approach for IVDD management.

Graphical Abstract
The promoting effect and mechanism of MAD2L2 on stemness maintenance and malignant progression in glioma
Authors: Liu Zhiyuan , Wang Songtao , Yu Kuo , Chen Kaile , Zhao Liang , Zhang Jiayue , Dai Kexiang , Zhao Peng
Published: November 2023

Background

Glioblastoma, the most common primary malignant tumor of the brain, is associated with poor prognosis. Glioblastoma cells exhibit high proliferative and invasive properties, and glioblastoma stem cells (GSCs) have been shown to play a crucial role in the malignant behavior of glioblastoma cells. This study aims to investigate the molecular mechanisms involved in GSCs maintenance and malignant progression.

Methods

Bioinformatics analysis was performed based on data from public databases to explore the expression profile of Mitotic arrest deficient 2 like 2 (MAD2L2) and its potential function in glioma. The impact of MAD2L2 on glioblastoma cell behaviors was assessed through cell viability assays (CCK8), colony formation assays, 5-Ethynyl-2ʹ-deoxyuridine (EDU) incorporation assays, scratch assays, and transwell migration/invasion assays. The findings from in vitro experiments were further validated in vivo using xenograft tumor model. GSCs were isolated from the U87 and LN229 cell lines through flow cytometry and the stemness characteristics were verified by immunofluorescence staining. The sphere-forming ability of GSCs was examined using the stem cell sphere formation assay. Bioinformatics methods were conducted to identified the potential downstream target genes of MAD2L2, followed by in vitro experimental validation. Furthermore, potential upstream transcription factors that regulate MAD2L2 expression were confirmed through chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.

Results

The MAD2L2 exhibited high expression in glioblastoma samples and showed significant correlation with patient prognosis. In vitro and in vivo experiments confirmed that silencing of MAD2L2 led to decreased proliferation, invasion, and migration capabilities of glioblastoma cells, while decreasing stemness characteristics of glioblastoma stem cells. Conversely, overexpression of MAD2L2 enhanced these malignant behaviors. Further investigation revealed that MYC proto-oncogene (c-MYC) mediated the functional role of MAD2L2 in glioblastoma, which was further validated through a rescue experiment. Moreover, using dual-luciferase reporter gene assays and ChIP assays determined that the upstream transcription factor E2F-1 regulated the expression of MAD2L2.

Conclusion

Our study elucidated the role of MAD2L2 in maintaining glioblastoma stemness and promoting malignant behaviors through the regulation of c-MYC, suggesting its potential as a therapeutic target.
Finite element analyses of three minimally invasive fixation techniques for treating Sanders type II intra-articular calcaneal fractures
Authors: Song Guoxun , Gu Wenqi , Shi Zhongmin , Li Xueqian , Fu Shaoling , Yu Xiaowei , Song Facheng
Published: November 2023

Background and objective

Calcaneal Sanders type II or III fractures are highly disabling with significant burden. Surgical treatment modalities include open reduction and internal fixation (ORIF) techniques and a variety of minimally invasive surgical (MIS) approaches. ORIF techniques are associated with complications and traditional MIS techniques need extensive intraoperative fluoroscopic procedures. The present study aims to investigate the effects of three different minimally invasive internal fixation (MIIF) techniques used to treat Sanders type II intra-articular calcaneal fractures using finite element analyses.

Methods

A 64-row spiral computed tomography scan was used to observe the calcaneus of a healthy adult. The scanning data were imported into Mimics in a DICOM format. Using a new model of a Sanders type II-B intra-articular calcaneal fracture, three minimally invasive techniques were simulated. Technique A involved fixation using an isolated minimally invasive locking plate; Technique B used a minimally invasive locking plate with one medial support screw; and Technique C simulated a screw fixation technique using four 4.0-mm screws. After simulating a 640-N load on the subtalar facet, the maximum displacement and von Mises stress of fragments and implants were recorded to evaluate the biomechanical stability of different fixation techniques using finite element analyses.

Results

After stress loading, the maximum displacements of the fragments and implants were located at the sustentaculum tali and the tip of sustentaculum tali screw, respectively, in the three techniques; however, among the three techniques, Technique B had better results for displacement of both. The maximum von Mises stress on the fragments was < 56 Mpa, and stress on the implants using the three techniques was less than the yield strength,with Technique C having the least stress.

Conclusion

All three techniques were successful in providing a stable fixation for Sanders type II intra-articular calcaneal fractures, while the minimally invasive calcaneal locking plate with medial support screw fixation approach exhibited greater stability, leading to improved enhancement for the facet fragment; however, screw fixation dispersed the stress more effectively than the other two techniques.
Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer
Authors: Tan Zheqiong , Deme Pragney , Boyapati Keerti , Claes Britt S. R. , Duivenvoorden Annet A. M. , Heeren Ron M. A. , Tressler Caitlin M. , Haughey Norman James , Glunde Kristine
Published: November 2023

Background

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC.

Methods

We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties. Our studies were performed in a large panel of human breast cancer cell lines and patient samples.

Results

Comprehensive lipid profiling revealed that phospholipid metabolism is reprogrammed in TNBC cells. We discovered that patatin-like phospholipase domain-containing lipase 8 (PNPLA8) is overexpressed in TNBC cell lines and tissues from breast cancer patients. Silencing of PNPLA8 disrupted phospholipid metabolic reprogramming in TNBC, particularly affecting the levels of phosphatidylglycerol (PG), phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and glycerophosphocholine (GPC). We showed that PNPLA8 is essential in regulating cell viability, migration and antioxidation in TNBC cells and promoted arachidonic acid and eicosanoid production, which in turn activated PI3K/Akt/Gsk3β and MAPK signaling.

Conclusions

Our study highlights PNPLA8 as key regulator of phospholipid metabolic reprogramming and malignant phenotypes in TNBC, which could be further developed as a novel molecular treatment target.
Chromatin balances cell redox and energy homeostasis
Authors: Suganuma Tamaki , Workman Jerry L.
Published: November 2023

Chromatin plays a central role in the conversion of energy in cells: alteration of chromatin structure to make DNA accessible consumes energy, and compaction of chromatin preserves energy. Alteration of chromatin structure uses energy sources derived from carbon metabolism such as ATP and acetyl-CoA; conversely, chromatin compaction and epigenetic modification feedback to metabolism and energy homeostasis by controlling gene expression and storing metabolites. Coordination of these dual chromatin events must be flexibly modulated in response to environmental changes such as during development and exposure to stress. Aging also alters chromatin structure and the coordination of metabolism, chromatin dynamics, and other cell processes. Noncoding RNAs and other RNA species that associate directly with chromatin or with chromatin modifiers contribute to spatiotemporal control of transcription and energy conversion. The time required for generating the large amounts of RNAs and chromatin modifiers observed in super-enhancers may be critical for regulation of transcription and may be impacted by aging. Here, taking into account these factors, we review alterations of chromatin that are fundamental to cell responses to metabolic changes due to stress and aging to maintain redox and energy homeostasis. We discuss the relationship between spatiotemporal control of energy and chromatin function, as this emerging concept must be considered to understand how cell homeostasis is maintained.
A phenome-wide scan reveals convergence of common and rare variant associations
Authors: Zhou Dan , Zhou Yuan , Xu Yue , Meng Ran , Gamazon Eric R.
Published: November 2023

Background

Common and rare variants contribute to the etiology of complex traits. However, the extent to which the phenotypic effects of common and rare variants involve shared molecular mediators remains poorly understood. The question is essential to the basic and translational goals of the science of genomics, with critical basic-science, methodological, and clinical consequences.

Methods

Leveraging the latest release of whole-exome sequencing (WES, for rare variants) and genome-wide association study (GWAS, for common variants) data from the UK Biobank, we developed a metric, the COmmon variant and RAre variant Convergence (CORAC) signature, to quantify the convergence for a broad range of complex traits. We characterized the relationship between CORAC and effective sample size across phenome-wide association studies.

Results

We found that the signature is positively correlated with effective sample size (Spearman ρ = 0.594, P < 2.2e − 16), indicating increased functional convergence of trait-associated genetic variation, across the allele frequency spectrum, with increased power. Sensitivity analyses, including accounting for heteroskedasticity and varying the number of detected association signals, further strengthened the validity of the finding. In addition, consistent with empirical data, extensive simulations showed that negative selection, in line with enhancing polygenicity, has a dampening effect on the convergence signature. Methodologically, leveraging the convergence leads to enhanced association analysis.

Conclusions

The presented framework for the convergence signature has important implications for fine-mapping strategies and drug discovery efforts. In addition, our study provides a blueprint for the expectation from future large-scale whole-genome sequencing (WGS)/WES and sheds methodological light on post-GWAS studies.
Deciphering the role of extrachromosomal circular DNA in adipose stem cells from old and young donors
Authors: Ren Sen , Wu Du , Shen Xiaoyong , Wu Qian , Li Chengcheng , Xiong Hewei , Xiong Zhongwei , Gong Rui , Liu Zheng , Wang Wei , Chen Jincao
Published: November 2023

Background

The functional impairment of adipose stem cells (ASCs) during aging limits their clinical transformation. Studies have shown that extrachromosomal circular DNAs (eccDNAs) are associated with tumor progression and cell aging, but the roles of eccDNAs in ASCs remain unknown.

Method

We conducted Circle sequencing (Circle-seq) to identify eccDNAs in ASCs isolated from young and old donors. The differentially expressed eccDNAs were calculated, annotated and validated via polymerase chain reaction.

Results

Thousands of eccDNAs were identified and comprehensively characterized. Most of them were GC-rich, < 1000 base pairs in size, and were enriched on chromosome 19 and 17 with a high density of Alu elements and genes, 2 kb upstream/downstream of genes and satellites. In total, 3025 eccDNAs were differentially expressed among the two ASC groups. Conjoint analysis of the Circle-seq results and previous RNA-seq results revealed that 73 eccDNAs and 55 genes exhibited the same differential expression between the two groups. KEGG and GO analyses revealed that genes encoding differentially expressed eccDNAs were enriched for cell adhesion, cellular senescence and TGF-β receptor signaling pathway. We also found that aged ASCs exhibited loss of eccDNAs, including CAMK2G (chr10: 75577899-75578176), TRABD2B (chr1: 48305638-48307008) and TRABD2B (chr1: 48305425-48307091).

Conclusion

In this study, we elucidated the first eccDNA profile relating to ASCs and demonstrated that three eccDNAs are lost in aged ASCs, which may be potential biomarkers of stem cell aging and valuable targets for stem cell rejuvenation.
Anesthetic management of a huge retroperitoneal leiomyoma: a case report
Authors: Shi Yue , Zhu Bo , Zhang Yu , Huang Yuguang
Published: November 2023

Background

Retroperitoneal leiomyomas are rare, with just over 100 cases reported in the literature. Perioperative management of retroperitoneal leiomyomas can be challenging due to the large tumor size and the risk of hemorrhage.

Case presentation

We report a case of a 40-year-old Han woman with a 40-cm retroperitoneal leiomyoma. General anesthesia was performed for the surgical resection. Key flow parameters like cardiac output and stroke volume variation, as shown by the Vigileo™-FloTrac™ system, enabled the anesthesiologist to implement goal-directed fluid optimization. Acute normovolemic hemodilution and cell salvage technique were used resulting in a successful en bloc tumor resection with a 6000-mL estimated blood loss. Although the patient experienced postoperative bowel obstruction, no other significant complications were observed.

Conclusion

Advanced hemodynamic monitoring and modern patient blood management strategies are particularly helpful for anesthetic management of huge retroperitoneal leiomyomas.
EFL teachers’ cognition of social and psychological consequences of high-stake national language tests: role of teacher training workshops
Authors: Allahyari Rahmatolah , Abbasabady Mahmoud Moradi , Akhter Shamim , Alibakhshi Goudarz
Published: November 2023

Consequential validity, a facet of construct validity, has been extensively explored by educational psychologists and scholars focused on English language assessment. It is widely recognized that English language instructors must possess a thorough understanding of high-stake language tests. However, the body of research concerning EFL teachers’ perceptions of high-stake tests is quite limited. This study aims to delve into the cognitions of Iranian EFL teachers regarding the social and psychological ramifications of high-stake English language tests. Additionally, the study investigates the influence of a teacher training workshop on EFL teachers’ perceptions of test consequences. The research employs a two-phase quantitative research design. A total of 210 EFL teachers participated in the survey, completing a scale comprising 25 items that delineated their perceptions of test consequences. Furthermore, thirty teachers engaged in a two-session workshop focused on test consequences. Data analysis encompassed both one-sample and paired-sample t tests.

The results reveal that EFL teachers possess knowledge regarding certain social and psychological consequences of language tests; however, their awareness of some adverse consequences remains limited. Notably, the outcomes indicate that teacher training workshops have a positive impact on teachers’ cognitions of both positive and negative test consequences. The implications of these findings extend to teacher trainers and English language educators, offering practical insights to enhance the effectiveness of their teaching practices.
Thermochronology of hydrothermal alteration zones in the Kii Peninsula, southwest Japan: an attempt for detecting the thermal anomalies and implications to the regional exhumation history
Authors: Sueoka Shigeru , Iwano Hideki , Danhara Tohru , Niwa Masakazu , Kanno Mizuho , Kohn Barry P. , Kawamura Makoto , Yokoyama Tatsunori , Kagami Saya , Ogita Yasuhiro , Hirata Takafumi
Published: November 2023

Fluid-inclusion and thermochronometric analyses have been applied to hydrothermal alteration zones and their host rocks outcropping in the Hongu area of the Kii Peninsula, southwestern Japan in an attempt to detect thermal anomalies related to hydrothermal events and quantify the thermal effects on the host rocks. Hydrothermal events at ~ 150 °C and ~ 200 °C were identified by fluid-inclusion microthermometry of quartz veins in the alteration zones. For the host rocks and alteration zones, in the youngest population zircon yielded U–Pb dates ranging between ~ 74.7–59.2 Ma, fission-track dates of ~ 27.2–16.6 Ma, and (U–Th)/He single-grain dates of ~ 23.6–8.7 Ma. Apatite yielded pooled fission-track ages of ~ 14.9–9.0 Ma. The zircon U–Pb dates constrain the maximum depositional ages of the sedimentary samples. However, the fission-track and (U–Th)/He dates show no clear trend as a function of distance from the alteration zones. Hence, no thermal anomaly was detected in the surrounding host rocks based on the thermochronometric data patterns. The fission-track and (U–Th)/He dates are rather thought to record regional thermal and exhumation histories rather than a direct thermal imprint of fluid flow, probably because the duration of such activity was too short or because fluid flow occurred before regional cooling events and were later thermally overprinted. Apatite fission-track ages of ~ 10 Ma may reflect regional mountain uplift and exhumation related to the obduction of the SW Japan lithospheric sliver onto the Shikoku Basin, or the rapid subduction of the Philippine Sea slab associated with the clockwise rotation of the Southwest Japan Arc.

Graphical Abstract
Self-diagnose is associated with knowledge and attitude towards mental illness of university students in Indonesia
Authors: Ismail Naufal Arif , Kusumaningtyas Intan , Firngadi Moetrarsi Sri Kanapsijah
Published: November 2023

Background

Mental illness is still stigmatized and poorly understood in Indonesian society, but university students could be a key target for promoting positive attitudes and increasing awareness. This study aims to explore the knowledge and attitudes of university students in Indonesia toward mental illness and to identify associated factors, emphasizing self-diagnosis.

Method

An analytical cross-sectional study on university students in Yogyakarta, Indonesia, was conducted from September to November 2022. Participants completed an online questionnaire about their sociodemographic data, mental health knowledge (utilized Mental Health Knowledge Schedule questionnaire), and attitudes toward mental illness (utilized Community Attitude to Mental Illness Inventory questionnaire). Univariate, bivariate, and multivariate logistic regression were performed to analyze collected data.

Results

A total of 402 university students were included in the study. Results demonstrated that half of the students had good mental illness knowledge (50.7%), and slightly more than half had favorable attitudes (53.0%). Self-diagnosis was significantly associated with poorer knowledge and negative attitudes (adjusted odds ratio [AOR]: 2.31, 95% confidence interval [CI] 1.19 to 4.50 and AOR: 2.12, 95% CI 1.13 to 3.99; P < 0.05, respectively). Additionally, students who had never studied psychology or psychiatry and had a family mental illness history were at higher risk (P < 0.05) for poor knowledge of mental illness (AOR: 2.24, 95% CI 1.18 to 4.25 and AOR: 1.82, 95% CI 1.00 to 3.30, respectively). Interestingly, students with lower monthly family incomes had more positive attitudes (AOR: 0.39, 95% CI 0.18 to 0.86; P < 0.05). A very weak negative correlation (ρ = − 0.173; P < 0.001) between mental illness knowledge and attitudes was observed.

Conclusion

Promoting awareness and knowledge about mental health, as well as preventing self-diagnosis, is crucial in addressing the lack of knowledge and negative attitudes toward mental illness among university students in Indonesia, which is expected to play a role in the wider community ultimately.
Investigation of barium sulphate shielding during panoramic radiography
Authors: Bawazeer Omemh , Fallatah Alaa , Alasmary Mohamed , Bokhary Younis , Almerabi Areej , Khan Suha , Abuhadi Nouf , Alalawi Amani , Asiri Naseem , Bawazir Saeed , Al-Qahtani Saeed , Algethami Merfat , Badawy Mohamed
Published: November 2023

Background

Radiation shielding in radiology has historically been achieved with lead; however, there has been an increasing demand for radiation shielding to be more environmentally friendly. Barium has shown promise as a substitute in many radiology applications. This study aims to investigate a barium sulphate shield in protecting the thyroid and the eye lens during panoramic radiography.

Methods

During a simulated panoramic examination, an anthropomorphic phantom and a solid-state detector measured the radiation dose to the surface thyroid and the eye lens. The measurements were taken using no shield and a barium sulphate shield. A Welch's T-test was employed to compute the shield's effect on radiation. Two radiologists assessed the image quality with and without the thyroid shields.

Results

The dose reduction was between 66 and 75% for the barium shield at the thyroid. The dose reduction ranged between 15 and 61% in the eye region. Images using a barium shield were deemed adequate for diagnostic interpretation.

Conclusions

Barium shields effectively reduce the radiation dose in the thyroid region during panoramic radiography without degrading image quality. The dose reduction depends on the tube voltage and the area of interest.
Revealing Sexual Dimorphism in Prolactin Regulation From Early Postnatal Development to Adulthood in Murine Models
Authors: Abeledo-Machado Alejandra , Peña-Zanoni Milagros , Bornancini Dana , Díaz-Torga Graciela
Published: November 2023

Serum prolactin (PRL) levels exhibit a gradual rise both in male and female rats from birth to adulthood, with females consistently displaying higher levels compared to age-matched males. This pattern has traditionally been attributed to the development and maturation of endocrine and neuroendocrine networks responsible for regulating PRL synthesis and secretion. However, the effect of dopamine (DA), which acts as an inhibitory factor on lactotroph function, also increases from birth to puberty, particularly in females. Nonetheless, the secretion of PRL remains higher in females compared to males. On the other hand, the observed sex differences in serum PRL levels during early postnatal development cannot be attributed to the influence of estradiol (E2). While serum E2 levels gradually increase after birth, only after 45 days of life do the disparities in E2 levels between females and males become evident. These observations collectively suggest that neither the maturation of hypothalamic DA regulation nor the rise in E2 levels can account for the progressive and sustained elevation in serum PRL levels and the observed sexual dimorphism during postnatal development. This review highlights the importance of recent discoveries in animal models that shed light on inhibitory mechanisms in the control of PRL secretion within the pituitary gland itself, that is intrapituitary mechanisms, with a specific emphasis on the role of transforming growth factor β1 and activins in PRL secretion.
Prevalence, Incidence, and Clinical Characteristics of Thyroid Eye Disease in Japan
Authors: Watanabe Natsuko , Kozaki Ai , Inoue Kosuke , Narimatsu Hiroto , Shinohara Masahiko , LoPresti Michael Goddard
Published: November 2023

Background

Although thyroid eye disease (TED) can impact social and psychological well-being, the epidemiological evidence of TED is lacking in Japan.

Methods

Nationwide claims databases provided by JMDC Inc. and Medical Data Vision Co., Ltd. and national population statistics are used. Three TED definitions ranging from a strict definition only including a TED diagnosis to a broad definition including a TED diagnosis and considering ocular symptoms are considered. The proportion of patients by severity and disease activity are estimated based on definitions that would allow identification of those patients within the claims data.

Results

The incidence rate per 100 000 person-years ranged from 7.3 to 11.1 for the strict and broad TED definitions, respectively. For fiscal year 2020 (April 2020 to March 2021) the prevalence rate ranged between 24.65 (strict TED) and 37.58 (broad TED) per 100 000 persons. These correspond to 25 383 and 38 697 patients for the strict and broad TED definitions, respectively. Regardless of the definition used, a predominance of female patients was observed, and the highest burden of the disease was seen in the age group of 35 to 59. Mild and inactive forms of TED were predominant (about 85% and 74%, respectively).

Conclusion

The incidence and prevalence of TED in Japan were 7.3 to 11.1 per 100 000 person-years and 24.65 to 37.58 per 100 000 persons, respectively. The robust results of this database study add valuable real-world evidence on the incidence and prevalence of TED in Japan.