Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis

ABSTRACT DNA methylation status is closely associated with diverse diseases, and is generally more stable than gene expression, thus abnormal DNA methylation could be important biomarkers for tumor diagnosis, treatment and prognosis. However, the signatures regarding DNA methylation changes for pan-cancer diagnosis and prognosis are less explored. Here we systematically analyzed the genome-wide DNA methylation patterns in diverse TCGA cancers with machine learning. We identified seven CpG sites that could effectively discriminate tumor samples from adjacent normal tissue samples for 12 main cancers of TCGA (1216 samples, AUC > 0.99). Those seven potential diagnostic biomarkers were further validated in the other 9 different TCGA cancers and 4 independent datasets (AUC > 0.92). Three out of the seven CpG sites were correlated with cell division, DNA replication and cell cycle. We also identified 12 CpG sites that can effectively distinguish 26 different cancers (7605 samples), and the result was repeatable in independent datasets as well as two disparate tumors with metastases (micro-average AUC > 0.89). Furthermore, a series of potential signatures that could significantly predict the prognosis of tumor patients for 7 different cancer were identified via survival analysis (p-value < 1e-4). Collectively, DNA methylation patterns vary greatly between tumor and adjacent normal tissues, as well as among different types of cancers. Our identified signatures may aid the decision of clinical diagnosis and prognosis for pan-cancer and the potential cancer-specific biomarkers could be used to predict the primary site of metastatic breast and prostate cancers.
M1b Disease in the 8th Edition of TNM Staging of Lung Cancer: Pattern of Single Extrathoracic Metastasis and Clinical Outcome

The 8th edition of TNM staging of lung cancer revised M staging and defined M1b disease with single extrathoracic metastasis, to be distinguished from M1c with multiple extrathoracic metastases in one or more organs. This new distinct category of M1b disease consists of patients with a single extrathoracic metastasis, thus consisting of a strictly defined oligometastatic disease. This article reports the prevalence of M1b disease among patients with stage IV non‐small cell lung cancer, focusing on the clinical characteristics and patterns of single extrathoracic metastasis and relationships with overall survival.
Evaluation of dosimetric uncertainty caused by MR geometric distortion in MRI‐based liver SBRT treatment planning

Abstract Purpose MRI‐based treatment planning is a promising technique for liver stereotactic‐body radiation therapy (SBRT) treatment planning to improve target volume delineation and reduce radiation dose to normal tissues. MR geometric distortion, however, is a source of potential error in MRI‐based treatment planning. The aim of this study is to investigate dosimetric uncertainties caused by MRI geometric distortion in MRI‐based treatment planning for liver SBRT. Materials and Methods The study was conducted using computer simulations. 3D MR geometric distortion was simulated using measured data in the literature. Planning MR images with distortions were generated by integrating the simulated 3D MR geometric distortion onto planning CT images. MRI‐based treatment plans were then generated on the planning MR images with two dose calculation methods: (1) using original CT numbers; and (2) using organ‐specific assigned CT numbers. Dosimetric uncertainties of various dose‐volume‐histogram parameters were determined as their differences between the simulated MRI‐based plans and the original clinical CT‐based plans for five liver SBRT cases. Results The average simulated distortion for the five liver SBRT cases was 2.77 mm. In the case of using original CT numbers for dose calculation, the average dose uncertainties for target volumes and critical structures were <0.5 Gy, and the average target volume percentage at prescription dose uncertainties was 0.97%. In the case of using assigned CT numbers, the average dose uncertainties for target volumes and critical structures were <1.0 Gy, and the average target volume percentage at prescription dose uncertainties was 2.02%. Conclusions Dosimetric uncertainties caused by MR geometric distortion in MRI‐based liver SBRT treatment planning was generally small (<1 Gy) when the distortion is 3 mm.
Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion.

Background Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling. Methods By comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n = 5) and controls (n = 3). All statistical tests were two-sided. Results EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = . 03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = . 02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P < .001; median OS anti-PAPP-A + anti-IGF1R = 63.0 days, 95% CI = 52.0 to 67.0 days vs IgG2a-CTRL; P < .001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways. Conclusion This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.
A multi‐faceted approach testing the effects of previous bacterial exposure on resistance and tolerance

Abstract Hosts can alter their strategy towards pathogens during their lifetime; that is, they can show phenotypic plasticity in immunity or life history. Immune priming is one such example, where a previous encounter with a pathogen confers enhanced protection upon secondary challenge, resulting in reduced pathogen load (i.e., resistance) and improved host survival. However, an initial encounter might also enhance tolerance, particularly to less virulent opportunistic pathogens that establish persistent infections. In this scenario, individuals are better able to reduce the negative fecundity consequences that result from a high pathogen burden. Finally, previous exposure may also lead to life‐history adjustments, such as terminal investment into reproduction. Using different Drosophila melanogaster host genotypes and two bacterial pathogens, Lactococcus lactis and Pseudomonas entomophila, we tested whether previous exposure results in resistance or tolerance and whether it modifies immune gene expression during an acute‐phase infection (one day post‐challenge). We then asked whether previous pathogen exposure affects chronic‐phase pathogen persistence and longer‐term survival (28 days post‐challenge). We predicted that previous exposure would increase host resistance to an early stage bacterial infection while it might come at a cost to host fecundity tolerance. We reasoned that resistance would be due in part to stronger immune gene expression after challenge. We expected that previous exposure would improve long‐term survival, that it would reduce infection persistence, and we expected to find genetic variation in these responses. We found that previous exposure to P. entomophila weakened host resistance to a second infection independent of genotype and had no effect on immune gene expression. Fecundity tolerance showed genotypic variation but was not influenced by previous exposure. However, L. lactis persisted as a chronic infection, whereas survivors cleared the more pathogenic P. entomophila infection. To our knowledge, this is the first study that addresses host tolerance to bacteria in relation to previous exposure, taking a multi‐faceted approach to address the topic. Our results suggest that previous exposure comes with transient costs to resistance during the early stage of infection in this host–pathogen system and that infection persistence may be bacterium‐specific.
Private but not social information validity modulates social conformity bias

It is well established that human behaviors are susceptible to others' opinions. However, optimal decision theory mandates choices be made upon the estimated validities of different information sources and little is known about whether and how people could wean themselves off social conformity bias, especially when the social signals are uninformative. Here, we asked subjects to participate in a probabilistic urn guessing task based on their private information as well as observed choices from their partners. Specifically, we manipulated the information validity of these two sources such that only the private evidence was informative. Across trials, social conformity declined, manifested by the increased influence of the private evidence but steady effect of social information. Correspondingly, we found dorsomedial prefrontal cortex (dmPFC) was involved in detecting the conflict of private and social information and conforming to social signal whereas striatum was responsible for selectively updating the influence of private (but not social) evidence contingent on its inferred validity. Furthermore, functional coupling between striatum and dmPFC predicted the resistance toward the influence of social information. Together, these results may provide a mechanistic account of how the conformity bias toward uninformative social information can be remedied.
Phosphate Starvation Alters Abiotic-Stress-Induced Cytosolic Free Calcium Increases in Roots1[OPEN]

Phosphate starvation, but not nitrogen starvation, changes the cytosolic free calcium signatures of Arabidopsis thaliana roots in response to mechanical, salt, osmotic, and oxidative stress as well as to extracellular nucleotides. Phosphate (Pi) deficiency strongly limits plant growth, and plant roots foraging the soil for nutrients need to adapt to optimize Pi uptake. Ca2+ is known to signal in root development and adaptation but has to be tightly controlled, as it is highly toxic to Pi metabolism. Under Pi starvation and the resulting decreased cellular Pi pool, the use of cytosolic free Ca2+ ([Ca2+]cyt) as a signal transducer may therefore have to be altered. Employing aequorin-expressing Arabidopsis (Arabidopsis thaliana), we show that Pi starvation, but not nitrogen starvation, strongly dampens the [Ca2+]cyt increases evoked by mechanical, salt, osmotic, and oxidative stress as well as by extracellular nucleotides. The altered root [Ca2+]cyt response to extracellular ATP manifests during seedling development under chronic Pi deprivation but can be reversed by Pi resupply. Employing ratiometric imaging, we delineate that Pi-starved roots have a normal response to extracellular ATP at the apex but show a strongly dampened [Ca2+]cyt response in distal parts of the root tip, correlating with high reactive oxygen species levels induced by Pi starvation. Excluding iron, as well as Pi, rescues this altered [Ca2+]cyt response and restores reactive oxygen species levels to those seen under nutrient-replete conditions. These results indicate that, while Pi availability does not seem to be signaled through [Ca2+]cyt, Pi starvation strongly affects stress-induced [Ca2+]cyt signatures. These data reveal how plants can integrate nutritional and environmental cues, adding another layer of complexity to the use of Ca2+ as a signal transducer.
Association of aortic stiffness, carotid intima-media thickness and endothelial function with cardiovascular events in metabolic syndrome subjects

Abstract Purpose: The objective of this study was to assess predictive value of various arterial markers for cardiovascular (CV) events in patients with metabolic syndrome (MetS). Materials and methods: A longitudinal study with the follow-up period of 3.9 ± 1.7 years investigated 2728 middle-aged (53.9 ± 6.2 years old, 63% women) MetS subjects without overt CV disease. The study cohort was comprised of the participants of the Lithuanian High Cardiovascular Risk primary prevention program. The baseline assessment included the evaluation of brachial flow-mediated dilatation (FMD), carotid intima-media thickness (cIMT), carotid stiffness index, aortic pulse wave velocity (aPWV), aortic augmentation index (AIx), and cardio-ankle vascular index). The data on the cardiovascular outcome (fatal or non-fatal myocardial infarction or stroke) was collected by using the databases of the two major national registries. Results: Over the follow-up period, 83 (3%) patients had at least one cardiovascular event. In a univariate analysis, occurrence of CV events was associated with the following parameters: higher mean blood pressure, aPWV, AIx and cIMT, and lower FMD (all p < .05). In Cox proportional hazard regression analysis, the occurrence of CV event was associated with an increase in aPWV (HR 1.29, 95% CI 1.04–1.60, p = .019), AIx (HR 1.53, 95% CI 1.16–2.02, p = .003), and cIMT (HR 1.31, 95% CI 1.14–1.50, p < .001), and with the decrease in FMD (HR 0.83, 95% CI 0.71–0.97, p = .016) even after the adjustment for age, gender, and common cardiometabolic risk factors. In a two-level survival trees analysis, we established that patients with cIMT > 794 mcm had higher CV risk (p < .001) and their prognosis was further compromised by aPWV > 11.1 m/s (p = .023). Meanwhile, in patients with cIMT ≤ 794mcm, the FMD cut-off point of 6.5% further stratified the risk (p = .003). Conclusions: In our prospective study, CV risk in the middle-aged patients with MetS was associated with an increase in cIMT and aPWV, and with a decrease in FMD.
Intravascular ultrasound-guided drug-eluting stent implantation for patients with unprotected left main coronary artery lesions: A single-center randomized trial

Objective: Intravascular ultrasound (IVUS) has developed as a preferable choice for optimizing the stenting procedures mainly because it will have good access to vessel size, lesion length, or severity accurately. However, it still remains unclear about the benefits of IVUS guidance in drug-eluting stent (DES) implantation for patients with unprotected left main coronary artery (ULMCA) stenosis. The aim of the present study was to evaluate the clinical outcomes with respect to IVUS-guided DES implantation for these patients. Methods: A total of 336 consecutive patients from December 2010 to December 2015 were enrolled in the study. The patients were then randomly assigned into two groups: IVUS-guided group (n=167) and control group (n=169). The primary endpoint was the incidence of composite major adverse cardiac events (MACEs), including cardiac death, myocardial infarction (MI), and target vessel revascularization (TVR). The risk of stent thrombosis (ST) was chosen as the safety endpoint. Results: After a 1-year follow-up, the occurrence of composite MACE in the IVUS-guided group was significantly lower than that in the control group (13.2% vs. 21.9%, p=0.031), which might mainly result from the significant reduction in the risk of cardiac death (1.8% vs. 5.9%, p=0.048). Dramatically, the risk of MI did not differ significantly between the two groups (11.4% vs. 13.6%, p=0.478), though a tended reduction in TVR was observed under IVUS guidance (4.2% vs. 8.9%, p=0.068). There was no statistical significance between the two groups with respect to the risk of target lesion revascularization (IVUS-guided vs. control: 1.2% vs. 3.0%, p=0.239) and ST (IVUS-guided vs. control: 1.2% vs. 3.0%, p=0.246). Conclusion: The possible feasibility of IVUS-guided DES implantation for patients with ULMCA stenosis was supported by the present study. Larger and more powerful randomized trials were still warranted to research the whole benefits of IVUS guidance for these patients.
Characterization of Aerobic Denitrifying Bacterium Pseudomonas mendocina Strain GL6 and Its Potential Application in Wastewater Treatment Plant Effluent

To remove nitrate in wastewater treatment plant effluent, an aerobic denitrifier was newly isolated from the surface flow constructed wetland and identified as Pseudomonas mendocina strain GL6. It exhibited efficient aerobic denitrification ability, with the nitrate removal rate of 6.61 mg (N)·L−1·h−1. Sequence amplification indicated that the denitrification genes napA, nirK, norB, and nosZ were present in strain GL6. Nitrogen balance analysis revealed that approximately 74.5% of the initial nitrogen was removed as gas products. In addition, the response surface methodology experiments showed that the maximum removal of total nitrogen occurred at pH 7.76, C/N ratio of 11.2, temperature of 27.8 °C, and with shaking at 133 rpm. Furthermore, under the optimized cultivation condition, strain GL6 was added into wastewater treatment plant effluent and the removal rates of nitrate nitrogen and total nitrogen reached 95.6% and 73.6%, respectively. Thus, P. mendocina strain GL6 has high denitrification potential for deep improvement of effluent quality.
Effect of IL-6 Receptor Blockade on Proprotein Convertase Subtilisin/Kexin Type-9 and Cholesterol Efflux Capacity in Rheumatoid Arthritis Patients

Abstract The aim of the work was to examine whether abnormalities in the lipid profile that tocilizumab (TCZ), an anti-IL-6 receptor Ab, exerts in rheumatoid arthritis (RA) patients is related to changes in either proprotein convertase subtilisin/kexin-9 (PCSK9) serum concentrations or in serum cholesterol efflux capacity (CEC). TOCRIVAR is a one-year prospective clinical trial that analyzes the influence of TCZ on cardiovascular risk factors. Twenty-seven RA patients receiving TCZ (8 mg/kg IV/q4w) were assessed at baseline and weeks 12, 24, and 52. Disease activity indexes, adiposity composition, physical activity, serum CEC, PCSK9, and lipoproteins serum concentrations were assessed at every visit. Basal high-sensitivity C-reactive protein (hs-CRP) and disease activity were markedly reduced throughout one-year TCZ treatment. While initially total cholesterol and LDL cholesterol increased their plasma concentration, decreasing to basal afterwards, lipoprotein(a) was significantly lower than basal in all visits of the study. CEC increased after 24 week of treatment proportionally to hs-CRP reduction, and remained significantly higher after week 52 [median % change 32 (3–141), p=0.021]. Interestingly, variations in LDL cholesterol basal concentration along the one year of TCZ treatment correlated directly with changes of PCSK9 serum concentration (r=0.37, p=0.003). Basal abdominal adiposity, BMI, and physical activity remained stable during the study. Long-term TCZ-treated RA patients show an increment in CEC inversely proportional to hs-CRP reduction and changes in LDL cholesterol that might be explained, at least in part, by variations in PCSK9 plasma concentration. Overall, TCZ treatment produces a favorable qualitative net effect in terms of atherogenic implication in RA patients.
Effectiveness of DementiAbility Methods: The Montessori Way on agitation in long‐term care home residents with dementia in Hong Kong

To investigate the effect of the DementiAbility Methods: The Montessori Way (DMMW) on agitation in long‐term care home residents with dementia. The activities using the DMMW are hypothesized to reduce agitation in terms of its frequency and disruptiveness to greater extent than structured social activities as control.
Expression levels of circulating microRNAs‐126, ‐155, and ‐145 in Mexican women exposed to polycyclic aromatic hydrocarbons through biomass fuel use

Human exposure to polycyclic aromatic hydrocarbons (PAHs) has been considered a risk determinant for the development of cardiovascular diseases (CVD). Therefore, the aim of this study was to assess expression levels of vascular‐related miRNAs, miR‐126, miR‐155, and miR‐145, in plasma from women (aged 19–81 years) exposed (n = 100) and non‐exposed (n = 20) to PAHs via biomass combustion smoke.1‐hydroxypyrene (1‐OHP) was determined in urine as a biomarker of exposure to PAHs using high‐resolution liquid chromatography. Plasma expression levels of proposed miRNAs were determined by quantitative real‐time PCR. Additionally, traditional risk factors (age, blood pressure, serum lipid profile, blood glucose, and among others) associated with CVD were evaluated. Urinary 1‐OHP concentrations and plasma expression levels of miR‐126 and miR‐155 were significantly higher (P < 0.05) in women using wood as a fuel source in their homes (indoor) compared to women from the reference group (non‐exposed to biomass smoke). Besides, multivariate linear regression analyses revealed that miR‐126[β = 0.61; 95% confidence interval (0.32–0.90)] and miR‐155 [β = 0.45; 95% confidence interval (0.13–0.84)] expression levels were significantly associated with urinary 1‐OHP concentrations after being adjusted by traditional risk factors (P < 0.05). In contrast, no significant relationship was found between miR‐145 and urinary 1‐OHP levels. Furthermore, miRNAs assessed in this investigation are associated with CVD events. Consequently, actions to reduce exposure to PAHs in the evaluated population are warranted. Environ. Mol. Mutagen. 60:546–558, 2019. © 2019 Wiley Periodicals, Inc.