LACC1 deficiency leading to juvenile arthritis and anemia.

OBJECTIVE: Juvenile arthritis caused by loss-of-function LACC1 mutations is characterized by early onset of symmetric and chronic arthritis, associated with an elevation of inflammatory markers. We aimed to describe serum cytokine levels, explore the type I interferon pathway, and evaluate the efficacy of treatment in a patient presenting with polyarthritis and anemia caused by novel compound heterozygous variations in LACC1. METHODS: Clinical data of a patient with compound heterozygous variations in LACC1 was collected. Serum cytokine levels and IFN-stimulated cytokine genes were analyzed at diagnosis, at disease flare, and after treatment. Full-length cDNA of LACC1 was checked by RNA analysis. Single-cell RNA sequencing was performed in PBMCs. RESULTS: Two novel variants in the LACC1 gene were identified in a patient presenting with polyarthritis and anemia. LACC1-cDNA was normally expressed in the healthy control, the target production at 1384 bp was not observed in the patient. Compared to nine patient controls with non-systemic juvenile idiopathic arthritis, serum interleukin(IL)-6 level was significantly elevated in the affected patient. The median IFN score for the patient, her mother, and controls were 118, 8, and 4.9, respectively. The combined treatment of JAK inhibitors with prednisone or tocilizumab led to a complete response, including remission of joint symptoms, resolution of anemia, reduced expression of IFN-stimulated cytokine genes, and normalized levels of inflammatory markers, including CRP, ESR, SAA, and serum IL-6. CONCLUSION: LACC1 may play a crucial role in multiple inflammatory signaling pathways. The combination therapy of JAK inhibitors and tocilizumab may be effective for a subset of refractory patients.

Metabolomics and Molecular Networking-Guided Screening of Bacillus-Derived Bioactive Compounds Against a Highly Lethal Vibrio Species.

Microorganisms are important sources of bioactive natural products. However, the complexity of microbial metabolites and the low abundance of active compounds render the isolation and purification process laborious and inefficient. During our search for active substances capable of inhibiting the newly discovered highly lethal Vibrio strain vp-HL, we found that the fermentation broth of multiple Bacillus strains exhibited antibacterial activity. However, the substances responsible for the activity remained unclear. Metabolomics, molecular networking (MN), and the Structural similarity Network Annotation Platform for Mass Spectrometry (SNAP-MS) were employed in conjunction with bioactivity screening to predict the antibacterial compounds from Bacillus strains. The analysis of fractions, and their isolation, NMR-based annotation, and bioactivity evaluation of an amicoumacin compound partially confirmed the prediction from these statistical analyses. This work presents the potential of marine Bacillus in producing active substances against Vibrio species. Additionally, it highlighted the significance and feasibility of metabolomics and MN in the dereplication of compounds and the determination of isolation targets.

Characterization of the powdery mildew resistance locus in wheat breeding line Jimai 809 and its breeding application.

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a severe disease that affects the yield and quality of wheat. Popularization of resistant cultivars in production is the preferred strategy to control this disease. In the present study, the Chinese wheat breeding line Jimai 809 showed excellent agronomic performance and high resistance to powdery mildew at the whole growth stage. To dissect the genetic basis for this resistance, Jimai 809 was crossed with the susceptible wheat cultivar Junda 159 to produce segregation populations. Genetic analysis showed that a single dominant gene, temporarily designated PmJM809, conferred the resistance to different Bgt isolates. PmJM809 was then mapped on the chromosome arm 2BL and flanked by the markers CISSR02g-1 and CIT02g-13 with genetic distances 0.4 and 0.8 cM, respectively, corresponding to a physical interval of 704.12-708.24 Mb. PmJM809 differed from the reported Pm genes on chromosome arm 2BL in origin, resistance spectrum, physical position and/or genetic diversity of the mapping interval, also suggesting PmJM809 was located on a complex interval with multiple resistance genes. To analyze and screen the candidate gene(s) of PmJM809, six genes related to disease resistance in the candidate interval were evaluated their expression patterns using an additional set of wheat samples and time-course analysis post-inoculation of the Bgt isolate E09. As a result, four genes were speculated as the key candidate or regulatory genes. Considering its comprehensive agronomic traits and resistance findings, PmJM809 was expected to be a valuable gene resource in wheat disease resistance breeding. To efficiently transfer PmJM809 into different genetic backgrounds, 13 of 19 closely linked markers were confirmed to be suitable for marker-assisted selection. Using these markers, a series of wheat breeding lines with harmonious disease resistance and agronomic performance were selected from the crosses of Jimai 809 and several susceptible cultivars. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01467-8.

Left ventricular geometry characteristics and clinical outcomes in hemodialysis patients with heart failure with preserved ejection fraction.

BACKGROUND: The relationships among left heart remodeling, cardiac function, and cardiovascular events (CEs) in patients with heart failure (HF) with preserved ejection fraction (HFpEF) undergoing maintenance hemodialysis (MHD) remain unclear. We evaluated the echocardiographic characteristics and clinical outcomes of such patients with diverse left ventricular geometric (LVG) configurations. METHODS: Overall, 210 patients with HFpEF undergoing MHD (cases) and 60 healthy controls were enrolled. Cases were divided into four subgroups based on LVG and were followed up for three years. The primary outcomes were the first CEs and all-cause mortality. RESULTS: Left ventricular ejection fraction (LVEF) and right ventricular systolic function did significantly differ between cases and controls, whereas echocardiographic parameters of cardiac structure, diastolic function, and left ventricular global longitudinal strain (LVGLS) differed significantly. The proportion of cases with left ventricular hypertrophy (LVH) was 67.1%. In addition, 2.38%, 21.90%, 12.86%, and 62.86% of cases presented with normal geometry (NG), concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH), respectively. The left atrial diameter (LAD) was the largest and cardiac output index was the lowest in the EH subgroup. The score of Acute Dialysis Quality Initiative Workgroup (ADQI) HF class was worse in the EH subgroup than in other subgroups at baseline. The proportions of cases free of adverse CEs in the EH subgroup at 12, 24, and 36 months were 40.2%, 14.8%, and 0%, respectively, and the survival rates were 85.2%, 29.6%, 3.7%, respectively, which were significantly lower than those in other subgroups. Multivariate Cox regression revealed that age, TNI (Troponin I), EH, left ventricular mass index (LVMI), age and EH configuration were independent risk factors for adverse CEs and all-cause mortality in the cases. CONCLUSION: Most patients with HFpEF receiving MHD have LVH and diastolic dysfunction. Among the four LVGs, patients with HFpEF undergoing MHD who exhibited EH had the highest risk of adverse CEs and all-cause mortality.

Effect of sacubitril valsartan on heart failure with mid-range or preserved ejection fraction in patients on maintenance hemodialysis: real-world experience in a single-center, prospective study.

BACKGROUND: This study aimed to evaluate the effect of sacubitril valsartan (SV) on heart failure (HF) hospitalization and cardiovascular mortality in patients on hemodialysis with HF with preserved ejection fraction (EF; HFpEF). METHODS: This single-center, prospective study enrolled 155 stable hemodialysis patients with EF > 40% who were followed up for 12 months. Fifty-nine patients were treated with SV; the others were matched for EF (57.89 ± 9.35 vs. 58.00 ± 11.82, P = 0.9) at a ratio of 1:1 and included as controls. The target dosage of SV was 200 mg/day. RESULTS: Twenty-three (23/155; 14.84%) had HF with mid-range EF (HFmrEF), while 132 (85.16%) had HFpEF. After SV treatment, the peak early diastolic transmitral flow velocity/peak early diastolic mitral annular tissue velocity(E/e') improved from 17.19 ± 8.74 to 12.80 ± 5.52 (P = 0.006), the left ventricular (LV) end-diastolic diameter decreased from 53.14 ± 7.67 mm to 51.56 ± 7.44 mm (P = 0.03), and the LV mass index decreased from 165.7 ± 44.6 g/m2 to 154.8 ± 24.0 g/m2 (P = 0.02). LVEF (P = 0.08) and LV global longitudinal strain (P = 0.7) did not change significantly. The composite outcome of first and recurrent HF hospitalization or cardiovascular death showed no difference between group. However, the Acute Dialysis Quality Initiative Workgroup (ADQI) HF class improved in 39 and 15 patients and worsened in 1 and 11 patients in the SV and control groups, respectively (P < 0.001). Age, diabetes mellitus, and pulmonary arterial pressure were independent risk factors for HF hospitalization and cardiovascular mortality in patients with HFpEF. CONCLUSIONS: SV improved LV hypertrophy, diastolic function, and the ADQI class for HF; however, it failed to reduce the composite endpoints of HF hospitalization and cardiovascular disease-related mortality over 12 months of follow-up in patients on maintenance hemodialysis with EF of > 40%.

Single-atom iron boosts electrochemiluminescence for ultrasensitive carcinoembryonic antigen detection.

A simple and ultrasensitive sandwich-type electrochemiluminescence (ECL) immunosensor has been developed using porous three-dimensional gold nanoparticles (Au NPs) iron(Fe)-zinc(Zn) metal-organic frameworks (Au NPs-FeZn-MOFs@luminol) as high-efficiency ECL signal probes with Fe single-atom catalysts (SACs) (Fe-N-C SACs) as potentially advanced coreaction accelerators and dissolved oxygen as a coreaction agent to realize an H2O2-free amplification method for detecting carcinoembryonic antigen (CEA). The cathodic ECL of luminol, which was usually negligible, increased first. Because the Fe-N-C SACs exhibited an outstanding catalytic performance and a unique electronic structure, different reactive oxygen species (ROS) were generated via the oxygen reduction reaction. ROS oxidized the luminol anions to luminol anion radicals, preventing the time-consuming luminol electrochemical oxidation. Furthermore, the luminol anion radicals generated in situ reacted with ROS to produce potent cathodic ECL emissions. The immunosensor exhibited favorable analytical accuracy (detection range: 0.1 pg mL-1 - 80 ng mL-1), and its detection limit for serum samples was 0.031 pg mL-1 (S/N = 3). Consequently, the proposed strategy offers a new approach for early screening of CEA.

Comparison of ultrasound features and lesion sites in dysfunctional arteriovenous fistula.

This study aimed to investigate ultrasound features of arteriovenous fistula stenosis and their relationship with primary patency after percutaneous transluminal angioplasty (post-intervention primary patency) and compare this classification with that using lesion location. Hemodialysis patients who underwent ultrasound-guided percutaneous transluminal angioplasty for arteriovenous fistula stenosis from July 2020 to December 2021 were retrospectively evaluated. Lesions (excluding inflow arteries) were categorized into five groups based on ultrasound features, and the clinical characteristics and risk factors affecting the post-intervention primary patency of the arteriovenous fistula were analyzed. Among 185 patients, 100 (54.05%), 36 (19.46%), 22 (11.89%), 11 (5.95%), and 16 (8.65%) were classified into the intima-dominant, non-intima-dominant, valve obstruction, vascular calcification, and mixed groups, respectively. The dialysis duration and arteriovenous fistula use time were the highest in the vascular calcification group at 86 (interquartile range: 49-140) and 77 (interquartile range: 49-110) months, respectively. Diabetes mellitus was most common in the intima-dominant group (42.0%). In Kaplan-Meier and univariate Cox analysis, type III lesion location (stenosis in the venous confluence site) was associated with the lower post-intervention primary patency. In the multivariate Cox analysis, percutaneous transluminal angioplasty times (the number of times patients were treated with percutaneous transluminal angioplasty for arteriovenous fistula stenosis dysfunction), vascular calcification, calcification at the lesion site requiring percutaneous transluminal angioplasty, and serum parathyroid hormone levels were independent risk factors for post-intervention primary patency. Ultrasound features showed that calcification of the arteriovenous fistula was detrimental to the post-intervention primary patency of arteriovenous fistula.

Hypoxia-responsive lncRNA G077640 promotes ESCC tumorigenesis via the H2AX-HIF1α-glycolysis axis.

Long noncoding RNAs (lncRNAs) contribute to esophageal squamous cell carcinoma (ESCC) progression, but the underlying mechanisms remain elusive. In this study, we verified a hitherto uncharacterized hypoxia-responsive lncRNA, G077640, which is upregulated in human ESCC cells and tissues, supporting the proliferation and migration of ESCC cells. Mechanistically, G077640 prevented hypoxia-inducible factor-1α (HIF1α) from being degraded by directly interacting with histone H2AX and further modulated the interaction of HIF1α and H2AX. In addition, G077640 reprogrammed glycolytic metabolism by regulating the expression of glucose transporter 4 (GLUT4), hexokinase 2 (HK2) and pyruvate dehydrogenase kinase 1 (PDK1) for ESCC proliferation and migration. Clinically, G077640 was associated with poor prognosis in ESCC patients. Taken together, our findings identified a hypoxia-responsive lncRNA that contributes to ESCC cells proliferation and migration, and targeting G077640 and its pathway might be a potential therapeutic strategy for ESCC.

Genomic insight of sulfate reducing bacterial genus Desulfofaba reveals their metabolic versatility in biogeochemical cycling.

BACKGROUND: Sulfate-reducing bacteria (SRB) drive the ocean sulfur and carbon cycling. They constitute a diverse phylogenetic and physiological group and are widely distributed in anoxic marine environments. From a physiological viewpoint, SRB's can be categorized as complete or incomplete oxidizers, meaning that they either oxidize their carbon substrate completely to CO2 or to a stoichiometric mix of CO2 and acetate. Members of Desulfofabaceae family are incomplete oxidizers, and within that family, Desulfofaba is the only genus with three isolates that are classified into three species. Previous physiological experiments revealed their capability of respiring oxygen. RESULTS: Here, we sequenced the genomes of three isolates in Desulfofaba genus and reported on a genomic comparison of the three species to reveal their metabolic potentials. Based on their genomic contents, they all could oxidize propionate to acetate and CO2. We confirmed their phylogenetic position as incomplete oxidizers based on dissimilatory sulfate reductase (DsrAB) phylogeny. We found the complete pathway for dissimilatory sulfate reduction, but also different key genes for nitrogen cycling, including nitrogen fixation, assimilatory nitrate/nitrite reduction, and hydroxylamine reduction to nitrous oxide. Their genomes also contain genes that allow them to cope with oxygen and oxidative stress. They have genes that encode for diverse central metabolisms for utilizing different substrates with the potential for more strains to be isolated in the future, yet their distribution is limited. CONCLUSIONS: Results based on marker gene search and curated metagenome assembled genomes search suggest a limited environmental distribution of this genus. Our results reveal a large metabolic versatility within the Desulfofaba genus which establishes their importance in biogeochemical cycling of carbon in their respective habitats, as well as in the support of the entire microbial community through releasing easily degraded organic matters.

Axillary ultrasound after neoadjuvant therapy reduces the false-negative rate of sentinel lymph node biopsy in patients with cytologically node-positive breast cancer.

OBJECTIVES: This study aimed to determine whether post-neoadjuvant therapy (NAT) axillary ultrasound (AUS) could reduce the false-negative rate (FNR) of sentinel lymph node biopsy (SLNB). We also performed subgroup analyses to identify the appropriate patient for SLNB. METHODS: A total of 220 patients with cytologically proven axillary node-positive breast cancer who underwent both SLNB and axillary lymph node dissection (ALND) after NAT were included. We calculated the FNR of SLNB. In the case of post-NAT AUS results available, AUS was classified as negative or positive. Then the FNR of post-NAT AUS combined with SLNB was evaluated. Subgroup analyses based on the number of sentinel lymph nodes removed, molecular subtypes, and the clinical N stage were also performed. RESULTS: The overall axillary lymph node pathological complete response rate was 45.5% (100/220). The FNR of SLNB alone was 15.8% (95%CI: 9.2 to 22.5%). Post-NAT AUS results were available for 181 patients. When combined negative post-NAT AUS results and SLNB, the FNR was reduced to 7.5% (95%CI: 2.4 to 12.7%). Subgroup analyses of the FNR for SLNB alone and negative post-NAT AUS combined with SLNB were shown as follows: in cases patients with less than three sentinel lymph nodes (SLNs) and at least three SLNs removed, the FNR was decreased from 24.5 to 13.2%, and 9.0 to 5.0%, respectively. The FNR was decreased from 20.8 to 10.5% in HR+/HER2+subgroup, 21.4 to 16.7% in HR-/HER2+subgroup, 15.9 to 7.0% in HR+/HER2- subgroup, and 0% in HR-/HER2- subgroup, respectively. For cN1 patients, the FNR was decreased from 18.1 to 12.1% while 17.1 to 3.6% for cN2 patients and 0% for cN3 patients. CONCLUSION: Using negative post-NAT AUS may help to decrease the FNR and improve patient selection for SLNB.

MRI-based Quantification of Intratumoral Heterogeneity for Predicting Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Breast cancer is highly heterogeneous, resulting in different treatment responses to neoadjuvant chemotherapy (NAC) among patients. A noninvasive quantitative measure of intratumoral heterogeneity (ITH) may be valuable for predicting treatment response. Purpose To develop a quantitative measure of ITH on pretreatment MRI scans and test its performance for predicting pathologic complete response (pCR) after NAC in patients with breast cancer. Materials and Methods Pretreatment MRI scans were retrospectively acquired in patients with breast cancer who received NAC followed by surgery at multiple centers from January 2000 to September 2020. Conventional radiomics (hereafter, C-radiomics) and intratumoral ecological diversity features were extracted from the MRI scans, and output probabilities of imaging-based decision tree models were used to generate a C-radiomics score and ITH index. Multivariable logistic regression analysis was used to identify variables associated with pCR, and significant variables, including clinicopathologic variables, C-radiomics score, and ITH index, were combined into a predictive model for which performance was assessed using the area under the receiver operating characteristic curve (AUC). Results The training data set was comprised of 335 patients (median age, 48 years [IQR, 42-54 years]) from centers A and B, and 590, 280, and 384 patients (median age, 48 years [IQR, 41-55 years]) were included in the three external test data sets. Molecular subtype (odds ratio [OR] range, 4.76-8.39 [95% CI: 1.79, 24.21]; all P < .01), ITH index (OR, 30.05 [95% CI: 8.43, 122.64]; P < .001), and C-radiomics score (OR, 29.90 [95% CI: 12.04, 81.70]; P < .001) were independently associated with the odds of achieving pCR. The combined model showed good performance for predicting pCR to NAC in the training data set (AUC, 0.90) and external test data sets (AUC range, 0.83-0.87). Conclusion A model that combined an index created from pretreatment MRI-based imaging features quantitating ITH, C-radiomics score, and clinicopathologic variables showed good performance for predicting pCR to NAC in patients with breast cancer. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rauch in this issue.

Effect of proximal artery restriction on flow reduction and cardiac function in hemodialysis patients with high-flow arteriovenous fistulas.

OBJECTIVE: Arteriovenous fistula is the preferred vascular access for hemodialysis patients. High-flow arteriovenous fistula may cause high-output heart failure. Various procedures are used to reduce high-flow arteriovenous fistula. This study aimed to assess the efficacy of proximal artery restriction combined with distal artery ligation on flow reduction for high-flow arteriovenous fistula and on cardiac function and echocardiographic changes in patients undergoing hemodialysis. METHODS: A retrospective analysis was performed on data collected from the medical records of patients undergoing hemodialysis with heart failure and high-flow arteriovenous fistula between May 2018 and May 2021. Thirty-one patients were treated with proximal artery restriction (banding juxta-anastomosis of the proximal artery) combined with distal artery ligation (anastomosis distal artery ligation). Changes in the Acute Dialysis Quality Initiative Workgroup cardiac function class, blood pressure, and echocardiography before and 6 months after flow restriction were compared, and post-intervention primary patency was followed-up. RESULTS: The technical success rate of the surgery was 100%, and no surgery-related adverse events occurred. Blood flow and blood flow/cardiac output decreased significantly after flow restriction. Blood flow decreased from 2047.21 ± 398.08 mL/min to 1001.36 ± 240.42 mL/min, and blood flow/cardiac output decreased from 40.18% ± 6.76% to 22.34% ± 7.21% (P < .001). Post-intervention primary patency of arteriovenous fistula at 6, 12, and 24 months was 96.8%, 93.5%, and 75.2%, respectively. The Acute Dialysis Quality Initiative Workgroup cardiac function class improved significantly after 6 months of flow restriction (P < .001). The systolic and diastolic left heart function improved, as evidenced by a significant decrease in left atrial volume index, left ventricular end-diastolic/end-systolic diameters, left ventricular end-diastolic volume, left ventricular mass index, cardiac output, and cardiac index and an increase in lateral peak velocity of longitudinal contraction, average septal-lateral s', and lateral early diastolic peak velocity after flow restriction (P < .05). Systolic pulmonary artery pressure decreased from 32.36 ± 8.56 mmHg to 27.57 ± 8.98 mmHg (P < .05), indicating an improvement in right heart function. CONCLUSIONS: Proximal artery restriction combined with distal artery ligation effectively reduced the blood flow of high-flow arteriovenous fistula and improved cardiac function.

Ferrostatin-1 attenuates pathological angiogenesis in oxygen-induced retinopathy via inhibition of ferroptosis.

Retinopathy of prematurity (ROP) is a vision-threatening ocular disease that occurs in premature infants, but the underlying mechanism is still unclear. Since oxidative stress has been well documented in the ROP development, we aimed to investigate whether ferroptosis, a new type of cell death characterized by lipid peroxidation and iron overload, is also involved in ROP. We detected the lipid peroxidation, oxidative stress and the expression of ferroptosis markers in the retina of mouse model of oxygen-induced retinopathy. After ferroptosis inhibitor, ferrostatin-1, was administered by intravitreal injection, ferroptosis marker, lipid peroxidation, retinal vasculature and glial cell activation were examined. We found decreased expression of SLC7A11 and GPX4, increased expression of FTH1 and TFRC, as well as increase of lipid peroxidation in the retina of OIR mice. Ferrostatin-1 administration significantly reduced lipid peroxidation, and also reversed the change of ferroptosis marker. Neovascular area and avascular area were suppressed and the pathological vasculature changes including acellular vessels and ghost pericytes were decreased. Microglial cell and Müller cell activation was not evidently influenced by ferrostatin-1 treatment. Our findings suggest that ferroptosis is involved in the pathological angiogenesis and might be a promising target for ROP therapy.

Down-regulation of HuR inhibits pathological angiogenesis in oxygen-induced retinopathy.

HuR (also known as ELAV1), a ubiquitous RNA-binding protein, is implicated in the pathogenesis of diverse diseases via the mechanism of post-transcriptional regulation. Whether it is involved in pathological angiogenesis in oxygen-induced retinopathy is not clear. In this study, we detected HuR expression was increased in the retina of mouse model of oxygen-induced retinopathy (OIR) as well as in vascular endothelial cells exposed to hypoxia. With gain-of-function and loss-of-function studies using adenovirus infection, we found HuR over-expression promoted while HuR knockdown inhibited the migration, proliferation and tube formation of vascular endothelial cells. Moreover, HuR regulated the expression of VEGFA in vascular endothelial cells. We also found the retinal pathological angiogenesis in mouse OIR model was greatly reduced with HuR knockdown using recombinant AAV expressing HuR specific shRNA which was administered by intravitreal injection. The results of this study suggest HuR is involved in pathological angiogenesis via regulating angiogenic behaviors of endothelial cells, providing a potential target for the treatment of retinopathy of prematurity.

Examination of ADRB2 gene expression and influence of Dexmedetomidine and Propofol on Hemodynamics after Abdominal Surgery.

This study aimed to investigate ADRB2 gene expression and further understand the effects of dexmedetomidine on cardiac output and oxygen metabolism in tissues and organs by comparing the changes in hemodynamics after the patient has been sedated with dexmedetomidine and propofol after abdominal surgery. A total of 84 patients were randomly divided into the Dexmedetomidine Group (DEX Group with 40 cases) and Propofol Group (PRO Group with 44 cases). For the DEX Group, dexmedetomidine was used for sedation (loading dose: 1 ug/kg, infused for 10min; maintenance dose: 0.3ug/kg/h ~); for the PRO Group, propofol was used for sedation (loading dose: 0.5mg/kg, infused for 10min; maintenance dose: 0.5mg/kg/h ~), and the dosage of sedation drug was according to the sedation target (BIS value 60-80). Before the sedation and 5min, 10min, 30min, 1h, 2h, 4h and 6h after the loading dose, the Mindray and Vigileo monitors were used to record the BIS values and hemodynamics indices of the patients in both groups. Both DEX and PRO groups could reach the target BIS value (P> 0.05). The CI decreases before and after the administration in both groups were significant (P <0.01). The SV level of DEX group after administration was higher than before administration, while the SV level of the PRO Group after administration was lower than before administration (P <0.01). The lactate clearance rate (6h) of DEX Group was higher than that of PRO Group (P <0.05). The incidence of postoperative delirium in the Dexmedetomidine Group was lower than in the Propofol Group (P <0.05). Compared with propofol, dexmedetomidine for sedation can reduce the heart rate and increase the cardiac stroke output. Cell analysis of the ADRB2 gene showed that this gene is more expressed in the cytosol. Also, its expression in the respiratory system is more than in other organs. Considering that this gene plays a role in stimulating the sympathetic nervous system and the cardiovascular system, it can be used in the safety regulation of clinical prognosis and treatment resistance along with Dexmedetomidine and Propofol.

A hybrid machine learning model for landslide-oriented risk assessment of long-distance pipelines.

Preparation of pipeline risk zoning is essential for pipeline construction and safe operation. Landslides are one of the main sources of risk to the safe operations of oil and gas pipelines in mountainous areas. This work aims to propose a quantitative assessment model of landslide-induced long-distance pipeline risk by analyzing historical landslide hazard data along oil and gas pipelines. Using the Changshou-Fuling-Wulong-Nanchuan (CN) gas pipeline dataset, two independent assessments were carried out: landslide susceptibility assessment and pipeline vulnerability assessment. Firstly, the study combined the recursive feature elimination and particle swarm optimization-AdaBoost method (RFE-PSO-AdaBoost) to develop a landslide susceptibility mapping model. The RFE method was used to select the conditioning factors, while PSO was used to tune the hyper-parameters. Secondly, considering the angular relationship between the pipelines and landslides, and the segmentation of the pipelines using the fuzzy clustering (FC), the CRITIC method (FC-CRITIC) was combined to develop a pipeline vulnerability assessment model. Accordingly, a pipeline risk map was obtained based on pipeline vulnerability and landslide susceptibility assessment. The study results show that almost 35.3% of the slope units were in extremely high susceptibility zones, 6.68% of the pipelines were in extremely high vulnerability areas, the southern and eastern pipelines segmented in the study area were located in high risk areas and coincided well with the distribution of landslides. The proposed hybrid machine learning model for landslide-oriented risk assessment of long-distance pipelines can provide a scientific and reasonable risk classification for new planning or in service pipelines to avoid landslide-oriented risk and ensure their safe operation in mountainous areas.

Automated whole-slide images assessment of immune infiltration in resected non-small-cell lung cancer: towards better risk-stratification.

BACKGROUND: High immune infiltration is associated with favourable prognosis in patients with non-small-cell lung cancer (NSCLC), but an automated workflow for characterizing immune infiltration, with high validity and reliability, remains to be developed. METHODS: We performed a multicentre retrospective study of patients with completely resected NSCLC. We developed an image analysis workflow for automatically evaluating the density of CD3+ and CD8+ T-cells in the tumour regions on immunohistochemistry (IHC)-stained whole-slide images (WSIs), and proposed an immune scoring system "I-score" based on the automated assessed cell density. RESULTS: A discovery cohort (n = 145) and a validation cohort (n = 180) were used to assess the prognostic value of the I-score for disease-free survival (DFS). The I-score (two-category) was an independent prognostic factor after adjusting for other clinicopathologic factors. Compared with a low I-score (two-category), a high I-score was associated with significantly superior DFS in the discovery cohort (adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.33-0.86; P = 0.010) and validation cohort (adjusted HR, 0.57; 95% CI 0.36-0.92; P = 0.022). The I-score improved the prognostic stratification when integrating it into the Cox proportional hazard regression models with other risk factors (discovery cohort, C-index 0.742 vs. 0.728; validation cohort, C-index 0.695 vs. 0.685). CONCLUSION: This automated workflow and immune scoring system would advance the clinical application of immune microenvironment evaluation and support the clinical decision making for patients with resected NSCLC.

Multi-scale pathology image texture signature is a prognostic factor for resectable lung adenocarcinoma: a multi-center, retrospective study.

BACKGROUND: Tumor histomorphology analysis plays a crucial role in predicting the prognosis of resectable lung adenocarcinoma (LUAD). Computer-extracted image texture features have been previously shown to be correlated with outcome. However, a comprehensive, quantitative, and interpretable predictor remains to be developed. METHODS: In this multi-center study, we included patients with resectable LUAD from four independent cohorts. An automated pipeline was designed for extracting texture features from the tumor region in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) at multiple magnifications. A multi-scale pathology image texture signature (MPIS) was constructed with the discriminative texture features in terms of overall survival (OS) selected by the LASSO method. The prognostic value of MPIS for OS was evaluated through univariable and multivariable analysis in the discovery set (n = 111) and the three external validation sets (V1, n = 115; V2, n = 116; and V3, n = 246). We constructed a Cox proportional hazards model incorporating clinicopathological variables and MPIS to assess whether MPIS could improve prognostic stratification. We also performed histo-genomics analysis to explore the associations between texture features and biological pathways. RESULTS: A set of eight texture features was selected to construct MPIS. In multivariable analysis, a higher MPIS was associated with significantly worse OS in the discovery set (HR 5.32, 95%CI 1.72-16.44; P = 0.0037) and the three external validation sets (V1: HR 2.63, 95%CI 1.10-6.29, P = 0.0292; V2: HR 2.99, 95%CI 1.34-6.66, P = 0.0075; V3: HR 1.93, 95%CI 1.15-3.23, P = 0.0125). The model that integrated clinicopathological variables and MPIS had better discrimination for OS compared to the clinicopathological variables-based model in the discovery set (C-index, 0.837 vs. 0.798) and the three external validation sets (V1: 0.704 vs. 0.679; V2: 0.728 vs. 0.666; V3: 0.696 vs. 0.669). Furthermore, the identified texture features were associated with biological pathways, such as cytokine activity, structural constituent of cytoskeleton, and extracellular matrix structural constituent. CONCLUSIONS: MPIS was an independent prognostic biomarker that was robust and interpretable. Integration of MPIS with clinicopathological variables improved prognostic stratification in resectable LUAD and might help enhance the quality of individualized postoperative care.

TIM-1 promotes proliferation and metastasis, and inhibits apoptosis, in cervical cancer through the PI3K/AKT/p53 pathway.

BACKGROUND: T-cell immunoglobulin mucin-1 (TIM-1) has been reported to be associated with the biological behavior of several malignant tumors; however, it is not clear whether it has a role in cervical cancer (CC). METHODS: TIM-1 expression in cervical epithelial tumor tissues and cells was detected by immunohistochemistry or real-time quantitative-PCR and western blotting. CC cells from cell lines expressing low levels of TIM-1 were infected with lentiviral vectors encoding TIM-1. Changes in the malignant behavior of CC cells were assessed by CCK-8, wound healing, Transwell migration and invasion assays, and flow cytometry in vitro; while a xenograft tumor model was established to analyze the effects of TIM-1 on tumor growth in vivo. Changes in the levels of proteins related to the cell cycle, apoptosis, and Epithelial-mesenchymal transition (EMT) were determined by western blotting. RESULTS: TIM-1 expression was higher in CC tissues, than in high grade squamous intraepithelial lesion, low grade squamous intraepithelial lesion, or normal cervical tissues, and was also expressed in three CC cell lines. In HeLa and SiHa cells overexpressing TIM-1, proliferation, invasion, and migration increased, while whereas apoptosis was inhibited. Furthermore, TIM-1 downregulated the expression of p53, BAX, and E-cadherin, and increased cyclin D1, Bcl-2, Snail1, N-cadherin, vimentin, MMP-2, and VEGF. PI3K, p-AKT, and mTOR protein levels also increased, while total AKT protein levels remained unchanged. CONCLUSIONS: Our study indicated that TIM-1 overexpression promoted cell migration and invasion, and inhibited cell apoptosis in CC through modulation of the PI3K/AKT/p53 and PI3K/AKT/mTOR signaling pathways, and may be a candidate diagnostic biomarker of this disease.

Early-life exposure to the Chinese famine and risk of hyperuricaemia in adult females in Qingdao.

Two population-based cross-sectional surveys involving randomly selected Chinese adults aged 35-74 years were conducted in Qingdao, China in 2006 and 2009. Nine thousand fifty-five subjects from the two surveys were grouped into four birth groups of fetal/infant exposed (born between 1 January 1959 and 31 December 1962), childhood exposed (born between 1 January 1950 and 31 December 1958), adolescence exposed (born between 1 January 1942 and 31 December 1949) and the unexposed (born before 1941 and after 1963). Multivariate logistic regression models were used to calculate the OR and 95 % CI of hyperuricaemia in different exposed groups. Overall, famine exposure in the fetal/infant period, childhood and adolescence was not associated with adulthood hyperuricaemia (all P > 0·05). In females, childhood exposed group (OR = 1·59, 95 % CI 1·25, 2·02) and adolescence exposed group (OR = 1·74, 95 % CI 1·30, 2·33) both had higher risks to have hyperuricaemia in adult. However, this difference was not found in fetal/infant exposed group. In males, no significant relation was observed in any famine exposed group (all P > 0·05). Exposure to famine in childhood and adolescence is associated with an increased risk of hyperuricaemia for adulthood of females, but not in males. Adequate nutrition during early life appears to be beneficial to prevent hyperuricaemia of adult females.