bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the novel SNPs in neuroticism and birth weight based on GWAS datasets
Authors: Zhou Xiao-Ying , Liu Rui-Ke , Zeng Chun-Ping 
Published: July 2023

Abstract
Objectives
Epidemiological studies have confirmed that low birth weight (BW) is related to neuroticism and they may have a common genetic mechanism based on phenotypic correlation research. We conducted our study on a European population with 159,208 neuroticism and 289,142 birth weight samples. In this study, we aimed to identify new neuroticism single nucleotide polymorphisms (SNPs) and pleiotropic SNPs associated with neuroticism and BW and to provide more theoretical basis for the pathogenesis of the disease.

Methods
We estimated the pleiotropic enrichment between neuroticism and BW in two independent Genome-wide association studies (GWAS) when the statistical thresholds were Conditional False Discovery Rate (cFDR) < 0.01 and Conjunctional Conditional False Discovery Rate (ccFDR) < 0.05. We performed gene annotation and gene functional analysis on the selected significant SNPs to determine the biological role of gene function and pathogenesis. Two-sample Mendelian Randomization (TSMR) analysis was performed to explore the causal relationship between the neuroticism and BW.

Results
The conditional quantile–quantile plots (Q-Q plot) indicated that neuroticism and BW have strong genetic pleiotropy enrichment trends. With the threshold of cFDR < 0.001, we identified 126 SNPs related to neuroticism and 172 SNPs related to BW. With the threshold of ccFDR < 0.05, we identified 62 SNPs related to both neuroticism and BW. Among these SNPs, rs8039305 and rs35755513 have eQTL (expressed quantitative trait loci) and meQTL (methylation quantitative trait loci) effects simultaneously. Through GO enrichment analysis we also found that the two pathways of positive regulation of “mesenchymal cell proliferation” and “DNA-binding transcription factor activity” were significantly enriched in neuroticism and BW. Mendelian randomization analysis results indicate that there is no obvious causal relationship between neuroticism and birth weight.

Conclusion
We found 126 SNPs related to neuroticism, 172 SNPs related to BW and 62 SNPs associated with both neuroticism and BW, which provided a theoretical basis for their genetic mechanism and novel potential targets for treatment/intervention development.
Glioma-BioDP: database for visualization of molecular profiles to improve prognosis of brain cancer
Authors: Deng Xiang , Das Shaoli , Kaur Harpreet , Wilson Evan , Camphausen Kevin , Shankavaram Uma 
Published: July 2023

AbstractCancer researchers often seek user-friendly interactive tools for validation, exploration, analysis, and visualization of molecular profiles in cancer patient samples. To aid researchers working on the both low- and high-grade gliomas, we developed Glioma-BioDP, a web tool for exploration and visualization of RNA and protein expression profiles of interest in these tumor types. Glioma-BioDP is user friendly application that include expression data from both the low- and high-grade glioma patient samples from The Cancer Genome Atlas and enabled querying by mRNA, microRNA, and protein level expression data from Illumina HiSeq and RPPA platforms respectively. Glioma-BioDP provides advance query interface and enables users to explore the association of genes, proteins, and miRNA expression with molecular and/or histological subtypes of gliomas, surgical resection status and survival. The prognostic significance and visualization of the selected expression profiles can be explored using interactive utilities provided. This tool may also enable validation and generation of new hypotheses of novel therapies impacting gliomas that aid in personalization of treatment for optimum outcomes.
Supra-additive effect of chronic inflammation and atherogenic dyslipidemia on developing type 2 diabetes among young adults: a prospective cohort study
Authors: Lan Yulong , Wu Dan , Cai Zhiwei , Xu Yuancheng , Ding Xiong , Wu Weiqiang , Lan Shaocong , Chen Lan , Guo Zheng , Balmer Lois , Li Xingang , Song Manshu , Wu Shouling , Gao Jingli , Wang Wei , Chen Youren 
Published: July 2023

Abstract
Background
Both elevated inflammation and atherogenic dyslipidemia are prominent in young-onset diabetes and are increasingly identified as biologically intertwined processes that contribute to diabetogenesis. We aimed to investigate the age-specific risks of type 2 diabetes (T2D) upon concomitant chronic inflammation and atherogenic dyslipidemia.

Methods
Age-stratified Cox regression analysis of the risk of incident diabetes upon co-exposure to time-averaged cumulative high-sensitivity C-reactive protein (CumCRP) and atherogenic index of plasma (CumAIP) among 42,925 nondiabetic participants from a real-world, prospective cohort (Kailuan Study).

Results
During a median 6.41 years of follow-up, 3987 T2D developed. Isolated CumAIP and CumCRP were significantly associated with incident T2D in the entire cohort and across all age subgroups. Both CumAIP and CumCRP were jointly associated with an increased risk of diabetes (P-interaction = 0.0126). Compared to CumAIP < -0.0699 and CumCRP < 1 mg/L, co-exposure to CumAIP ≥ − 0.0699 and CumCRP ≥ 3 mg/L had a significant hazard ratio (HR) [2.55 (2.23–2.92)] after adjusting for socio-demographic, life-style factors, family history of diabetes, blood pressure, renal function and medication use. The co-exposure-associated risks varied greatly by age distribution (P-interaction = 0.0193): < 40 years, 6.26 (3.47–11.28); 40–49 years, 2.26 (1.77–2.89); 50–59 years, 2.51 (2.00–3.16); 60–69 years, 2.48 (1.86–3.30); ≥ 70 years, 2.10 (1.29–3.40). In young adults (< 45 years), both exposures had a significant supra-additive effect on diabetogenesis (relative excess risk due to interaction: 0.80, 95% CI 0.10–1.50).

Conclusions
These findings highlight the need for age-specific combined assessment and management of chronic inflammation and dyslipidemia in primary prevention against T2D, particularly for young adults. The clinical benefit derived from dual-target intervention against dyslipidemia and inflammation will exceed the sum of each part alone in young adults.
High triglyceride-glucose index and stress hyperglycemia ratio as predictors of adverse cardiac events in patients with coronary chronic total occlusion: a large-scale prospective cohort study
Authors: Song Yanjun , Cui Kongyong , Yang Min , Song Chenxi , Yin Dong , Dong Qiuting , Gao Ying , Dou Kefei 
Published: July 2023

Abstract
Background
The triglyceride-glucose (TyG) index and the stress hyperglycaemia ratio (SHR) are both positively associated with cardiovascular (CV) risk in patients with coronary heart disease. However, the prognostic value of these two biomarkers has not been well elucidated in patients with chronic total occlusion (CTO). Therefore, this study aims to evaluate the association of the TyG index and the SHR with long-term prognosis in patients with CTO.

Methods
This prospective cohort study consecutively included 2740 angina patients with CTO from January 2017 to December 2018 at Fuwai Hospital. The outcomes are a composite of CV death and target vessel myocardial infarction (TVMI) and major CV cerebrovascular adverse events (MACCEs, including all-cause death, nonfatal MI, ischaemia-driven target vessel revascularization, and stroke). The association between biomarkers and prognosis was analysed by multivariable Cox proportional hazard models, and the predictive value was determined by a receiver-operating characteristic (ROC) curve.

Results
During the follow-up with a median time of 3 years, 179 (6.5%) cases of MACCEs and 47 (1.7%) cases of CV death or TVMI were recorded. Patients with a high TyG index (> 9.10) and a high SHR (> 0.87) showed a significantly increased risk of CV death/TVMI (TyG index: HR 4.23, 95% CI 1.58–11.37; SHR: HR 5.14, 95% CI 1.89–13.98) and MACCEs (TyG index: HR 2.47, 95% CI 1.54–3.97; SHR: HR 2.91, 95% CI 1.84–4.60) compared with those with a low Tyg index and a low SHR (TyG < 8.56, SHR < 0.76). The area under the curve (AUC) values were 0.623 (TyG index) and 0.589 (SHR) for CV death/TVMI and 0.659 (TyG index) and 0.624 (SHR) for MACCEs. Furthermore, patients with both a high TyG index and a high SHR showed the highest risk of clinical outcomes among patients with different levels of these two biomarkers, and the AUC for the TyG-SHR combination was larger than the TyG index alone in predicting MACCE risk.

Conclusions
The study revealed that a high TyG index and a high SHR were significantly correlated with poor prognosis in patients with CTO and suggested that these two biomarkers are reliable in predicting long-term prognosis in CTO patients.
High prevalence of colistin heteroresistance in specific species and lineages of Enterobacter cloacae complex derived from human clinical specimens
Authors: Fukuzawa Shota , Sato Toyotaka , Aoki Kotaro , Yamamoto Soh , Ogasawara Noriko , Nakajima Chie , Suzuki Yasuhiko , Horiuchi Motohiro , Takahashi Satoshi , Yokota Shin-ichi 
Published: July 2023

Abstract
Background
Colistin (CST) is a last-line drug for multidrug-resistant Gram-negative bacterial infections. CST-heteroresistant Enterobacter cloacae complex (ECC) has been isolated. However, integrated analysis of epidemiology and resistance mechanisms based on the complete ECC species identification has not been performed.

Methods
Clinical isolates identified as “E. cloacae complex” by MALDI-TOF MS Biotyper Compass in a university hospital in Japan were analyzed. Minimum inhibitory concentrations of CST were determined by the broth microdilution method. The population analysis profiling (PAP) was performed for detecting the heteroresistant phenotype. The heat shock protein 60 (hsp60) cluster was determined from its partial nucleotide sequence. From the data of whole-genome sequencing, average nucleotide identity (ANI) for determining ECC species, multilocus sequence type, core genome single-nucleotide-polymorphism-based phylogenetic analysis were performed. phoPQ-, eptA-, and arnT-deleted mutants were established to evaluate the mechanism underlying colistin heteroresistance. The arnT mRNA expression levels were determined by reverse transcription quantitative PCR.

Results
Thirty-eight CST-resistant isolates, all of which exhibited the heteroresistant phenotype by PAP, were found from 138 ECC clinical isolates (27.5%). The prevalence of CST-resistant isolates did not significantly differ among the origin of specimens (29.0%, 27.8%, and 20.2% for respiratory, urine, and blood specimens, respectively). hsp60 clusters, core genome phylogeny, and ANI revealed that the CST-heteroresistant isolates were found in all or most of Enterobacter roggenkampii (hsp60 cluster IV), Enterobacter kobei (cluster II), Enterobacter chuandaensis (clusters III and IX), and Enterobacter cloacae subspecies (clusters XI and XII). No heteroresistant isolates were found in Enterobacter hormaechei subspecies (clusters VIII, VI, and III) and Enterobacter ludwigii (cluster V). CST-induced mRNA upregulation of arnT, which encodes 4-amino-4-deoxy-l-arabinose transferase, was observed in the CST-heteroresistant isolates, and it is mediated by phoPQ pathway. Isolates possessing mcr-9 and mcr-10 (3.6% and 5.6% of total ECC isolates, respectively) exhibited similar CST susceptibility and PAP compared with mcr-negative isolates.

Conclusions
Significant prevalence (approximately 28%) of CST heteroresistance is observed in ECC clinical isolates, and they are accumulated in specific species and lineages. Heteroresistance is occurred by upregulation of arnT mRNA induced by CST. Acquisition of mcr genes contributes less to CST resistance in ECC.
Immunotherapy: an emerging modality to checkmate brain metastasis
Authors: Ahmad Aatiya , Khan Parvez , Rehman Asad Ur , Batra Surinder Kumar , Nasser Mohd Wasim 
Published: July 2023

AbstractThe diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.
Expression of mTOR in normal and pathological conditions
Authors: Marques-Ramos A , Cervantes R 
Published: July 2023

AbstractThe mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By comprising two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, it is a central cellular hub that integrates intra- and extracellular signals of energy, nutrient, and hormone availability, modulating the molecular responses to acquire a homeostatic state through the regulation of anabolic and catabolic processes. Accordingly, dysregulation of mTOR pathway has been implicated in a variety of human diseases. While major advances have been made regarding the regulators and effectors of mTOR signaling pathway, insights into the regulation of mTOR gene expression are beginning to emerge. Here, we present the current available data regarding the mTOR expression regulation at the level of transcription, translation and mRNA stability and systematize the current knowledge about the fluctuations of mTOR expression observed in several diseases, both cancerous and non-cancerous. In addition, we discuss whether mTOR expression changes can be used as a biomarker for diagnosis, disease progression, prognosis and/or response to therapeutics. We believe that our study will contribute for the implementation of new disease biomarkers based on mTOR as it gives an exhaustive perspective about the regulation of mTOR gene expression in both normal and pathological conditions.
UTX deletion promotes M2 macrophage polarization by epigenetically regulating endothelial cell-macrophage crosstalk after spinal cord injury
Authors: Peng Wei , Xie Yong , Luo Zixiang , Liu Yudong , Xu Jiaqi , Li Chengjun , Qin Tian , Lu Hongbin , Hu Jianzhong 
Published: July 2023

AbstractMacrophages polarized to the M2 subtype after spinal cord injury (SCI) are beneficial for promoting neurological recovery. The crosstalk between endothelial cells (ECs) and macrophages is crucial for the imbalance between proinflammatory and pro-resolving responses caused by macrophage heterogeneity; however, this crosstalk is strengthened post-SCI, leading to inflammatory cascades and second damage. As a powerful means to regulate gene expression, epigenetic regulation of the interaction between immune cells and ECs in SCI is still largely unknown. Our previous research demonstrated that the histone demethylase UTX deletion in ECs (UTX−/− ECs) promotes neurological recovery, while the precise mechanism is unrevealed. Here, we discovered that UTX−/− ECs polarize macrophages toward the M2 subtype post-SCI. Macrophage deficiency could block the neurological recovery caused by the knockdown of UTX. The exosomes from UTX−/− ECs mediate this crosstalk. In addition, we found UTX, H3K27, and miR-467b-3p/Sfmbt2 promoters forming a regulatory complex that upregulates the miR-467b-3p in UTX−/− ECs. And then, miR-467b-3p transfers to macrophages by exosomes and activates the PI3K/AKT/mTOR signaling by decreasing PTEN expression, finally polarizing macrophage to the M2 subtype. This study reveals a mechanism by epigenetic regulation of ECs-macrophages crosstalk and identifies potential targets, which may provide opportunities for treating SCI.
Graphical Abstract
Development and validation of a blood biomarker score for predicting mortality risk in the general population
Authors: Yang Jing , Lu Jiayi , Miao Junyan , Li Jiacong , Zhu Meng , Dai Juncheng , Ma Hongxia , Jin Guangfu , Hang Dong 
Published: July 2023

Abstract
Background
Blood biomarkers for multiple pathways, such as inflammatory response, lipid metabolism, and hormonal regulation, have been suggested to influence the risk of mortality. However, few studies have systematically evaluated the combined predictive ability of blood biomarkers for mortality risk.

Methods
We included 267,239 participants from the UK Biobank who had measurements of 28 blood biomarkers and were free of cardiovascular disease (CVD) and cancer at baseline (2006–2010). We developed sex-specific blood biomarker scores for predicting all-cause mortality risk in a training set of 247,503 participants from England and Wales, and validated the results in 19,736 participants from Scotland. Cox and LASSO regression analyses were performed to identify independent predictors for men and women separately. Discrimination and calibration were evaluated by C-index and calibration plots, respectively. We also assessed mediating effects of the biomarkers on the association between traditional risk factors (current smoking, obesity, physical inactivity, hypertension, diabetes) and mortality.

Results
A total of 13 independent predictive biomarkers for men and 17 for women were identified and included in the score development. Compared to the lowest tertile of the score, the highest tertile showed a hazard ratio of 5.36 (95% confidence interval [CI] 5.04–5.71) in men and 4.23 (95% CI 3.87–4.62) in women for all-cause mortality. In the validation set, the score yielded a C-index of 0.73 (95% CI 0.72–0.75) in men and 0.70 (95% CI 0.68–0.73) in women for all-cause mortality; it was also predictive of CVD (C-index of 0.76 in men and 0.79 in women) and cancer (C-index of 0.70 in men and 0.67 in women) mortality. Moreover, the association between traditional risk factors and all-cause mortality was largely mediated by cystatin C, C-reactive protein, 25-hydroxyvitamin D, and hemoglobin A1c.

Conclusions
We established sex-specific blood biomarker scores for predicting all-cause and cause-specific mortality in the general population, which hold the potential to identify high-risk individuals and improve targeted prevention of premature death.
Clinicopathological features of incidentally detected metastatic thyroid papillary carcinoma in cervical lymph nodes of non-thyroid cancer patients: a retrospective analysis of 31cases
Authors: Hu Chunfang , Zhang Haifeng , Chu Lixia , Qiu Tian , Lu Haizhen 
Published: July 2023

Abstract
Background
The incidental finding of thyroid inclusions in lymph nodes of neck dissections of non-thyroid cancer patients is an unusual event. It is still controversial for pathologists about whether this represents benign inclusions or metastatic papillary thyroid carcinoma (PTC). This study is to analyze clinicopathological features of such cases in an attempt to explore their clinical implications.

Methods
Pathological data were searched for incidentally detected PTC of cervical lymph nodes in non-thyroid cancer cases. Clinicopathological characteristics were reevaluated and recorded. BRAF V600E protein expression and sequencing analysis was then performed in cases with sufficient tissues.

Results
31 patients had an incidental finding of PTC in lymph nodes of patients with non-thyroid cancer. BRAF immunohistochemical staining were performed in 17 metastatic lymph nodes with sufficient tumor tissues, and 6 were positive. BRAF V600E point mutation was detected in 5 of 6 BRAF V600E positive cases. Subsequent imaging examinations of the thyroid showed no nodules or calcifications/benign nodules in 20 patients, and suspected malignant nodules in 5 patients. 12 patients underwent total thyroidectomy or ipsilateral lobectomy, and 6 showed PTC in postoperative pathological examinations. The remaining 19 patients without surgery were kept under active surveillance, and no one had recurrence of PTC.

Conclusion
Incidentally discovered PTC in lymph nodes has usually interpreted as metastasis from a clinical occult thyroid primary cancer, but primary PTC was not always detected. This suggests it could be double occult lesions. With regards to concurrence with highly malignant tumor, most patients could keep regular surveillance.
Metanephric stromal tumor in an adult with PDGFRA mutation: a case report
Authors: Guo Sanjun , Qian Huan , Zhu Hong , Yang Yue , Yang Xudan , Sun Huajun 
Published: July 2023

AbstractBackgroundMetanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase(BRAF)V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found.Case presentationWe report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. TheBRAFV600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal.ConclusionThis is the first report of alterations inPDGFRAin MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children.
Comparative fixation devices for preventing migration of the proximal tibiofibular joint during tibial lengthening: a tether versus screw fixation
Authors: Wongcharoenwatana Jidapa , Hoellwarth Jason S. , Greenstein Michael D. , Reif Taylor J. , Fragomen Austin T. , Rozbruch S. Robert 
Published: July 2023

Abstract
Background
When lengthening the tibia segment using motorized internal lengthening nails (MILN), undesired distal migration of the proximal fibula segment is prevented by tibiofibular stabilization, traditionally using a screw. A tightened cortical suspensory fixation rope (tether) is an alternative option, but its appropriateness has never been studied. The primary outcome was comparing the amount of proximal fibular migration between patients who were stabilized with either a tether or a screw. The secondary outcome was to evaluate the effect of fibular migration on the clinical outcome between both groups.

Methods
A retrospective study was conducted on patients who underwent tibial lengthening with MILN between April 2016 and June 2022. Two cohorts were compared: 18 limbs with tether fixation versus 29 limbs with screw fixation. Data on the patient's age, sex, etiologies, and clinical outcomes were collected. Radiographic measurements included the lengthening distance and the amount of proximal fibular migration.

Results
In total, 47 limbs from 41 patients, with average age 35.01 ± 13.72 years old. There were 28 males (68.29%) and 13 females (31.71%). The tether group demonstrated a statistically significant greater distance of migration than the screw group (p < 0.001), with an average migration distance of 8.39 ± 5.09 mm and 2.59 ± 3.06 mm, respectively. No correlation was found between the amount of tibial lengthening and the distance of proximal fibular migration in both the tether group (p = 0.96) and the screw group (p = 0.32). There was no significant difference in the change of knee extension between both groups (p = 0.3), and no patients reported knee pain or tightness.

Conclusion
A screw provides better resistance to proximal tibiofibular joint migration during MILN lengthening, but the difference appears clinically inconsequential. Either option appears suitable.