bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender differences in changes in metabolic syndrome status and its components and risk of cardiovascular disease: a longitudinal cohort study
Authors: Ramezankhani Azra , Azizi Fereidoun , Hadaegh Farzad 
Published: November 2022

Abstract
Background
We aimed to investigate the gender difference in the association between changes in metabolic syndrome (MetS) and its components with the risk of cardiovascular disease (CVD) and coronary heart disease (CHD) among adult participants in the Tehran lipid and glucose study cohort.

Methods
A total of 4624 adults (aged ≥ 30 years) who participated in two Phases 2 (2002–2005) and 3 (2005–2008) were included and followed up until 2018. Based on the status of MetS and its components in two phases, we divided participants into four groups: MetS-free, MetS-developed, MetS-recovery and MetS-stable groups, and similar categories were defined for MetS components. Multiple Cox regression models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs), and women-to-men ratios of HRs (RHRs).

Results
During a median follow-up of 11.6 years, 619 CVD events (292 women) and 512 CHD events (230 women) occurred. In both genders, the MetS-stable group had the highest risk of CVD and CHD, compared with the MetS-free group, but the associations were stronger in women than men: the HR (95% CI) were (2.76, 2.00-3.82) and (3.08, 2.15–4.40) for CVD and CHD, respectively, in women, and (1.60, 1.23–2.09) and (1.74, 1.30–2.31) for men. The multivariate adjusted women-to-men RHRs were (1.72, 1.16–2.56) for CVD and (1.77, 1.14–2.73) for CHD. Only among women, the risks for CVD in MetS-recovery group (1.67, 1.06–2.63) and MetS-developed group (1.89, 1.16–3.06|) were higher than MetS-free group. For CHD, women in MetS-developed group (1.86, 1.07–3.22) had higher risk than MetS-free group. However, no evidence of gender difference was observed in these associations. Among MetS components, persistent high blood pressure (BP) conferred greater risk for CVD and CHD in women than men; the women-to-men RHRs of CVD and CHD for high BP-stable groups were 1.54 (1.05–2.26) and 1.62 (1.07–2.47), respectively. For CHD events, persistent high fasting plasma glucose was associated with greater risk in women than men with women-to-men RHRs of 1.62 (1.09–2.40).

Conclusion
Change in MetS and its key components were associated with different risks for CVD events in both genders, with generally stronger associations in women than men.
Targeting the tumor stroma for cancer therapy
Authors: Xu Maosen , Zhang Tao , Xia Ruolan , Wei Yuquan , Wei Xiawei 
Published: November 2022

AbstractTumors are comprised of both cancer cells and surrounding stromal components. As an essential part of the tumor microenvironment, the tumor stroma is highly dynamic, heterogeneous and commonly tumor-type specific, and it mainly includes noncellular compositions such as the extracellular matrix and the unique cancer-associated vascular system as well as a wide variety of cellular components including activated cancer-associated fibroblasts, mesenchymal stromal cells, pericytes. All these elements operate with each other in a coordinated fashion and collectively promote cancer initiation, progression, metastasis and therapeutic resistance. Over the past few decades, numerous studies have been conducted to study the interaction and crosstalk between stromal components and neoplastic cells. Meanwhile, we have also witnessed an exponential increase in the investigation and recognition of the critical roles of tumor stroma in solid tumors. A series of clinical trials targeting the tumor stroma have been launched continually. In this review, we introduce and discuss current advances in the understanding of various stromal elements and their roles in cancers. We also elaborate on potential novel approaches for tumor-stroma-based therapeutic targeting, with the aim to promote the leap from bench to bedside.
Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a)
Authors: Schwarz Andrea , Demuth Ilja , Landmesser Ulf , Haghikia Arash , König Maximilian , Steinhagen-Thiessen Elisabeth 
Published: November 2022

Abstract
Background
Although potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals.

Methods
We performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) ≥ 50 mg/dL (≈ 107 nmol/L) was considered elevated.

Results
A total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence).

Conclusion
Most participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention.
The p-STAT3/ANXA2 axis promotes caspase-1-mediated hepatocyte pyroptosis in non-alcoholic steatohepatitis
Authors: Feng Yun , Li Wenhua , Wang Zhuoya , Zhang Ruling , Li Yan , Zang Lijuan , Wang Peiwen , Li Zhenghong , Dong Yuwei 
Published: November 2022

Abstract
Background
To explore the roles of Annexin A2 (ANXA2) on hepatocyte pyroptosis and hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and underlying molecular mechanism.

Methods
Bioinformatics analyses were performed on transcriptome data of liver tissues from mice and patients with liver fibrosis for screening the hepatocyte pyroptosis-related differential genes. The in vivo NASH mouse model and in vitro NASH cellular model were established. The expression levels of Anxa2/ANXA2 were quantified. Then, the upstream transcription factor of Anxa2 was screened by ChIP-Seq and experimentally verified. The effects of the p-STAT3/ANXA2 axis on Caspase-1 mediated pyroptosis and fibrosis were explored by in vivo and in vitro experiments.

Results
Bioinformatics analyses suggested that the expression of Anxa2/ANXA2 was significantly up-regulated in liver tissues of both NASH mice and patients scoring with high pyroptotic activity. Experimental data showed that the ANXA2 expression was positively associated with the development of hepatocyte pyroptosis and fibrosis. As a transcription factor of ANXA2, p-STAT3 can bind to the promoter of Anxa2 and promote its transcription. The inhibition of p-STAT3 can significantly suppress hepatocyte pyroptosis and fibrosis, which was significantly reversed after the over-expression of Anxa2. Caspase-1 was verified as the player of the p-STAT3/ANXA2 axis to promote pyroptosis and fibrosis. By specifically inhibiting Caspase-1, the promotion effect of the p-STAT3/ANXA2 axis on pyroptosis and fibrosis can be significantly weakened.

Conclusion
The p-STAT3 promoted Anxa2 expression at the transcription level, thus activating the Caspase-1 mediated hepatocyte pyroptosis and fibrosis in NASH.
Long-term Prophylaxis with Androgens in the management of Hereditary Angioedema (HAE) in emerging countries
Authors: Guo Yinshi , Zhang Huanping , Lai He , Wang Huiying , Chong-Neto Herberto J. , Valle Solange O. R. , Zhu Rongfei 
Published: November 2022

AbstractHereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries.
Identification and validation of a novel signature as a diagnostic and prognostic biomarker in colorectal cancer
Authors: Wang Di , Liufu Junye , Yang Qiyuan , Dai Shengqun , Wang Jiaqi , Xie Biao 
Published: November 2022

Abstract
Background
Colorectal cancer (CRC) is one of the most common malignant neoplasms worldwide. Although marker genes associated with CRC have been identified previously, only a few have fulfilled the therapeutic demand. Therefore, based on differentially expressed genes (DEGs), this study aimed to establish a promising and valuable signature model to diagnose CRC and predict patient’s prognosis.

Methods
The key genes were screened from DEGs to establish a multiscale embedded gene co-expression network, protein-protein interaction network, and survival analysis. A support vector machine (SVM) diagnostic model was constructed by a supervised classification algorithm. Univariate Cox analysis was performed to construct two prognostic signatures for overall survival and disease-free survival by Kaplan–Meier analysis, respectively. Independent clinical prognostic indicators were identified, followed by univariable and multivariable Cox analysis. GSEA was used to evaluate the gene enrichment analysis and CIBERSORT was used to estimate the immune cell infiltration. Finally, key genes were validated by qPCR and IHC.

Results
In this study, four key genes (DKC1, FLNA, CSE1L and NSUN5) were screened. The SVM diagnostic model, consisting of 4-gene signature, showed a good performance for the diagnostic (AUC = 0.9956). Meanwhile, the four-gene signature was also used to construct a risk score prognostic model for disease-free survival (DFS) and overall survival (OS), and the results indicated that the prognostic model performed best in predicting the DFS and OS of CRC patients. The risk score was validated as an independent prognostic factor to exhibit the accurate survival prediction for OS according to the independent prognostic value. Furthermore, immune cell infiltration analysis demonstrated that the high-risk group had a higher proportion of macrophages M0, and T cells CD4 memory resting was significantly higher in the low-risk group than in the high-risk group. In addition, functional analysis indicated that WNT and other four cancer-related signaling pathways were the most significantly enriched pathways in the high-risk group. Finally, qRT-PCR and IHC results demonstrated that the high expression of DKC1, CSE1L and NSUN5, and the low expression of FLNA were risk factors of CRC patients with a poor prognosis.

Conclusion
In this study, diagnosis and prognosis models were constructed based on the screened genes of DKC1, FLNA, CSE1L and NSUN5. The four-gene signature exhibited an excellent ability in CRC diagnosis and prognostic prediction. Our study supported and highlighted that the four-gene signature is conducive to better prognostic risk stratification and potential therapeutic targets for CRC patients.
PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ in the joint microenvironment
Authors: Yao Yao , Cai Xiaoyu , Zhang Meng , Zhang Xiao , Ren Fujia , Zheng Yan , Fei Weidong , Zhao Mengdan , Zheng Caihong 
Published: November 2022

Abstract
Background
The cytoskeletal protein, PSTPIP2, is associated with inflammation and is predominantly expressed in macrophages. Previous data have shown that PSTPIP2 inhibits articular bone damage in arthritic rats. The aim of this study is to explore the molecular mechanism of PSTPIP2’s resistance to bone erosion.

Methods
In the current study, peripheral blood and surgically excised synovial tissue from RA patients, DBA/1 mice, Pstpip2CreR26-ZsGreen reporter mice, and Esr2fl/fl/Adgre-Cre tool mice were used for in vivo studies. Adeno-associated viral vector was used to overexpress PSPTIP2 protein in vivo.

Results
We found that The level of PSTPIP2 in synovial macrophages is negatively correlated with RA disease activity, which is mediated by synovial macrophages polarization. PSTPIP2hi synovial macrophages form a tight immunological barrier in the lining layer. Notably, the ability of PSTPIP2 to regulate synovial macrophages polarization is dependent on ERβ. Additionally, PSTPIP2 regulates the dynamics of synovial macrophages via ERβ.

Conclusions
Together, this study reveals that PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form an immunological barrier (F4/80+PSTPIP2hi cell-enriched zone) for the joints. Thus, local modulation of PSTPIP2 expression in the joint microenvironment may be a potential strategy for controlling bone erosion in rheumatoid arthritis.

Graphical Abstract
PSTPIP2 regulates synovial macrophages polarization and dynamics via ERβ to form F4/80+PSTPIP2hi cellular barrier in joint microenvironment.
Sex differences in Alzheimer’s disease: plasma MMP-9 and markers of disease severity
Authors: Tsiknia Amaryllis A. , Sundermann Erin E. , Reas Emilie T. , Edland Steven D. , Brewer James B. , Galasko Douglas , Banks Sarah J. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

Abstract
Background
Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.

Methods
Our sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.

Results
Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).

Conclusions
MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women’s elevated susceptibility to AD.
Impact of nano silver composite structure on cadmium neurotoxicity in albino rats
Authors: El-Sherbiny Emad Mohamed , Abdel-Gawad Eman Ismail , Osman Hala Fawzy 
Published: November 2022

AbstractThe present study was planned to investigate the possible therapeutic effects of silver/hydroxyapatite nanocomposite (nAg/HAp) on neurotoxicity induced by cadmium chloride (CdCl2) in albino rats. The nanocomposite has been formulated by a chemical route and characterized by scanning electron microscope (SEM), Transmission Electron Microscopy (TEM), and energy-dispersive X-ray Analysis spectroscopy (EDAX). A population of rats was randomly assorted into three groups; the animals were subjected to intraperitoneal CdCl2administration every 2 days at a dose level of 1.0 mg/kg b.wt. for 3 months while the treatment with nAg/HAp was performed via intravenous injection at a dose level of 50 mg/kg b,wt. once a week for 4 weeks. Quantitative DNA fragmentation and biochemical analysis including the content of γ-aminobutyric acid (GABA), noradrenaline (NA), dopamine (DA), caspase-3, calmodulin (CaM), calcium adenosine 5′-triphosphatase (Ca++ATPase), tau protein, glutathione (GSH) and malondialdehyde (MDA) were measured in brain tissue. The results revealed the potent efficacy of nAg/HAp in attenuating DNA fragmentation and partially recovering most of the investigated parameters manifested by a significant elevation in GABA, NA, DA, Ca++ATPase, and GSH levels and a decrease in tau protein, caspase-3, CaM and MDA tissue content in comparison with Cd—intoxicated groups. Accordingly, the synthesized nAg/HAp at the selected dose can be used as a biosafe intravenous injection in neurodegenerative diseases.
Chimeric antigen receptor-engineered NK cells: new weapons of cancer immunotherapy with great potential
Authors: Wang Xiao , Yang Xuejiao , Yuan Xiang , Wang Wenbo , Wang Yueying 
Published: November 2022

AbstractChimeric antigen receptor (CAR)-engineered T (CAR-T) cells have obtained prominent achievement in the clinical immunotherapy of hematological malignant tumors, leading to a rapid development of cellular immunotherapy in cancer treatment. Scientists are also aware of the prospective advantages of CAR engineering in cellular immunotherapy. Due to various limitations such as the serious side effects of CAR-T therapy, researchers began to investigate other immune cells for CAR modification. Natural killer (NK) cells are critical innate immune cells with the characteristic of non-specifically recognizing target cells and with the potential to become “off-the-shelf” products. In recent years, many preclinical studies on CAR-engineered NK (CAR-NK) cells have shown their remarkable efficacy in cancer therapy and their superiority over autologous CAR-T cells. In this review, we summarize the generation, mechanisms of anti-tumor activity and unique advantages of CAR-NK cells, and then analyze some challenges and recent clinical trials about CAR-NK cells therapy. We believe that CAR-NK therapy is a promising prospect for cancer immunotherapy in the future.
Target-enriched long-read sequencing (TELSeq) contextualizes antimicrobial resistance genes in metagenomes
Authors: Slizovskiy Ilya B. , Oliva Marco , Settle Jonathen K. , Zyskina Lidiya V. , Prosperi Mattia , Boucher Christina , Noyes Noelle R. 
Published: November 2022

Abstract
Background
Metagenomic data can be used to profile high-importance genes within microbiomes. However, current metagenomic workflows produce data that suffer from low sensitivity and an inability to accurately reconstruct partial or full genomes, particularly those in low abundance. These limitations preclude colocalization analysis, i.e., characterizing the genomic context of genes and functions within a metagenomic sample. Genomic context is especially crucial for functions associated with horizontal gene transfer (HGT) via mobile genetic elements (MGEs), for example antimicrobial resistance (AMR). To overcome this current limitation of metagenomics, we present a method for comprehensive and accurate reconstruction of antimicrobial resistance genes (ARGs) and MGEs from metagenomic DNA, termed target-enriched long-read sequencing (TELSeq).

Results
Using technical replicates of diverse sample types, we compared TELSeq performance to that of non-enriched PacBio and short-read Illumina sequencing. TELSeq achieved much higher ARG recovery (>1,000-fold) and sensitivity than the other methods across diverse metagenomes, revealing an extensive resistome profile comprising many low-abundance ARGs, including some with public health importance. Using the long reads generated by TELSeq, we identified numerous MGEs and cargo genes flanking the low-abundance ARGs, indicating that these ARGs could be transferred across bacterial taxa via HGT.

Conclusions
TELSeq can provide a nuanced view of the genomic context of microbial resistomes and thus has wide-ranging applications in public, animal, and human health, as well as environmental surveillance and monitoring of AMR. Thus, this technique represents a fundamental advancement for microbiome research and application.
Combined, sequential dye analysis and radiocarbon dating of single ancient textile yarns from a Nazca tunic
Authors: Smith Gregory D. , Chen Victor J. , Holden Amanda , Haghipour Negar , Hendriks Laura 
Published: November 2022

Abstract
The accessioning of ancient textiles into museum collections often requires objective information regarding the object’s appropriateness and authenticity before purchase or gift acceptance. In the case of colored fabrics, the identification of dyestuffs consistent with the attributed time period and culture builds confidence and reduces the chances of the object being a simple forgery or fake produced using modern materials. Moreover, this information adds to the technical, cultural, and conservation knowledge regarding the object. Increasingly, chronometric age estimates in the form of radiocarbon dating are also needed to establish the object’s age or to further prove the materials match the purported date range of the textile. Each of these analyses consumes a small sample of the object, and typically they are conducted separately by different laboratories on individual sample yarns. This report demonstrates for the first time the sequential, combined analysis of dyes by liquid chromatography-diode array detection-mass spectrometry and radiocarbon dating of the same residual dye-extracted sample. The chemicals and solvents used in various dye extraction protocols are shown not to contaminate the extracted yarns for radiocarbon dating purposes. The approach was used in the authentication study of an ancient Nazca tunic made from natural fibers (wool) and dyes (indigoids, anthraquinones, and flavonoids) shown to have most likely been produced between 595 and 665 CE.