Cognitive benefits of folic acid, docosahexaenoic acid and a combination of both nutrients in mild cognitive impairment; possible alterations though mitochondrial function and DNA damage.

INTRODUCTION: It is uncertain whether folic acid (FA) combined with docosahexaenoic acid (DHA) could improve cognitive performance. This study evaluated the effects of a 12-month FA and DHA supplementation, in combination or alone, on cognitive function, DNA oxidative damage, and mitochondrial function in participants with mild cognitive impairment (MCI). METHODS: This randomized, double-blind, placebo-controlled trial recruited MCI participants aged 60 years and older. Two hundred and eighty participants were randomly divided in equal proportion into four groups: FA+DHA (FA 800µg/d + DHA 800mg/d), FA (800µg/d), DHA (800mg/d), and placebo groups daily orally for 12 months. The primary outcome was cognitive function evaluated by the Wechsler Adult Intelligence Scale-Revised (WAIS-RC). Cognitive tests and blood mechanism-related biomarkers were determined at baseline and 12 months. RESULTS: During the 12-month follow, scores of full intelligence quotient (FIQ) (ßDHA: 1.302, 95%CI: 0.615, 1.990, p < 0.001; ßFA: 1.992, 95%CI: 1.304, 2.679, p < 0.001; ßFA+DHA: 2.777, 95%CI: 2.090, 3.465, p < 0.001), verbal intelligence quotient, and some subtests of the WAIS-RC were significantly improved in FA+DHA and single intervention groups compared to the placebo group. Moreover, the FA and DHA intervention combination was superior to either intervention alone (p < 0.001). Meanwhile, FA, DHA and their combined use significantly decreased 8-OHdG level and increased mitochondrial DNA copy number compared to the placebo (p < 0.05). CONCLUSIONS: Supplementation of FA and DHA, alone or combined, for 12 months can improve cognitive function in MCI participants, possibly through mitigating DNA oxidative damage and enhancing mitochondrial function. Combined supplementation may provide more cognitive benefit than supplementation alone. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034351. Registered 3 July 2020 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=53345.

Toward the Briarane Core via 1,3-Dipolar Cycloaddition.

The complete C20 framework of brianthein W was established, featuring hydroboration/allylation, to provide the C1-C2 quaternary/tertiary stereoarray with excellent stereocontrol. Intramolecular nitrile oxide cycloaddition (INOC) was adopted as the key transformation to establish the trans-fused 6/10-bicyclic ring system. Evolution of the second INOC event revealed the intricacies governing regioselectivity, which ultimately led to construction of the highly strained 10-membered carbocycle.

Cell-free DNA methylation profile potential in the diagnosis of lung squamous cell carcinoma.

Background: Aberrant methylation plays an essential role in early cancer development. In this study, we investigated methylation patterns in lung squamous cell carcinoma (LUSC) and matched non-tumor tissue and plasma samples to evaluate the potential of these patterns in the diagnosis of LUSC. Methods: The study group included 49 patients with stage I-III LUSC. We collected resected tumor tissue, paired peritumoral tissue, distant normal tissue, and corresponding plasma samples. A bespoke lung cancer bisulfite sequencing panel was used to profile the methylation level. Another 48 healthy volunteers provided control plasma samples. Results: Peritumoral and distant normal tissues presented similar methylation signatures, distinct from those in tumor tissue samples. A comparison of methylation profiles led to the identification of 871 tumor-specific differentially methylated blocks, including 847 hypermethylated and 24 hypomethylated blocks (adjusted P value <0.05). All top-ranked blocks were tumor-related. Tissue samples were analyzed for field cancerization to identify progressively aggravating aberrant methylations during tumor initiation and development. The analysis revealed that 221 blocks presented a stepwise increase in methylation levels, while seven blocks presented a stepwise decrease in methylation pattern as the sampling drew nearer to the tumor. The malignant contaminated ratio (MCR) confirmed the presence of distinct methylation patterns between tumor and peritumoral tissue samples. We then constructed a diagnostic panel using a combined diagnostic score of cell-free DNA (cfDNA) that showed high sensitivity and specificity. The healthy controls had a significantly lower combined diagnostic score (cd-score) than LUSC patients. Additionally, based on the methylation profiles, LUSC could be classified into two subgroups, C1 and C2. The methylation profile of the C2 group was not distinct from the healthy controls, which had a significantly lower cd-score than did the C1 group. Conclusions: LUSC-specific methylation patterns could potentially discriminate between peritumoral tissue, distant normal tumor tissue, and tumor tissues. This preliminary study also supported the potential utility of cfDNA methylation analysis in diagnosing LUSC.

Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance.

Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.

Neo-adjuvant chemotherapy plus immunotherapy in resectable N1/N2 NSCLC.

BACKGROUND: Locally advanced non-small cell lung cancer (NSCLC) with N1/N2 lymph node metastasis is challenging with poor survival. Neo-adjuvant chemo-immunotherapy has gained benefits in a proportion of these patients. However no specific biomarker has been proved to predict the effect before therapy. In addition, the relationship of nodal status and survival after neo-adjuvant chemo-immunotherapy is still not well stated. METHODS: A total of 75 resectable NSCLC patients with N1/N2 stage who received neo-adjuvant chemo-immunotherapy plus surgery were retrospectively studied. The clinical characteristics, surgical information and safety parameters were collected. The correlations of major pathological response (MPR) and pathological complete response (pCR) with clinical data were analyzed. The progression free disease(PFS) and overall survival(OS) were evaluated with pathological response and nodal status. RESULTS: Of the 75 patients, 69 (92%) patients experienced treatment related adverse effects, while grade 3-4 adverse effects occurred in 8 (10%) patients. All the patients received surgical R0 resection with a MPR rate of 60% and a pCR rate of 36%. 67% of N1 patients and 77% of N2 patients had nodal clearance after neo-adjuvant treatment. A significant difference was observed between pathological response with age, histology and multiple lymph node metastasis. The PFS was better in the MPR cohort. The PFS was 90.1% and 83.6% at the nodal clearance group at the time of 12 and 18 months, compared with 70.1% and 63.7% at the nodal residual group. CONCLUSIONS: The neo-adjuvant chemo-immunotherapy for locally advanced NSCLC with nodal positive was safe and feasible. The patients with elder age and squamous-cell carcinoma (SCC) were more likely to have better pathological response, while multiple nodal metastasis was a negative predictor. The clearance of lymph node resulted in significantly longer PFS and OS.

Investigating subtypes of lung adenocarcinoma by oxidative stress and immunotherapy related genes.

Lung adenocarcinoma (LUAD) is one of the most widespread and fatal types of lung cancer. Oxidative stress, resulting from an imbalance in the production and accumulation of reactive oxygen species (ROS), is considered a promising therapeutic target for cancer treatment. Currently, immune checkpoint blockade (ICB) therapy is being explored as a potentially effective treatment for early-stage LUAD. In this research, we aim to identify distinct subtypes of LUAD patients by investigating genes associated with oxidative stress and immunotherapy. Additionally, we aim to propose subtype-specific therapeutic strategies. We conducted a thorough search of the Gene Expression Omnibus (GEO) datasets. From this search, we pinpointed datasets that contained both expression data and survival information. We selected genes associated with oxidative stress and immunotherapy using keyword searches on GeneCards. We then combined expression data of LUAD samples from both The Cancer Genome Atlas (TCGA) and 11 GEO datasets, forming a unified dataset. This dataset was subsequently divided into two subsets, Dataset_Training and Dataset_Testing, using a random bifurcation method, with each subset containing 50% of the data. We applied consensus clustering (CC) analysis to identify distinct LUAD subtypes within the Dataset_Training. Molecular variances associated with oxidative stress levels, the tumor microenvironment (TME), and immune checkpoint genes (ICGs) were then investigated among these subtypes. Employing feature selection combined with machine learning techniques, we constructed models that achieved the highest accuracy levels. We validated the identified subtypes and models from Dataset_Training using Dataset_Testing. A hub gene with the highest importance values in the machine learning model was identified. We then utilized virtual screening to discover potential compounds targeting this hub gene. In the unified dataset, we integrated 2,154 LUAD samples from TCGA-LUAD and 11 GEO datasets. We specifically selected 1,311 genes associated with immune and oxidative stress processes. The expression data of these genes were then employed for subtype identification through CC analysis. Within Dataset_Training, two distinct subtypes emerged, each marked by different levels of immune and oxidative stress pathway values. Consequently, we named these as the OX+ and IM+ subtypes. Notably, the OX+ subtype showed increased oxidative stress levels, correlating with a worse prognosis than the IM+ subtype. Conversely, the IM+ subtype demonstrated enhanced levels of immune pathways, immune cells, and ICGs compared to the OX+ subtype. We reconfirmed these findings in Dataset_Testing. Through gene selection, we identified an optimal combination of 12 genes for predicting LUAD subtypes: ACP1, AURKA, BIRC5, CYC1, GSTP1, HSPD1, HSPE1, MDH2, MRPL13, NDUFS1, SNRPD1, and SORD. Out of the four machine learning models we tested, the support vector machine (SVM) stood out, achieving the highest area under the curve (AUC) of 0.86 and an accuracy of 0.78 on Dataset_Testing. We focused on HSPE1, which was designated as the hub gene due to its paramount importance in the SVM model, and computed the docking structures for four compounds: ZINC3978005 (Dihydroergotamine), ZINC52955754 (Ergotamine), ZINC150588351 (Elbasvir), and ZINC242548690 (Digoxin). Our study identified two subtypes of LUAD patients based on oxidative stress and immunotherapy-related genes. Our findings provided subtype-specific therapeutic strategies.

Pan-mediastinal neoplasm diagnosis via nationwide federated learning: a multicentre cohort study.

BACKGROUND: Mediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODS: In this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGS: In the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATION: For mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

An investigation into the disturbance effects of coal mining on groundwater and surface ecosystems.

Coal mining disturbs surface ecosystems in coal mining subsidence areas. Based on the groundwater-surface composite ecosystem analysis, we constructed an ecological disturbance evaluation index system (18 indices) in a coal mining subsidence area using the analytic hierarchy process (AHP). Taking the Nalinhe mining area in Wushen Banner, China, in 2018-2020 as an example, the weight, ecological disturbance grade and correlation of different indicators were determined by implementing fuzzy mathematics, weighting method, and correlation analysis method. The major conclusions of this review were: (i) After two years of mining, ecological disturbance was the highest in the study area (Grade III) and the lowest in the non-mining area (Grade I). (ii) Coal mining not only directly interfered with the environment, but also strengthened the connection of different ecological indicators, forming multiple ecological disturbance chains such as "mining intensity-mining thickness-buried depth/Mining thickness", "coal mining-surface subsidence-soil chemical factors", and "natural environment-soil physical factors". The disturbance chain that controls the ecological response factors in the region remains to be determined. However, the ecological response factors are the most important factor that hinders the restoration of the ecology in a coal mining subsidence area. (iii) The ecological disturbance in the coal mining subsidence area continued increasing over two years due to coal mining. The ecological disturbance by coal mining cannot be completely mitigated by relying on the self-repair capability of the environment. This study is of great significance for ecological restoration and governance of coal mining subsidence areas.

Revealing platelet-related subtypes and prognostic signature in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) is a malignant tumor with high heterogeneity and poor prognosis. In this study, we sought to identify the value of platelet-related genes in prognosis and heterogeneity of PDAC through multiple transcriptomic methods. METHODS: Based on datasets from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA), platelet-related genes were screened out, and the TCGA cohort (n = 171) was identified into two subtypes by unsupervised clustering. The platelet-related risk score model (PLRScore) was constructed by univariate Cox and LASSO regression, and the predictive ability was evaluated by Kaplan-Meier test and time-dependent receiver operating characteristic (ROC) curves. The results were validated in two other external validation sets, ICGC-CA (n = 140) and GSE62452 (n = 66). Furthermore, predictive nomogram containing clinical characteristics and PLRScore was established. In addition, we determined the possible correlation between PLRScore and immune infiltration and response of immunotherapy. Finally, we analyzed the heterogeneity of our signature in various types of cells using single-cell analysis. RESULTS: Platelet-related subtypes that have significant difference of overall survival and immune states (p < 0.05) were identified. PLRScore model based on four-gene signature (CEP55, LAMA3, CA12, SCN8A) was constructed to predict patient prognosis. The AUCs of training cohort were 0.697, 0.687 and 0.675 for 1-, 3-and 5-year, respectively. Further evaluation of the validation cohorts yielded similar results. In addition, PLRScore was associated with immune cell infiltration and immune checkpoint expression, and had promising ability to predict response to immunotherapy of PDAC. CONCLUSIONS: In this study, the platelet-related subtypes were identified and the four-gene signature was constructed and validated. It may provide new insights into the therapeutic decision-making and molecular targets of PDAC.

Design, synthesis, and evaluation of hydrazones as dual inhibitors of ryanodine receptors and acetylcholinesterases for Alzheimer's disease.

Alzheimer's disease (AD) implicates neuronal loss, plaque and neurofibrillary tangle formation, and disturbed neuronal Ca2+ homeostasis, which leads to severe dementia, memory loss, as well as thinking and behavioral perturbations that could ultimately lead to death. Calcium dysregulation and low acetylcholine levels are two main mechanisms implicated in Alzheimer's disease progression. Simultaneous inhibition of calcium oscillations (store overload-induced Ca2+ release [SOICR]) and acetylcholinesterase (AChE) by a single molecule may bring a new breath of hope for AD treatment. Here, we described some dantrolene derivatives as dual inhibitors of the ryanodine receptor and AChE. Two series of acylhydrazone/sulfonylhydrazone derivatives with aromaticgroup were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit SOICR and AChE in vitro, using dantrolene and donepezil as positive controls. Compound 22a exhibited excellent and balanced inhibitory potency against SOICR (inhibition (%) = 90.1, IC50 = 0.162 µM) and AChE (inhibition (%) = 93.5, IC50 = 0.372 µM). Docking simulations showed that several preferred compounds could bind to the active sites of both the proteins, further validating the rationality of the design strategy. Potential therapeutic effects in AD were evaluated using the Barnes maze and Morris water maze tests, which demonstrated that compound 22a significantly improved memory and cognitive behavior in AD model mice. Moreover, it was also found that compound 22a could enhance synaptic strength by measuring hippocampal long-term potentiation (LTP) in brain slices. These results suggested that the introduction of a sulfonyl-hydrazone scaffold and aromatic substitution to dantrolene derivatives provided a useful template for the development of potential chemical entities against AD.

Effects of Underground Coal Mining on Soil Spatial Water Content Distribution and Plant Growth Type in Northwest China.

The impact of coal mining subsidence on surface ecology involves the influence of several ecological elements such as water, soil, and vegetation, which is systematic and complex. Given the unclear understanding of the synergistic change patterns of the water-soil-vegetation ecological elements in the influence of coal mining in the west, this paper investigates the impact of coal mining on the surface ecology, especially the distribution of soil water content (SWC). In 2020, this study collected 3000 soil samples from 60 sampling points (at depth of 0-10 m) and tested the SWC. All samples come from three different temporal and spatial areas of coal mining subsidence in the desert mining area of Northwest China where soil types are mainly aridisols. At the same time, the interactions among deep SWC and surface soil physical and chemical properties, surface SWC and soil fertility, and pH were analyzed. The spatial variability of soil moisture is reflected by kriging interpolation, and SWC values at different depths are predicted as a basis for monitoring the environmental impact of different coal mining subsidence years. The research has shown that the ground subsidence leads to a decrease in SWC value and changes in surface soil pH, physical and chemical properties, and covering vegetation, which have occurred from the beginning of coal mining. The impact of coal mining on the SWC of the unsaturated zone is mainly at the depth of 0-6 m, where SWC is not directly related to the nutrient content of the surface soil. The overall settlement of the ground will stir up simultaneous decline in the quality of deep SWC and topsoil. The findings of this investigation suggest that changes in the soil structure caused by coal mining subsidence are the key factor in SWC loss. Timely monitoring and repairing 0-6 m ground fissures, as well as selecting shrubs on the surface is the best choice for the restoration of the ecological environment and prevention of soil erosion in this area.

Prevalence of vitamin A and vitamin D deficiency in hospitalized neonates in Xi'an, China.

BACKGROUND AND OBJECTIVES: To investigate the prevalence of vitamin A and vitamin D deficiency and the associated factors in hospitalized neonates in Xi'an, China. METHODS AND STUDY DESIGN: A total of 524 hospitalized neonates were collected in this study. Serum vitamin A and D concentrations were detected in neonates within two weeks of birth. RESULTS: Serum vitamin A and D concentrations of hospitalized neonates were 0.55±0.21 µmol/L and 42.0±20.6 nmol/L, respectively. They were greater in full-term neonates than in preterm neonates, greater in rural neonates than in urban, and greater in single than in twin (all p<0.001). The prevalence of vitamin A and D deficiency were 14.9% and 33.0%, the prevalence of marginal vitamin A deficiency was 64.7%, and vitamin D insufficiency was 35.1%. Neonatal serum vitamin A and D concentrations were all positively correlated with birth weight and gestational age. Neonatal serum vitamin D concentration was also positively correlated with maternal serum vitamin D concentration. Additionally, neonatal vitamin A concentration was positively correlated with neonatal serum vitamin D concentration. CONCLUSIONS: Vitamin A and vitamin D statuses are compromised in hospitalized neonates in Xi'an, especially in premature neonates, low birth weight neonates, twins, and those born in urban areas. Individualized supplementation with vitamin A and vitamin D in neonates should be a clinical consideration.

The responses of Scrippsiella acuminata to the stresses of darkness: antioxidant activities and formation of pellicle cysts.

In order to understand the strategy of Scrippsiella acuminata to cold dark environment, the antioxidant responses and the formation of pellicle cysts of S. acuminata to darkness at 8°C and 20°C were investigated. Cell densities decreased significantly after 96 h dark treatment, and no live cells were observed after 9-days dark treatments. The darkness stress generally resulted in an increase of antioxidant defenses, including soluble protein, superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). Cellular soluble protein and SOD activity increased sharply under 20°C darkness, which protected algal cells against the oxidative stress from darkness, and resulted in relatively lower MDA levels. Soluble protein and SOD activity were enhanced under 8°C darkness as well however not in a sharp rise, and higher levels of MDA and GSH were recorded. The results suggested high SOD and protein levels protected cells against harsh darkness stress, while high GSH not only helped algae cells resist dark stress, but also played an important role in low temperature stress. Darkness promoted the formation of pellicle cysts of S. acuminata, and the maximum formation rates were 16.06% to 21.74% at 8°C and 20°C, respectively. Germination of pellicle cysts occurred within 24 h after light exposure, however pellicle cysts could not withstand long-time darkness stress, and all pellicle cysts died after 9-days darkness exposure. The results of this study suggest that S. acuminata is able to overcome temporary cold darkness through forming pellicle cysts.

Pyrethroid bioaccumulation in wild fish linked to geographic distribution and feeding habit.

The accumulation of pyrethroid insecticides in aquatic food webs has attracted increased research attention. Fish are key species in aquatic food webs, directly connecting invertebrates and human consumption. However, little is known about the bioaccumulation of pyrethroids in wild fish species. In this study, 19 species of wild fish were collected from 11 sites in the Pearl River, China, and the levels of seven pyrethroids in the fish were determined. Linear mixed-effects models were applied to estimate the means of pyrethroid concentrations, in which sample site and fish species were set as random effects. The concentrations of Σ7 pyrethroids in fish ranged from 4.99 to 50.82 ng/g. Permethrin and bifenthrin were present at the highest concentration (8.89 ± 1.47 ng/g) and frequency (100%) in fish muscle, respectively. The composition patterns of pyrethroids varied in fish organs. Fish species contributed a higher proportion of the variance than geographic distribution (28.6% vs. 26.4%). The pyrethroids in carnivorous fish (23.5 ± 2.9 ng/g) were significantly higher than in omnivorous (14.6 ± 1.9 ng/g) and phytophagous fish (16.0 ± 4.7 ng/g). To our knowledge, this is the first report examining the effect of feeding habits on pyrethroid bioaccumulation in wild fish. The results can provide evidence for the risk of pyrethroid pollution in aquatic ecosystems.

Nomogram for predicting survival of patients with metastatic nonfunctioning pancreatic neuroendocrine tumors: A SEER based study.

ABSTRACT: More attention has been placed on nonfunctioning pancreatic neuroendocrine tumors due to the increase in its incidence in recent years. Whether tumor resection at the primary site of metastatic NFpNET is effective remains controversial. Moreover, clinicians need a more precise prognostic tool to estimate the survival of these patients.Patients with metastatic NFpNET were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Significant prognostic factors were identified using a multivariate Cox regression model and included in the nomogram. Coarsened exact matching analysis was used to balance the clinical variables between the non-surgical and surgical groups in our study.A total of 1464 patients with metastatic nonfunctioning pancreatic neuroendocrine tumors (NFpNETs) were included in our cohort. Multivariate analysis identified age, sex, tumor size, differentiated grade, lymph node metastases, resection of primary tumors, and marital status as independent predictors of metastatic NFpNET. The nomogram showed excellent accuracy in predicting 1-, 3-, and 5-year overall survival, with a C-index of 0.812. The calibration curve revealed good consistency between the predicted and actual survival.Coarsened exact matching analysis using SEER data indicated the survival advantages of resection of primary tumors. Our study is the first to build a nomogram model for patients with metastatic NFpNETs. This predictive tool can help clinicians identify high-risk patients and more accurately assess patient survival times.

Novel Compound Heterozygous Pathogenic Variants in SUOX Cause Isolated Sulfite Oxidase Deficiency in a Chinese Han Family.

AIM: To explore the clinical imaging, laboratory and genetic characteristics of a newborn boy with isolated sulfite oxidase deficiency (ISOD) in a Chinese mainland cohort. METHODS: Homocysteine and uric acid in plasma and cysteine and total homocysteine in the blood spot were assessed in a Chinese newborn patient with progressive encephalopathy, tonic seizures, abnormal muscle tone, and feeding difficulties. Whole exome sequencing and Sanger sequencing facilitated an accurate diagnosis. The pathogenicity predictions and conservation analysis of the identified mutations were conducted by bioinformatics tools. RESULTS: Low total homocysteine was detected in the blood spot, while homocysteine and uric acid levels were normal in the plasma. S-sulfocysteine was abnormally elevated in urine. A follow-up examination revealed several progressive neuropathological findings. Also, intermittent convulsions and axial dystonia were observed. However, the coordination of sucking and swallowing was slightly improved. A novel paternal nonsense variant c.475G > T (p.Glu159∗) and a novel maternal missense variant c.1201A > G (p.Lys401Glu) in SUOX were identified in this case by co-segregation verification. CONCLUSION: This is the second report of early-onset ISOD case in a non-consanguineous Chinese mainland family. Combined with the clinical characteristics and biochemical indexes, we speculated that these two novel pathogenic variants of the SUOX gene underlie the cause of the disease in this patient. Next-generation sequencing (NGS) and Sanger sequencing provided reliable basis for clinical and prenatal diagnoses of this family, it also enriched the mutation spectrum of the SUOX gene.

Exploration of Prognostic Biomarkers for Lung Adenocarcinoma Through Bioinformatics Analysis.

With the development of computer technology, screening cancer biomarkers based on public databases has become a common research method. Here, an eight-gene prognostic model, which could be used to judge the prognosis of patients with lung adenocarcinoma (LUAD), was developed through bioinformatics methods. This study firstly used several gene datasets from GEO database to mine differentially expressed genes (DEGs) in LUAD tissue and healthy tissue via joint analysis. Later, enrichment analysis for the DEGs was performed, and it was found that the DEGs were mainly activated in pathways involved in extracellular matrix, cell adhesion, and leukocyte migration. Afterward, a TCGA cohort was used to perform univariate Cox, least absolute shrinkage and selection operator method, and multivariate Cox regression analyses for the DEGs, and a prognostic model consisting of eight genes (GPX3, TCN1, ASPM, PCP4, CAV2, S100P, COL1A1, and SPOK2) was established. Receiver operation characteristic (ROC) curve was then used to substantiate the diagnostic efficacy of the prognostic model. The survival significance of signature genes was verified through the GEPIA database, and the results exhibited that the risk coefficients of the eight genes were basically congruous with the effects of these genes on the prognosis in the GEPIA database, which suggested that the results were accurate. Finally, combined with clinical characteristics of patients, the diagnostic independence of the prognostic model was further validated through univariate and multivariate regression, and the results indicated that the model had independent prognostic value. The overall finding of the study manifested that the eight-gene prognostic model is closely related to the prognosis of LUAD patients, and can be used as an independent prognostic indicator. Additionally, the prognostic model in this study can help doctors make a better diagnosis in treatment and ultimately benefit LUAD patients.

[Isovaleric acidemia due to compound heterozygous variants of IVD gene in a case].

OBJECTIVE: To analyze the clinical features, biochemical characteristics and molecular pathogenesis of a girl with isovaleric acidemia. METHODS: Clinical features, blood spot amino acid profiles and urinary organic acid profiles of the patient were analyzed. Targeted capture, next generation sequencing and Sanger sequencing were carried out to detect potential variant of the IVD gene. RESULTS: The patient presented with poor weight gain, poor feeding, lethargy, and a "sweaty feet" odor 10 days after birth. Biochemical test suggested hyperammonemia. Blood spot amino acid profiles displayed a dramatic increase in isovalerylcarnitine (C5: 3. 044, reference range 0.04 - 0.4 µmol/L). Organic acid analysis of her urine sample revealed a high level of isovaleric glycine (669. 53, reference range 0 - 0.5). The child was ultimately diagnosed with isovaleric acidemia, and was found to harbor a paternally derived heterozygous variant c.149G>A (p.R50H) and a maternally derived heterozygous variant c.1123G>A (p.G375S) of the IVD gene. Her elder brother was a heterozygous carrier of c.1123G>A (p.G375S) variant. The c.149G>A (p.R50H) was a known pathogenic variant, while the c.1123G>A (p.G375S) variant was previously unreported. CONCLUSION: The pathogenesis of the patient was delineated from the perspective of genetics, which has provided a basis for clinical diagnosis, treatment as well as genetic counseling.

Uniportal video-assisted thoracoscopic surgery and robot-assisted thoracoscopic surgery are feasible approaches with potential advantages in minimally invasive mediastinal lesions resection.

BACKGROUND: This study aims to identify the feasibility of uniportal video-assisted thoracoscopic surgery (VATS) and robot-assisted thoracoscopic surgery (RATS) compared with multiportal VATS in the resection of mediastinal lesions. METHODS: Patients who underwent mediastinal lesion resection were enrolled and allocated to the uni-VATS, tri-VATS, and RATS groups according to the surgical approach. Propensity score-matched (PSM) analysis was performed between the VATS and RATS groups as well as the uni-VATS and tri-VATS groups. The operative and recovery parameters were compared. RESULTS: Totally, 274 patients were enrolled. There was no difference in the operative parameters among the groups. Compared with multiportal VATS, uniportal VATS and RATS had a significantly shorter chest tube placement time (2.43±0.88 vs. 1.78±1.22 vs. 2.21±1.11 days, P<0.001) and hospital length of stay (LOS) (4.07±1.75 vs. 3.27±1.05 vs. 3.62±1.21 days, P=0.001) without increasing the incidence rate of complications (5.6% vs. 7.2% vs. 5.7%, P=0.864). After PSM, the RATS group showed a significantly lower unplanned conversion rate than the VATS group (0.0% vs. 8.2%, P=0.041), while the uni-VATS group had a shorter chest tube placement time (1.83±1.20 vs. 2.35±0.86 days, P=0.013) and hospital LOS (3.23±1.03 vs. 3.95±2.00 days) than the tri-VATS group. CONCLUSIONS: Compared with multiportal VATS, uniportal VATS and RATS are technically safe and feasible with potential advantages for mediastinal lesion resection.

CD123 thioaptamer protects against sepsis via the blockade between IL-3/CD123 in a cecal ligation and puncture rat model.

Sepsis is one of the most common causes of death in ICU and especially is a harmful and a life-threatened disease to pediatrics in the world. It has been demonstrated that IL-3 plays an essential role in the processing of sepsis and the inhibition of IL-3 may alleviate sepsis progress. In our previous study, we selected a novel CD123 aptamer successfully which could inhibit the interaction of CD123 and IL-3. The aim of this study is to explore the protection ability of the first thioaptamer SS30 against sepsis in a cecal ligation and puncture (CLP) rat model. Serum IL-3 level of sepsis patients was assessed by ELISA. CLP rat model was applied in all experimental groups. CD123 thioaptamer SS30 and CD123 antibody were used to block the recognition between IL-3 and CD123. Body weight, temperature, blood gas, MAP, and serum cytokines of four grouped rats were assessed. Flow cytometry was utilized to evaluate JAK2 and STAT5 proteins. After the administration of SS30 or CD123 antibody, the rats in SS30 and CD123 antibody group had lower cytokines values(lactate, TNF-α, IL-1ß, and IL-6), whereas exhibited higher value of core temperature, MAP, PO2/FiO2, and ETCO2 than those in the CLP group. The expression level of phosphorylated JAK2 and STAT5 was declined and the survival rate of rats was increased. In addition, the protection ability of SS30 was better than CD123 antibody. Therefore, CD123 thioaptamer SS30 could reduce mortality by down-regulating the phosphorylated JAK2/STAT5 signaling pathway, and reduce serum cytokines which involving in sepsis development in CLP rat model.