TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro.

BACKGROUND: There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide a rapid approach to meet the urgent need for treatment. METHODS: To identify therapeutic targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization analysis using cis-eQTL of druggable gene and ALS GWAS data collections to determine annotated druggable gene targets that exhibited significant associations with ALS. By subsequent repurposing drug discovery coupled with inclusion criteria selection, we identified several drug candidates corresponding to their druggable gene targets that have been genetically validated. The pharmacological assays were then conducted to further assess the efficacy of genetics-supported repurposed drugs for potential ALS therapy in various cellular models. RESULTS: Through MR analysis, we identified potential ALS druggable genes in the blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 [OR 1.36, 95%CI (1.19, 1.56)], GPX3 [OR 1.28, 95%CI (1.15, 1.43)], TNFSF13 [OR 0.45, 95%CI (0.32, 0.64)], and CD68 [OR 0.38, 95%CI (0.24, 0.58)]. Additionally, we identified potential ALS druggable genes in the brain, including RESP18 [OR 1.11, 95%CI (1.07, 1.16)], GPX3 [OR 0.57, 95%CI (0.48, 0.68)], GDF9 [OR 0.77, 95%CI (0.67, 0.88)], and PTPRN [OR 0.17, 95%CI (0.08, 0.34)]. Among them, TBK1, TNFSF12, RESP18, and GPX3 were confirmed in further colocalization analysis. We identified five drugs with repurposing opportunities targeting TBK1, TNFSF12, and GPX3, namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, and glutathione as potential repurposing drugs. R788 and AMX were prioritized due to their genetic supports, safety profiles, and cost-effectiveness evaluation. Further pharmacological analysis revealed that R788 and AMX mitigated neuroinflammation in ALS cell models characterized by overly active cGAS/STING signaling that was induced by MSA-2 or ALS-related toxic proteins (TDP-43 and SOD1), through the inhibition of TBK1 phosphorylation. CONCLUSIONS: Our MR analyses provided genetic evidence supporting TBK1, TNFSF12, RESP18, and GPX3 as druggable genes for ALS treatment. Among the drug candidates targeting the above genes with repurposing opportunities, FDA-approved drug-R788 and AMX served as effective TBK1 inhibitors. The subsequent pharmacological studies validated the potential of R788 and AMX for treating specific ALS subtypes through the inhibition of TBK1 phosphorylation.

Jasmonate/ethylene- and NaWRKY6/3-regulated Alternaria resistance depends on ethylene response factor 1B-like in Nicotiana attenuata.

Biosynthesis of the phytoalexins scopoletin and scopolin in Nicotiana species is regulated by upstream signals including jasmonate (JA), ethylene (ET), and NaWRKY3 in response to the necrotrophic fungus Alternaria alternata, which causes brown spot disease. However, how these signals are coordinated to regulate these phytoalexins remains unknown. By analyzing RNA sequencing data and RNAi, we identified NaERF1B-like (NaERF1B-L) as a key player in Nicotiana attenuata during A. alternata infection by regulating the transcripts of Feruloyl-CoA 6'-hydroxylase 1 (NaF6'H1), encoding a key enzyme for scopoletin biosynthesis, and NaVS1-like (NaVS1-L), a putative biosynthetic gene of the phytoalexin solavetivone. We further demonstrated that the synergistic induction of these two genes by JA and ET signaling is mediated by NaERF1B-L. Additionally, we found that the two closely related proteins, NaWRKY6 and NaWRKY3, physically interact to enhance NaERF1B-L expression by directly binding to and activating the NaERF1B-L promoter. Collectively, our current results demonstrate that NaERF1B-L plays a positive role in resistance to A. alternata by modulating phytoalexin biosynthesis through the integration of JA/ET and NaWRKY6/3 signaling. Our findings reveal a fine-tuned transcriptional regulatory hierarchy mediated by NaERF1B-L for brown spot disease resistance in wild tobacco.

The role of cytokines in acute and chronic postsurgical pain after major musculoskeletal surgeries in a quaternary pediatric center.

STUDY OBJECTIVE: To determine if baseline cytokines/chemokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. DESIGN: Prospective, observational, longitudinal nested study. SETTING: University-affiliated quaternary children's hospital. PATIENTS: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. MEASUREMENTS: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score > 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. MAIN RESULTS: Analyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (ß = 0.95, SE 0.31; p = 0.003), IL-1ß (ß = 0.84, SE 0.36; p = 0.02), IL-2 (ß = 0.78, SE 0.34; p = 0.03), and IL-12 p70 (ß = 0.88, SE 0.40; p = 0.03) and longitudinal postoperative elevations in GM-CSF (ß = 1.38, SE 0.57; p = 0.03), IFNγ (ß = 1.36, SE 0.6; p = 0.03), IL-1ß (ß = 1.25, SE 0.59; p = 0.03), IL-7 (ß = 1.65, SE 0.7; p = 0.02), and IL-12 p70 (ß = 1.17, SE 0.58; p = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß = -0.39, SE 0.17; p = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß = -0.57, SE 0.26; p = 0.03), IL-8 (ß = -0.68, SE 0.24; p = 0.006), and IL-13 (ß = -0.48, SE 0.22; p = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively. CONCLUSION: We identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest heterogenous outcomes of cytokine/chemokine signaling that can both promote and protect against post-surgical pain. These may serve as predictive and prognostic biomarkers of pain outcomes following surgery.

Morphologies and magnetic properties of α-Fe2O3 nanoparticles calcined at different temperatures.

Different morphologies and sizes of α-Fe2O3 were prepared by a coprecipitation method using polyvinylpyrrolidone as a dispersant. In the preparation process, homogeneous and dispersed nanoscale FeOOH particles were first obtained by the coprecipitation method, and then the FeOOH particles were calcined at high temperature to form α-Fe2O3. The growth and aggregation of the α-Fe2O3 particles at different calcination temperatures resulted in α-Fe2O3 powders with diversiform morphologies (nanoscale microsphere, pinecone ellipsoidal, polyhedral, and quasi-spherical structures). By analyzing the SEM images, it was inferred that the polyhedral structure of α-Fe2O3 particles was formed by the accumulation of rhomboid sheet structures and high-temperature growth. In terms of the magnetic properties, the samples belonged to the class of canted antiferromagnetic materials, and the morphology, particle size, and crystallite size of the α-Fe2O3 particles were important factors affecting the coercivity. Among these, when the calcination temperature was increased from 700 °C to 800 °C, the growth rate of the particle size was significantly faster than that of the crystallite size, and the coercivity increased substantially from 1411 Oe to 2688 Oe.

Antibody and transcription landscape in peripheral blood mononuclear cells of elderly adults over 70 years of age with third dose of COVID-19 BBIBP-CorV and ZF2001 booster vaccine.

BACKGROUND: In the context of the COVID-19 pandemic and extensive vaccination, it is important to explore the immune response of elderly adults to homologous and heterologous booster vaccines of COVID-19. At this point, we detected serum IgG antibodies and PBMC sample transcriptome profiles in 46 participants under 70 years old and 25 participants over 70 years old who received the third dose of the BBIBP-CorV and ZF2001 vaccines. RESULTS: On day 7, the antibody levels of people over 70 years old after the third dose of booster vaccine were lower than those of young people, and the transcriptional responses of innate and adaptive immunity were also weak. The age of the participants showed a significant negative correlation with functions related to T-cell differentiation and costimulation. Nevertheless, 28 days after the third dose, the IgG antibodies of elderly adults reached equivalence to those of younger adults, and immune-related transcriptional regulation was significantly improved. The age showed a significant positive correlation with functions related to "chemokine receptor binding", "chemokine activity", and "chemokine-mediated signaling pathway". CONCLUSIONS: Our results document that the response of elderly adults to the third dose of the vaccine was delayed, but still able to achieve comparable immune effects compared to younger adults, in regard to antibody responses as well as at the transcript level.

Spatial-temporal drivers and incidence heterogeneity of hemorrhagic fever with renal syndrome transmission in Shandong Province, China, 2016-2022.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. METHODS: The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. RESULTS: The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. CONCLUSIONS: The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic.

Assessing Mailuoning injection in wound healing and thrombophlebitis management: A rat model study.

Thrombophlebitis is the inflammatory condition characterized by obstruction of one or more vessels, commonly in the legs, due to the formation of blood clots. It has been reported that traditional Chinese medicine, including Mailuoning injection, is advantageous for treating inflammatory and blood disorders. This research assessed the therapeutic efficacy of Mailuoning injection in the treatment of thrombophlebitis in rodents, as well as investigated its impact on fibrinolysis, inflammation, and coagulation. An experimental setup for thrombophlebitis was established in rodents via modified ligation technique. Five groups comprised the animals: sham operation group, model group, and three Mailuoning treatment groups (low, medium, and high dosages). The pain response, edema, coagulation parameters (PT, APTT, TT, FIB), serum inflammatory markers (IL-6, TNF-α, CRP), and expression levels of endothelial markers (ICAM-1, VCAM-1, NF-κB) were evaluated. Blood flow and vascular function were further assessed by measuring hemorheological parameters and the concentrations of TXB2, ET, and 6-k-PGF1α. In contrast to the sham group, model group demonstrated statistically significant increases in endothelial expression levels, coagulation latencies, and inflammatory markers (p < 0.05). The administration of mailing, specifically at high and medium dosages, resulted in a substantial reduction in inflammatory markers, enhancement of coagulation parameters, suppression of ICAM-1 and VCAM-1 expression, and restoration of hemorheological measurements to baseline (p < 0.05). Significantly higher concentrations of 6-k-PGF1α and lower levels of TXB2 and ET were observed in high-dose group, suggesting that pro- and anti-thrombotic factors were restored to equilibrium. Utilization of Mailuoning injection in rat model of thrombophlebitis exhibited significant therapeutic impact. This effect was manifested through pain alleviation, diminished inflammation, enhanced blood viscosity and facilitation of fibrinolysis. The study indicated that Mailuoning injection may serve as a viable therapeutic option for thrombophlebitis, potentially aiding in the improvement of wound healing by virtue of its anti-inflammatory and blood flow-enhancing characteristics.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and discover novel therapeutic targets. Thus, we aimed to identify novel therapeutic targets for AD and analyse their pathophysiological mechanisms and potential side effects. METHODS: A two-sample MR integrating the identified druggable genes was performed to estimate the causal effects of blood and brain druggable expression quantitative trait loci (eQTLs) on AD. A repeat study was conducted using different blood and brain eQTL data sources to validate the identified genes. Using AD markers with available genome-wide association studies data, we evaluated the causal relationship between established AD markers to explore possible mechanisms. Finally, the potential side effects of the druggable genes for AD treatment were assessed using a phenome-wide MR. RESULTS: Overall, 5883 unique druggable genes were aggregated; 33 unique potential druggable genes for AD were identified in at least one dataset (brain or blood), and 5 were validated in a different dataset. Among them, three prior druggable genes (epoxide hydrolase 2 (EPHX2), SERPINB1 and SIGLEC11) reached significant levels in both blood and brain tissues. EPHX2 may mediate the pathogenesis of AD by affecting the entire hippocampal volume. Further phenome-wide MR analysis revealed no potential side effects of treatments targeting EPHX2, SERPINB1 or SIGLEC11. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting the three druggable genes for AD treatment, which will be useful for prioritising AD drug development.

Spatiotemporal distribution and environmental influences of severe fever with thrombocytopenia syndrome in Shandong Province, China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. The purpose of this study was to describe the spatiotemporal distribution of SFTS and to identify its environmental influencing factors and potential high-risk areas in Shandong Province, China. METHODS: Data on the SFTS incidence from 2010 to 2021 were collected. Spatiotemporal scan statistics were used to identify the time and area of SFTS clustering. The maximum entropy (MaxEnt) model was used to analyse environmental influences and predict high-risk areas. RESULTS: From 2010 to 2021, a total of 5705 cases of SFTS were reported in Shandong. The number of SFTS cases increased yearly, with a peak incidence from April to October each year. Spatiotemporal scan statistics showed the existence of one most likely cluster and two secondary likely clusters in Shandong. The most likely cluster was in the eastern region, from May to October 2021. The first secondary cluster was in the central region, from May to October 2021. The second secondary cluster was in the southeastern region, from May to September 2020. The MaxEnt model showed that the mean annual wind speed, NDVI, cattle density and annual cumulative precipitation were the key factors influencing the occurrence of SFTS. The predicted risk map showed that the area of high prevalence was 28,120 km2, accounting for 18.05% of the total area of the province. CONCLUSIONS: The spatiotemporal distribution of SFTS was heterogeneous and influenced by multidimensional environmental factors. This should be considered as a basis for delineating SFTS risk areas and developing SFTS prevention and control measures.

Short-term outcomes of a new gastrointestinal decompression tube combined with conservative treatment in patients with esophagojejunal anastomotic leakage after total gastrectomy.

To compare the short-term outcomes of a new gastrointestinal decompression tube combined with conservative treatment in patients with esophagojejunal anastomotic leakage (EJAL) after total gastrectomy. We retrospectively analyzed the data of 81 patients with EJAL who had undergone total gastrectomy and Roux-en-Y reconstruction at Fujian Medical University Union Hospital between January 2014 and December 2021. The patients were divided into experimental (12 patients with new gastrointestinal decompression tube plus conservative treatment) and control (69 patients with conservative treatment) groups, according to the different treatment methods they received. Anatomic defect size linearly correlated with time to clinical success, hospital stay, and hospital cost in the control group. The two groups showed no significant differences in anastomotic defect size, time of defect after surgery, hospitalization cost, and time of antibiotic use. However, the time to clinical success was significantly shorter in the experimental group than in the control group (16.0 ± 8.3 vs. 23.6 ± 17.8, P = 0.04), as was the length of hospital stay (30.1 ± 6.3 vs. 36.8 ± 16.7, P = 0.017). Furthermore, when the defect size was ≥ 4 mm, the time to clinical success, hospital stay, and hospital cost in the experimental group were lower than those in the control group (P < 0.05). Placement of a new gastrointestinal decompression tube is a safe treatment. When the defect size is ≥ 4 mm, the time to clinical success, length of hospital stay, and hospital cost can be reduced.

CircSOD2 Contributes to Tumor Progression, Immune Evasion and Anti-PD-1 Resistance in Hepatocellular Carcinoma by Targeting miR-497-5p/ANXA11 Axis.

Circular RNAs (circRNAs) can function as functional molecules in hepatocellular carcinoma (HCC). Herein, circRNA superoxide dismutase 2 (circSOD2) was researched in HCC progression and immune system. The real-time polymerase chain reaction (qRT-PCR) was used for quantification of circSOD2, microRNA-497-5p (miR-497-5p) and Annexin A11 (ANXA11). Cell assays were performed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assays for proliferation, flow cytometry for apoptosis and cell cycle, wound healing assay for migration and transwell assay for migration/invasion. ANXA11 and metastatic protein levels were measured by western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to analyze target binding. CD8+ T cell immunity was assessed by Immunohistochemistry (IHC) assay, and the effect of circSOD2 on programmed cell death 1 (PD-1) immune checkpoint inhibitors (anti-PD-1) therapy was evaluated by mice xenograft assay. CircSOD2 was upregulated in HCC tissues and cells. Knockdown of circSOD2 resulted in HCC cell growth inhibition, apoptosis promotion, cell cycle arrest and metastasis suppression. Mechanically, circSOD2 promoted HCC development by acting as a miR-497-5p sponge and miR-497-5p played a tumor-inhibitory role in HCC cells by targeting ANXA11. Moreover, circSOD2 induced upregulation of ANXA11 expression by interacting with miR-497-5p. Also, the promoting effects of circSOD2 on immune evasion and anti-PD-1 resistance were related to miR-497-5p/ANXA11 axis. This study elucidated the pivotal function of circSOD2 in HCC progression and immunosuppression by mediating miR-497-6p/ANXA11 axis. CircSOD2/miR-497-5p/ANXA11 axis was a novel view of circRNA research in HCC.

LIM Homeobox 2 Increases Adhesion-Regulating Molecule 1 Transcription to Facilitate the Pathological Progression of Oxidized Low-Density Lipoprotein-Stimulated Atherosclerotic Cell Models.

Endothelial-mesenchymal transition (EndMT) and endothelial cell apoptosis have been documented to have a role in atherosclerosis (AS) progression. To deepen knowledge in this aspect, our study investigated the effect of LIM homeobox 2 (LHX2) and adhesion-regulating molecule 1 (ADRM1) on EndMT and endothelial cell apoptosis in the oxidized low-density lipoprotein (ox-LDL) -stimulated AS cell model.Ox-LDL was utilized to treat human umbilical vein endothelial cells (HUVECs) for constructing an AS model in vitro, followed by measurement of LHX2 and ADRM1 expressions. Afterward, gain- and loss-of-function assays were performed in HUVECs, followed by detection of cell viability, invasion, migration, and apoptosis and the expression of inflammatory factors [tumor necrosis factor (TNF) -α, interleukin (IL) -1ß, and IL-6], EndMT-related proteins [CD31, vascular epithelium (VE) -cadherin, vimentin, α-smooth muscle actin (SMA), Snai1, Snai2, and Twist1], and the apoptotic protein cleaved caspase-3. Interactions between LHX2 and ADRM1 were analyzed with dual-luciferase reporter gene and chromatin immunoprecipitation assays.High levels of LHX2 and ADRM1 were observed in ox-LDL-induced HUVECs. In ox-LDL-treated HUVECs, LHX2, or ADRM1 knockdown promoted CD31 and VE-cadherin levels, viability, invasion, and migration and reduced apoptosis and the expressions of TNF-α, IL-1ß, IL-6, vimentin, α-SMA, Snai1, Snai2, Twist1, and cleaved caspase-3. Mechanistically, LHX2 bound to the ADRM1 promoter to promote ADRM1 transcription. Overexpression of ADRM1 annulled the aforementioned effects of LHX2 knockdown on ox-LDL-induced HUVECs.LHX2 facilitates the pathological progression of ox-LDL-stimulated AS cell models by increasing ADRM1 transcription.

Genetic factors for survival in amyotrophic lateral sclerosis: an integrated approach combining a systematic review, pairwise and network meta-analysis.

BACKGROUND: The time of survival in patients with amyotrophic lateral sclerosis (ALS) varies greatly, and the genetic factors that contribute to the survival of ALS are not well studied. There is a lack of a comprehensive study to elucidate the role of genetic factors in the survival of ALS. METHODS: The published studies were systematically searched and obtained from PubMed, EMBASE, and the Cochrane Library without any language restrictions from inception to Oct 27, 2021. A network meta-analysis for ALS causative/risk genes and a systematic review and pairwise meta-analysis for other genetic modifiers were conducted. The PROSPERO registration number: CRD42022311646. RESULTS: A total of 29,764 potentially relevant references were identified, and 71 papers were eligible for analysis based on pre-decided criteria, including 35 articles in network meta-analysis for 9 ALS causative/risk genes, 17 articles in pairwise meta-analysis for four genetic modifiers, and 19 articles described in the systematic review. Variants in three genes, including ATXN2 (HR: 3.6), C9orf72 (HR: 1.6), and FUS (HR:1.8), were associated with short survival of ALS, but such association was not identified in SOD1, TARDBP, TBK1, NEK1, UBQLN2, and CCNF. In addition, UNC13A rs12608932 CC genotype and ZNF521B rs2275294 C allele also caused a shorter survival of ALS; however, APOE ε4 allele and KIFAP3 rs1541160 did not be found to have any effect on the survival of ALS. CONCLUSIONS: Our study summarized and contrasted evidence for prognostic genetic factors in ALS and would help to understand ALS pathogenesis and guide clinical trials and drug development.

Investigating the relationship between melatonin patterns and methylation in circadian genes among day shift and night shift workers.

OBJECTIVES: Mechanisms underlying the carcinogenicity of night shift work remain uncertain. One compelling yet understudied cancer mechanism may involve altered DNA methylation in circadian genes due to melatonin secretion patterns. The objective of this study was to explore the relationship between melatonin secretion patterns and circadian gene methylation among day and night shift workers. METHODS: Female healthcare employees (n=38 day workers, n=36 night shift workers) for whom we had urinary 6-sulfatoxymelatonin secretion data from a previous study were recontacted. New blood samples were collected and used to measure methylation levels at 1150 CpG loci across 22 circadian genes using the Illumina Infinium MethylationEPIC beadchip. Linear regression was used to examine the association between melatonin (acrophase and mesor) and M values for each CpG site (false discovery rate, q=0.2), while testing for effect modification by shift work status. RESULTS: Among night shift workers, a higher mesor (24 hours of mean production of melatonin) was associated with increased methylation in the body of RORA (q=0.02) and decreased methylation in the putative promoter region of MTNR1A (q=0.03). Later acrophase (ie, time of peak concentration) was associated with increased methylation in the putative promoter region of MTNR1A (q=0.20) and decreased methylation in the body of PER3 (q=0.20). No associations were identified among day workers. CONCLUSIONS: In conclusion, patterns in melatonin secretion were associated with differential circadian gene methylation among night shift workers. Melatonin and alteration of DNA methylation in circadian genes may be one pathway towards increased cancer risk, although larger-scale studies examining multiple time points are needed.

MRI features of responsible contacts in vascular compressive trigeminal neuralgia and prediction modeling.

BACKGROUND: Multiple neurovascular contacts in patients with vascular compressive trigeminal neuralgia often challenge the diagnosis of responsible contacts. PURPOSE: To analyze the magnetic resonance imaging (MRI) features of responsible contacts and establish a predictive model to accurately pinpoint the responsible contacts. MATERIAL AND METHODS: Sixty-seven patients with unilateral trigeminal neuralgia were enrolled. A total of 153 definite contacts (45 responsible, 108 non-responsible) were analyzed for their MRI characteristics, including neurovascular compression (NVC) grading, distance from pons to contact (Dpons-contact), vascular origin of compressing vessels, diameter of vessel (Dvessel) and trigeminal nerve (Dtrigeminal nerve) at contact. The MRI characteristics of the responsible and non-responsible contacts were compared, and their diagnostic efficiencies were further evaluated using a receiver operating characteristic (ROC) curve. The significant MRI features were incorporated into the logistics regression analysis to build a predictive model for responsible contacts. RESULTS: Compared with non-responsible contacts, NVC grading and arterial compression ratio (84.44%) were significantly higher, Dpons-contact was significantly lower at responsible contacts (P < 0.001, 0.002, and 0.033, respectively). NVC grading had a highest diagnostic area under the ROC curve (AUC) of 0.742, with a sensitivity of 64.44% and specificity of 75.00%. The logistic regression model showed a higher diagnostic efficiency, with an AUC of 0.808, sensitivity of 88.89%, and specificity of 62.04%. CONCLUSION: Contact degree and position are important MRI features in identifying the responsible contacts of the trigeminal neuralgia. The logistic predictive model based on Dpons-contact, NVC grading, and vascular origin can qualitatively improve the prediction of responsible contacts for radiologists.

Beyond Boolean: Ternary networks and dynamics.

Boolean networks introduced by Kauffman, originally intended as a prototypical model for gaining insights into gene regulatory dynamics, have become a paradigm for understanding a variety of complex systems described by binary state variables. However, there are situations, e.g., in biology, where a binary state description of the underlying dynamical system is inadequate. We propose random ternary networks and investigate the general dynamical properties associated with the ternary discretization of the variables. We find that the ternary dynamics can be either ordered or disordered with a positive Lyapunov exponent, and the boundary between them in the parameter space can be determined analytically. A dynamical event that is key to determining the boundary is the emergence of an additional fixed point for which we provide numerical verification. We also find that the nodes playing a pivotal role in shaping the system dynamics have characteristically distinct behaviors in different regions of the parameter space, and, remarkably, the boundary between these regions coincides with that separating the ordered and disordered dynamics. Overall, our framework of ternary networks significantly broadens the classical Boolean paradigm by enabling a quantitative description of richer and more complex dynamical behaviors.

Novel MicroRNA-Regulated Transcript Networks Are Associated with Chemotherapy Response in Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic cancer, in part due to resistance to platinum-based chemotherapy reported among 20% of patients. This study aims to generate novel hypotheses of the biological mechanisms underlying chemotherapy resistance, which remain poorly understood. Differential expression analyses of mRNA- and microRNA-sequencing data from HGSOC patients of The Cancer Genome Atlas identified 21 microRNAs associated with angiogenesis and 196 mRNAs enriched for adaptive immunity and translation. Coexpression network analysis identified three microRNA networks associated with chemotherapy response enriched for lipoprotein transport and oncogenic pathways, as well as two mRNA networks enriched for ubiquitination and lipid metabolism. These network modules were replicated in two independent ovarian cancer cohorts. Moreover, integrative analyses of the mRNA/microRNA sequencing and single-nucleotide polymorphisms (SNPs) revealed potential regulation of significant mRNA transcripts by microRNAs and SNPs (expression quantitative trait loci). Thus, we report novel transcriptional networks and biological pathways associated with resistance to platinum-based chemotherapy in HGSOC patients. These results expand our understanding of the effector networks and regulators of chemotherapy response, which will help to improve the management of ovarian cancer.

[Retrospective Study of Mite-Specific Subcutaneous Immunotherapy in Children].

OBJECTIVE: To explore the clinical efficacy and influencing factors of children receiving mite-specific subcutaneous immunotherapy (SCIT). METHODS: We retrospectively analyzed the data of children who had received mite SCIT for 3 years at the Desensitization Center of our hospital. We used the daily medication score (DMS) to evaluate the medication use status (the higher the score, the higher the amount of medications given and the less satisfactorily was the primary disease controlled) and we used the visual analogue scale (VAS) to evaluate clinical symptoms (the higher the score, the more severe the symptoms). Evaluation was performed after the first SCIT treatment and after treatment was given for 3 months, 4 months, 12 months, and 3 years. According to whether medication for the primary disease was stopped after 3 years, the patients were divided into two groups, the discontinued medication group (discontinued group) and the continued medication group (continued group). The general data, DMS, VAS and the decline rate of the two groups were compared, and logistic regression was performed to analyze the influencing factors of the outcome. RESULTS: A total of 711 children were enrolled in the study, with an average age of 8.38 years at the time of the first visit to the hospital. There were 442 males and 269 females. Skin prick test showed that 445 cases only had mite allergy, and 266 cases had mite allergy combined with other allergies. 360 cases have discontinued the medication for the primary disease after 3 years, and 351 cases had relieved symptoms, but still needed to continue with the medication. At the beginning of SCIT treatment, the DMS and VAS of the discontinued group were lower than those of the continued group ( P<0.05). Evaluations from 3 months to 3 years showed that both DMS and VAS continued to decrease compared with those from the beginning, and the decline rate of DMS and VAS of the discontinued group was higher than that of the continued group after 3 years of SCIT ( P<0.05). After 3 months of SCIT, the positive rates of nasal and ocular symptoms in the discontinued group were lower than those in the continued group ( P<0.05). After 3 years of SCIT, the positive rates of nasal, ocular, and chest symptoms in the discontinued group were lower than those in the continued group ( P<0.05). Univariate analysis combined with multivariate logistic regression showed that initial DMS>4 points and initial VAS>3.5 points were protective factors for the discontinuation of the medication for the primary disease at the end of 3 years of SCIT, while the female sex and DMS reduction rate after 12 months of treatment>50% were risk factors for discontinuation. CONCLUSIONS: Mite SCIT can help relieve clinical symptoms and reduce the use of medication for symptomatic treatment. Symptoms can be improved after 3 months of SCIT, with the fastest improvement shown in nasal and eye symptoms. It is not recommended to discontinue the medication for the primary disease for too much after 1 year of treatment.

Gene networks and expression quantitative trait loci associated with adjuvant chemotherapy response in high-grade serous ovarian cancer.

BACKGROUND: A major impediment in the treatment of ovarian cancer is the relapse of chemotherapy-resistant tumors, which occurs in approximately 25% of patients. A better understanding of the biological mechanisms underlying chemotherapy resistance will improve treatment efficacy through genetic testing and novel therapies. METHODS: Using data from high-grade serous ovarian carcinoma (HGSOC) patients in the Cancer Genome Atlas (TCGA), we classified those who remained progression-free for 12 months following platinum-taxane combination chemotherapy as "chemo-sensitive" (N = 160) and those who had recurrence within 6 months as "chemo-resistant" (N = 110). Univariate and multivariate analysis of expression microarray data were used to identify differentially expressed genes and co-expression gene networks associated with chemotherapy response. Moreover, we integrated genomics data to determine expression quantitative trait loci (eQTL). RESULTS: Differential expression of the Valosin-containing protein (VCP) gene and five co-expression gene networks were significantly associated with chemotherapy response in HGSOC. VCP and the most significant co-expression network module contribute to protein processing in the endoplasmic reticulum, which has been implicated in chemotherapy response. Both univariate and multivariate analysis findings were successfully replicated in an independent ovarian cancer cohort. Furthermore, we identified 192 cis-eQTLs associated with the expression of network genes and 4 cis-eQTLs associated with BRCA2 expression. CONCLUSION: This study implicates both known and novel genes as well as biological processes underlying response to platinum-taxane-based chemotherapy among HGSOC patients.

A direct comparison of 3 T contrast-enhanced whole-heart coronary cardiovascular magnetic resonance angiography to dual-source computed tomography angiography for detection of coronary artery stenosis: a single-center experience.

BACKGROUND: In recent years, substantial advances have been made in noninvasive cardiac imaging, including cardiac computed tomography (CT) and cardiovascular magnetic resonance (CMR). The purpose of this study was to prospectively compare the diagnostic performance of contrast-enhanced whole heart coronary CMR angiography (CCMRA) to dual-source coronary CT angiography (CCTA) for the diagnosis of significant coronary stenoses (≥50%) in patients with known or suspected coronary artery disease (CAD) referred for conventional x-ray coronary angiography. METHODS: Our objective was to directly compare the diagnostic accuracy of contrast-enhanced whole-heart CCMRA (CE-CCMRA) to dual-source CCTA (DS-CCTA) for the detection of CAD. We prospectively studied 57 symptomatic patients with suspected or known CAD who were scheduled for conventional x-ray coronary angiography. Significant CAD was defined as an x-ray defined diameter reduction of ≥50% in a coronary artery with a reference diameter of ≥1.5 mm. RESULTS: CE-CCMRA and DS-CCTA were completed in 51 (89%) of 57 patients without complications. The acquisition times of CE-CCMRA and DS-CCTA, respectively, were 9.5 ± 3.1 min and 8.3 ± 1.4 s. On patient-based analysis, the sensitivity, specificity, positive and negative predictive value of CE-CCMRA and DS-CCTA were 93.5% versus 93.5%(P > 0.05), 85% versus 90%(P > 0.05), 90.6% versus 93.5%(P > 0.05), and 89.4% versus 90%(P > 0.05), respectively. The area under the curve (AUC) was 0.89 (95% CI: 0.79 to 0.99) for CE-CCMRA and 0.92 (95% CI: 0.83 to 1.00) for DS-CCTA. CONCLUSIONS: DS-CCTA was found to be superior to CE-CCMRA in the diagnosis of significant coronary stenoses (≥50%) in patients with suspected or known CAD scheduled for conventional x-ray coronary angiography, owing to shorter scanning times and higher spatial resolution. However, CE-CCMRA and DS-CCTA have similar diagnostic accuracies.