Mechanically strained osteocyte-derived exosomes contained miR-3110-5p and miR-3058-3p and promoted osteoblastic differentiation.

BACKGROUND: Osteocytes are critical mechanosensory cells in bone, and mechanically stimulated osteocytes produce exosomes that can induce osteogenesis. MicroRNAs (miRNAs) are important constituents of exosomes, and some miRNAs in osteocytes regulate osteogenic differentiation; previous studies have indicated that some differentially expressed miRNAs in mechanically strained osteocytes likely influence osteoblastic differentiation. Therefore, screening and selection of miRNAs that regulate osteogenic differentiation in exosomes of mechanically stimulated osteocytes are important. RESULTS: A mechanical tensile strain of 2500 µÎµ at 0.5 Hz 1 h per day for 3 days, elevated prostaglandin E2 (PGE2) and insulin-like growth factor-1 (IGF-1) levels and nitric oxide synthase (NOS) activity of MLO-Y4 osteocytes, and promoted osteogenic differentiation of MC3T3-E1 osteoblasts. Fourteen miRNAs differentially expressed only in MLO-Y4 osteocytes which were stimulated with mechanical tensile strain, were screened, and the miRNAs related to osteogenesis were identified. Four differentially expressed miRNAs (miR-1930-3p, miR-3110-5p, miR-3090-3p, and miR-3058-3p) were found only in mechanically strained osteocytes, and the four miRNAs, eight targeted mRNAs which were differentially expressed only in mechanically strained osteoblasts, were also identified. In addition, the mechanically strained osteocyte-derived exosomes promoted the osteoblastic differentiation of MC3T3-E1 cells in vitro, the exosomes were internalized by osteoblasts, and the up-regulated miR-3110-5p and miR-3058-3p in mechanically strained osteocytes, were both increased in the exosomes, which was verified via reverse transcription quantitative polymerase chain reaction (RT-qPCR). CONCLUSIONS: In osteocytes, a mechanical tensile strain of 2500 µÎµ at 0.5 Hz induced the fourteen differentially expressed miRNAs which probably were in exosomes of osteocytes and involved in osteogenesis. The mechanically strained osteocyte-derived exosomes which contained increased miR-3110-5p and miR-3058-3p (two of the 14 miRNAs), promoted osteoblastic differentiation.

Anoikis-related gene signatures predict prognosis of lung adenocarcinoma patients and reveal immune infiltration.

Background: Lung adenocarcinoma (LUAD), a type of lung cancer, is one of the most aggressive and deadly malignancies worldwide. Malignant tumor cells exhibit strong anti-anoikis properties to achieve distant metastasis through the circulatory system. However, more research is needed to understand how anoikis is involved in the progression, metastasis and especially the prognosis of LUAD. Methods: We obtained anoikis-related genes (ARGs) from two websites, Harmonizome and Genecards, and integrated them to select and model the genes associated with LUAD prognosis. In addition, we investigated differences in the immune cell microenvironment and pathways of enrichment analysis between subtypes. We finally constructed a nomogram based on ARGs and used decision curve analysis (DCA) to demonstrate that this model could help clinicians make clinical decisions. Results: Sixty-four differentially expressed genes (DEGs) were found to be associated with survival, and of these, six were chosen to build a prognostic model. The time-dependent receiver operating characteristic (ROC) curves showed that the model had a satisfactory predictive ability. Enrichment analysis and immune microenvironment analysis revealed that the immune status and drug sensitivity of populations at high and low risk were different. We integrated the clinicopathological features of LUAD with the risk score to build the nomogram. The nomogram was shown to be a good predictor of short- and long-term survival in LUAD patients through DCA analysis. Conclusions: This new model based on six ARGs and nomograms in our study could help patients with LUAD develop personalized treatment plans.

Dietary factors and hypertension: A Mendelian randomization analysis.

This research explores the causal link between dietary habits and hypertension through Mendelian randomization, providing distinct perspectives on the role of diet in addressing this worldwide health issue. Utilizing instrumental variables, we applied advanced statistical methods, including the weighted median, inverse variance weighted, and MR-Egger, to evaluate the impact of 17 dietary elements on hypertension. These elements ranged across various food groups, such as fruits, meats, vegetables, and beverages, both alcoholic and nonalcoholic. Our results identified a significant positive association of hypertension with weekly alcohol consumption (OR 1.340 [95%CI 1.0001 to 1.794], p = .0499) and poultry intake (OR 2.569 [95%CI 1.305 to 5.057], p = .00631). Conversely, a negative association was observed with lamb/mutton (OR 0.550 [95%CI 0.343 to 0.881], p = .0129), cheese (OR 0.650 [95%CI 0.519 to 0.813], p = .000159), tea (OR 0.797 [95%CI 0.640 to 0.993], p = .0433), cereal (OR 0.684 [95%CI 0.494 to 0.948], p = .0227), and dried fruit consumption (OR 0.492 [95%CI 0.343 to 0.707], p = .000127). These findings suggest that dietary modifications, such as increasing consumption of specific foods like cheese, lamb/mutton, tea, cereals, and dried fruits, could potentially reduce hypertension risk while reducing intake of alcoholic beverages and poultry might mitigate its increase. No direct causal relationships were established between other dietary factors and hypertension. The study highlights the importance of specific dietary modifications for the prevention and control of hypertension, making a substantial contribution to public health tactics and recommendations.

Nomogram for predicting prognosis and identifying chemotherapy beneficiaries for completely resected stage I invasive mucinous lung adenocarcinoma.

Background: At present, there is a lack of studies in invasive mucinous adenocarcinoma (IMA) that combine clinicopathological and imaging features to stratify risk and select optimal treatment regimen. We aimed to develop and validate a nomogram for predicting recurrence-free survival (RFS) and identifying adjuvant chemotherapy (ACT) beneficiaries for completely resected stage I primary IMA. Methods: This retrospective study included 750 patients from three hospitals. Patients from two hospitals were divided into training (n=424) and validating cohort (n=185), and patients from the remaining other one hospital constituted external test cohort (n=141) and preoperative computed tomography (CT) image features of each patient were consecutively evaluated. The nomogram was developed by integrating significant prognostic factors of RFS identified in the multivariate analysis. The risk score (RS) based on nomogram was calculated in the entire cohort and the optimal cut-off point for risk stratification was obtained by X-tile software. The Kaplan-Meier method, log-rank test and interaction were used to evaluate the difference in RFS and overall survival (OS) between different risk and treatment groups. Results: Visceral pleural invasion (VPI, P<0.001), lymph-vascular invasion (LVI, P<0.001), tumor size (P<0.001), smoking history (P<0.001), lobulation (P<0.001) were identified as independent prognostic factors for RFS. The concordance index (C-index) of the nomogram was higher than that of tumor-node-metastasis (TNM) staging system (validation cohort: 0.73±0.09 vs. 0.62±0.08, P<0.001; external test cohort: 0.74±0.10 vs. 0.70±0.09, P=0.035). The patients with higher RS were associated with worse RFS [hazard ratios (HRs) ≥4.76] and OS (HRs ≥2.55) in all included cohorts. Chemotherapy benefits in terms of RFS and OS were observed for patients in higher RS group in both stage IB (interaction P=0.012 for RFS and P=0.037 for OS) and stage I IMA (interaction P<0.001 for both RFS and OS). Conclusions: The nomogram based on CT image and clinicopathologic features showed superior performance in predicting RFS for stage I IMA and might identify ACT candidates for personalized patient treatment.

How to assess the accuracy of volume conduction models? A validation study with stereotactic EEG data.

Introduction: Volume conduction models of the human head are used in various neuroscience fields, such as for source reconstruction in EEG and MEG, and for modeling the effects of brain stimulation. Numerous studies have quantified the accuracy and sensitivity of volume conduction models by analyzing the effects of the geometrical and electrical features of the head model, the sensor model, the source model, and the numerical method. Most studies are based on simulations as it is hard to obtain sufficiently detailed measurements to compare to models. The recording of stereotactic EEG during electric stimulation mapping provides an opportunity for such empirical validation. Methods: In the study presented here, we used the potential distribution of volume-conducted artifacts that are due to cortical stimulation to evaluate the accuracy of finite element method (FEM) volume conduction models. We adopted a widely used strategy for numerical comparison, i.e., we fixed the geometrical description of the head model and the mathematical method to perform simulations, and we gradually altered the head models, by increasing the level of detail of the conductivity profile. We compared the simulated potentials at different levels of refinement with the measured potentials in three epilepsy patients. Results: Our results show that increasing the level of detail of the volume conduction head model only marginally improves the accuracy of the simulated potentials when compared to in-vivo sEEG measurements. The mismatch between measured and simulated potentials is, throughout all patients and models, maximally 40 microvolts (i.e., 10% relative error) in 80% of the stimulation-recording combination pairs and it is modulated by the distance between recording and stimulating electrodes. Discussion: Our study suggests that commonly used strategies used to validate volume conduction models based solely on simulations might give an overly optimistic idea about volume conduction model accuracy. We recommend more empirical validations to be performed to identify those factors in volume conduction models that have the highest impact on the accuracy of simulated potentials. We share the dataset to allow researchers to further investigate the mismatch between measurements and FEM models and to contribute to improving volume conduction models.

Genomic divergence and demographic history of Quercus aliena populations.

BACKGROUND: Quercus aliena is a major montane tree species of subtropical and temperate forests in China, with important ecological and economic value. In order to reveal the species' population dynamics, genetic diversity, genetic structure, and association with mountain habitats during the evolutionary process, we re-sequenced the genomes of 72 Q. aliena individuals. RESULTS: The whole chloroplast and nuclear genomes were used for this study. Phylogenetic analysis using the chloroplast genome dataset supported four clades of Q. aliena, while the nuclear dataset supported three major clades. Sex-biased dispersal had a critical role in causing discordance between the chloroplast and nuclear genomes. Population structure analysis showed two groups in Q. aliena. The effective population size sharply declined 1 Mya, coinciding with the Poyang Glaciation in Eastern China. Using genotype-climate association analyses, we found a positive correlation between allele frequency variation in SNPs and temperature, suggesting the species has the capacity to adapt to changing temperatures. CONCLUSION: Overall, this study illustrates the genetic divergence, genomic variation, and evolutionary processes behind the demographic history of Q. aliena.

Head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis staging in non-small cell lung cancer: a meta-analysis.

PURPOSE: The current meta-analysis aimed to compare the diagnostic performance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with 18F-FDG PET/magnetic resonance imaging (MRI) in non-small cell lung cancer (NSCLC) lymph node metastasis staging. METHODS: We searched the PubMed, Web of Science, and Embase databases for relevant articles between November 1992 and September 2022. Studies evaluating the head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MRI for lymph node metastasis in patients with NSCLC were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 tool. RESULTS: The analysis includes six studies with a total of 434 patients. The pooled sensitivity of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.78 [95% confidence interval (CI): 0.59-0.90] and 0.84 (95% CI: 0.68-0.93), and the pooled specificity was 0.87 (95% CI: 0.72-0.94) and 0.87 (95% CI: 0.80-0.92), respectively. The accuracy of 18F-FDG PET/CT and 18F-FDG PET/MRI was 0.81 (95% CI: 0.71-0.90) and 0.84 (95% CI: 0.75-0.92), respectively. When the pre-test probability was set at 50%, the post-test probability for 18F-FDG PET/CT could increase to 85%, and the post-test probability for 18F-FDG PET/MRI could increase to 87%. CONCLUSION: 18F-FDG PET/CT and 18F-FDG PET/MRI have similar diagnostic performance in detecting lymph node metastasis in NSCLC. However, the results of this study were from a small sample study, and further studies with larger sample sizes are needed.

Electrical stimulation induced self-related auditory hallucinations correlate with oscillatory power change in the default mode network.

Self-related information is crucial in our daily lives, which has led to the proposal that there is a specific brain mechanism for processing it. Neuroimaging studies have consistently demonstrated that the default mode network (DMN) is strongly associated with the representation and processing of self-related information. However, the precise relationship between DMN activity and self-related information, particularly in terms of neural oscillations, remains largely unknown. We electrically stimulated the superior temporal and fusiform areas, using stereo-electroencephalography to investigate neural oscillations associated with elicited self-related auditory hallucinations. Twenty-two instances of auditory hallucinations were recorded and categorized into self-related and other-related conditions. Comparing oscillatory power changes within the DMN between self-related and other-related auditory hallucinations, we discovered that self-related hallucinations are associated with significantly stronger positive power changes in both alpha and gamma bands compared to other-related hallucinations. To ensure the validity of our findings, we conducted controlled analyses for factors of familiarity and clarity, which revealed that the observed effects within the DMN remain independent of these factors. These results underscore the significance of the functional role of the DMN during the processing of self-related auditory hallucinations and shed light on the relationship between self-related perception and neural oscillatory activity.

Diagnostic potential of [18F]FDG PET/MRI in non-small cell lung cancer lymph node metastasis: a meta-analysis.

PURPOSE: This meta-analysis evaluated the diagnostic accuracy and diagnostic value of [18F]FDG PET/MRI for mediastinal lymph node staging of NSCLC. METHODS: Relevant articles in PubMed, Embase, Web of Science, and the Cochrane Library were searched until January 2023. Research evaluating [18F]FDG PET/MRI for mediastinal lymph node staging of NSCLC was included. Pooled estimates of sensitivity, specificity, PLR, and NLR were calculated by the "Stata" software. RESULTS: Nine researches were included, containing 618 patients. The pooled sensitivity of [18F]FDG PET/MRI for detecting mediastinal lymph node staging of NSCLC was 0.82 (0.70-0.90), and the pooled specificity was 0.88 (0.82-0.93). PLR and NLR were 7.38 (4.73-11.52) and 0.20 (0.11-0.36), respectively. The AUC value of this imaging modality was 0.92 (0.90-0.94). The post-test probability for [18F]FDG PET/MRI might rise to 88% when the pre-test probability was set at 50%. CONCLUSIONS: We considered [18F]FDG PET/MRI as an effective imaging tool with relatively high specificity and sensitivity. It has great potential to be used in the clinical management of patients in NSCLC who are amenable to early surgery. More studies with large sample sizes in the same direction are needed in future to obtain more reliable evidence-based support.

Socioeconomic status, obesity, individual behaviors, diabetes, and risk for frozen shoulder: A Mendelian randomization study.

There are few studies on risk factors for frozen shoulder, and even fewer Mendelian randomization (MR) studies on frozen shoulder. Therefore, we conducted a two-sample MR study to explore whether socioeconomic status (years of schooling, average total household income before tax), obesity (body mass index and waist circumference), individual behaviors (smoking initiation, alcohol intake frequency, coffee intake, nonoily fish intake, tea intake, beef intake, bread intake, cheese intake, oily fish intake, and fresh fruit intake), and diabetes (type 1 and type 2 diabetes) are associated with frozen shoulder. The exposure datasets and the outcome dataset were extracted from the MRC Integrative Epidemiology Unit at the University of Bristol Open genome-wide association studies project (https://gwas.mrcieu.ac.uk/). We conducted MR analyses using the inverse variance weighted (primary method), MR-Egger, and weighted median methods and conducted heterogeneity and pleiotropy analyses. Type 1 diabetes (OR: 1.103; 95% CI: 1.053-1.156; P = .0000410) was associated with an increased risk of frozen shoulder. Cheese intake (OR: 0.490; 95% CI: 0.267-0.899; P = .0213), non-oily fish intake (OR: 0.0993; 95% CI: 0.0220-0.448; P = .00267), years of schooling (OR: 0.453; 95% CI: 0.349-0.588; P = .00000000277), and average total household income before tax (OR: 0.434; 95% CI: 0.253-0.743; P = .00236) were discovered as protective factors. No horizontal pleiotropy was found in all analyzes we performed (P > .05). Our study indicated that type 1 diabetes was a risk factor for frozen shoulder while cheese intake, non-oily fish intake, years of schooling, and average total household income before tax were considered as protective factors for frozen shoulder.

Telomere-to-telomere and haplotype-resolved genome assembly of the Chinese cork oak (Quercus variabilis).

The Quercus variabilis, a deciduous broadleaved tree species, holds significant ecological and economical value. While a chromosome-level genome for this species has been made available, it remains riddled with unanchored sequences and gaps. In this study, we present a nearly complete comprehensive telomere-to-telomere (T2T) and haplotype-resolved reference genome for Q. variabilis. This was achieved through the integration of ONT ultra-long reads, PacBio HiFi long reads, and Hi-C data. The resultant two haplotype genomes measure 789 Mb and 768 Mb in length, with a contig N50 of 65 Mb and 56 Mb, and were anchored to 12 allelic chromosomes. Within this T2T haplotype-resolved assembly, we predicted 36,830 and 36,370 protein-coding genes, with 95.9% and 96.0% functional annotation for each haplotype genome. The availability of the T2T and haplotype-resolved reference genome lays a solid foundation, not only for illustrating genome structure and functional genomics studies but also to inform and facilitate genetic breeding and improvement of cultivated Quercus species.

Exploring the potential mechanism of Kaixinsan powder for the same pathogenesis of PTSD and anxiety based on network pharmacology and molecular docking: A review.

BACKGROUND: Post-traumatic stress disorder (PTSD) and anxiety are common mental illnesses and there are many similar pathogenesis and clinical manifestations between PTSD and anxiety. Kaixinsan powder (KXS), a commonly used prescription in traditional Chinese medicine, has been widely used to treat PTSD and anxiety. This study aims to explore the potential mechanisms of KXS for the same pathogenesis of PTSD and anxiety using a network pharmacology approach. METHODS: The bioactive components and relevant target genes of KXS were obtained from the database about Traditional Chinese Medicine. The key genes of PTSD and anxiety were derived from disease databases. Subsequently, the network of protein-protein interaction and a network of "drug-components-disease-targets" was constructed. In order to treat PTSD and anxiety, gene ontology enrichment and signaling pathway enrichment were analyzed by using R language and components-core targets associated were validated by molecular docking. RESULTS: One hundred three targets of KXS in treating PTSD and anxiety were identified. The results of protein-protein interaction analysis and molecular docking indicated that AKT1 and IL-6 were crucial targets. Moreover, KEGG analysis has shown that neuroactive ligand-receptor interaction, calcium signaling pathway, and cAMP signaling pathway may play crucial roles in treating PTSD and anxiety. Ten biological process, 10 molecular function, and 10 cellular component were revealed via gene ontology analysis. CONCLUSIONS: The network pharmacology study and molecular docking indicated that KXS treated anxiety and PTSD by multiple components, targets, and signaling pathways. These results provide an important reference for subsequent basic research on PTSD and anxiety.

Leveraging GPT-4 for food effect summarization to enhance product-specific guidance development via iterative prompting.

Food effect summarization from New Drug Application (NDA) is an essential component of product-specific guidance (PSG) development and assessment, which provides the basis of recommendations for fasting and fed bioequivalence studies to guide the pharmaceutical industry for developing generic drug products. However, manual summarization of food effect from extensive drug application review documents is time-consuming. Therefore, there is a need to develop automated methods to generate food effect summary. Recent advances in natural language processing (NLP), particularly large language models (LLMs) such as ChatGPT and GPT-4, have demonstrated great potential in improving the effectiveness of automated text summarization, but its ability with regard to the accuracy in summarizing food effect for PSG assessment remains unclear. In this study, we introduce a simple yet effective approach,iterative prompting, which allows one to interact with ChatGPT or GPT-4 more effectively and efficiently through multi-turn interaction. Specifically, we propose a three-turn iterative prompting approach to food effect summarization in which the keyword-focused and length-controlled prompts are respectively provided in consecutive turns to refine the quality of the generated summary. We conduct a series of extensive evaluations, ranging from automated metrics to FDA professionals and even evaluation by GPT-4, on 100 NDA review documents selected over the past five years. We observe that the summary quality is progressively improved throughout the iterative prompting process. Moreover, we find that GPT-4 performs better than ChatGPT, as evaluated by FDA professionals (43% vs. 12%) and GPT-4 (64% vs. 35%). Importantly, all the FDA professionals unanimously rated that 85% of the summaries generated by GPT-4 are factually consistent with the golden reference summary, a finding further supported by GPT-4 rating of 72% consistency. Taken together, these results strongly suggest a great potential for GPT-4 to draft food effect summaries that could be reviewed by FDA professionals, thereby improving the efficiency of the PSG assessment cycle and promoting generic drug product development.

Biomechanical analysis of fixation strength at different nailing angles for femoral neck fracture with insufficient reduction.

To analyze the fixation strength of cannulated screws fixation in the treatment of femoral neck fracture with posterior tilt due to insufficient reduction. Two sets of digital models of anatomical reduction and 15° tilting reduction were established by CT data. Each group of models was modeled with two different fixation methods. One fixation method was fixed according to the standard cannulated screws recommended by AO. Another fixation method is to tilt the screw posterior tilt 15°. The final four groups of models were obtained: AO principle nailing posterior tilt model (Group A), posterior direction nailing posterior tilt model (Group B), AO principle nailing anatomic reduction model (Group C) and posterior direction nailing anatomic reduction model (Group D). The maximum displacement of the fracture end, the maximum Von-Mises stress and the stress distribution of the internal fixation were compared among the four groups. Four groups of models were established on artificial bone by 3D printing guide plate technology. The 600 N pressure test and yield test were performed on a biomechanical machine. The finite element and biomechanical models showed that groups B and C were more stable than groups A and D. The stability of group B was not worse than that of group C. When the femoral neck fracture produces a posterior tilt, a posterior reduction is allowed. The change of AO screw to posterior tilting screw fixation has more powerful advantages. No posterior tilt or posterior reduction, AO screw placement is still required.

Detection of fluid motion direction based on the rotational Doppler effect of grafted perfect vortex beam.

Vortex beams have attracted much attention due to their unique rotational Doppler effect. With the in-depth study of vortex beams, many new vortex beams have been proposed gradually, while the detection of fluid motion is of great significance for the study of ocean turbulence. Based on the rotational Doppler effect of the grafted perfect vortex beam, we propose a non-embedded optical method for real-time detection of the magnitude and direction of fluid velocity and establish a two-dimensional fluid model for simulation verification. It is proved that the grafted perfect vortex beam can detect the magnitude and direction of the fluid velocity at the same time, which may provide a new way and theoretical support for the detection of fluid motion direction.

Esophageal cancer stem cells reduce hypoxia-induced apoptosis by inhibiting the GRP78-perk-eIF2α-ATF4-CHOP pathway in vitro.

Background: Due to the abnormal angiogenesis, cancer stem cells (CSCs) in esophageal cancer (EC) have the characteristics of a hypoxic microenvironment. However, they can resist hypoxia-induced apoptosis. the molecular mechanism underlying the resistance of esophageal CSCs to hypoxia-induced apoptosis is currently unclear. Therefore, this study will investigate the molecular mechanism based on CHOP-mediated endoplasmic reticulum stress. Methods: CD44+CD24- cells in EC9706 cells were screened by fluorescence-activated cell sorting (FACS). To clarify which apoptosis pathway esophageal CSCs resist hypoxia-induced cell apoptosis through, the effects of hypoxia on apoptosis were detected by nuclear staining, flow cytometry, and JC-1 reagent, the effects of hypoxia on the expression of apoptosis-related proteins were detected by western blotting (WB) assay and quantitative polymerase chain reaction (qPCR) assay. To clarify the mechanisms of CD44+CD24- cells resistance to hypoxia-induced apoptosis is achieved by inhibiting the activation of endoplasmic reticulum stress (ERS) pathway, silenced CHOP and PERK cell lines of EC9706 cells and overexpressed CHOP and PERK cell lines of CD44+CD24- cells were constructed, the effects of hypoxia on apoptosis, cell cycle, and mitochondrial membrane potential were detected by flow cytometry and JC-1 reagent. WB assay and qPCR assay were used to detect the expressions of apoptosis-related proteins and ERS-related proteins. Results: Hypoxia significantly induce apoptosis and cycle arrest of EC9706 cells (P<0.05), but did not affect apoptosis and cycle of CD44+CD24- cells (P>0.05). Hypoxia considerably induced the activation of mitochondrial and ERS apoptosis pathways in EC9706 cells (P<0.05), but did not affect Fas receptor apoptosis pathways (P>0.05). The three apoptosis pathways were not affected by hypoxia in CD44+CD24- cells (P>0.05). Silencing the CHOP and PERK gene inhibited hypoxia-induced apoptosis of EC9706 cells (P<0.05). CHOP and PERK overexpression promoted hypoxia-induced apoptosis of CD44+CD24- cells (P<0.05), whereas mitochondrial membrane permeability inhibitors inhibited hypoxia-induced apoptosis of CD44+CD24- cells overexpressed CHOP gene. Conclusions: CD44+CD24- tumor stem cells in EC resist to hypoxia-induced apoptosis by the inhibition of ERS-mediated mitochondrial apoptosis pathway, which suggested that ERS pathway can serve as a potential target for reducing EC treatment resistance in clinical treatment.

Obesity and risk for respiratory diseases: a Mendelian randomization study.

Background: No existing comprehensive Mendelian randomization studies have focused on how obesity affects respiratory diseases. Methods: BMI and waist circumference, mainly from the UK Biobank, and 35 respiratory diseases from the FinnGen Biobank were subjected to Mendelian randomization analyses. In this study, the inverse variance weighting method was used as the predominant analysis method and was complemented by MR-Egger and weighted median methods. Horizontal pleiotropy and potential outliers were detected by employing the MR-PRESSO method. Results: This study indicated that obesity rises the possibility of acute upper respiratory infections (BMI: OR=1.131, p<0.0001; WC: OR=1.097, p=0.00406), acute sinusitis (BMI: OR=1.161, p=0.000262; WC: OR=1.209, p=0.000263), acute pharyngitis (WC: OR=1.238, p=0.0258), acute laryngitis and tracheitis (BMI: OR=1.202, p=0.0288; WC: OR=1.381, p=0.00192), all influenza (BMI: OR=1.243, p=0.000235; WC: OR=1.206, p=0.0119), viral pneumonia (WC: OR=1.446, p=0.000870), all pneumoniae (BMI: OR=1.174, p <0.0001; WC: OR=1.272, p <0.0001), bacterial pneumoniae (BMI: OR=1.183, p=0.000290; WC: OR=1.274, p<0.0001), acute bronchitis (BMI: OR=1.252, p <0.0001; WC: OR=1.237, p=0.000268), acute unspecified lower respiratory infection (BMI: OR=1.303, p=0.000403), chronic tonsils and adenoids diseases (BMI: OR=1.236, p <0.0001; WC: OR=1.178, p=0.000157), chronic laryngotracheitis and laryngitis (WC: OR=1.300, p=0.00785), COPD (BMI: OR=1.429, p <0.0001; WC: OR=1.591, p <0.0001), asthma (BMI: OR=1.358, p <0.0001; WC: OR=1.515, p <0.0001), necrotic and suppurative conditions of lower respiratory tract (WC: OR=1.405, p=0.0427), pleural effusion (BMI: OR=1.277, p=0.00225; WC: OR=1.561, p<0.0001), pleural plaque (BMI: OR=1.245, p=0.0312), other diseases of the respiratory system (BMI: OR=1.448, p <0.0001; WC: OR=1.590, p <0.0001), and non-small cell lung cancer (BMI: OR=1.262, p=0.00576; WC: OR=1.398, p=0.00181). This study also indicated that obesity decreases the possibility of bronchiectasis (BMI: OR=0.705; p=0.00200). Conclusion: This study revealed that obesity increases the risk of the majority of respiratory diseases (including 20 of all 35 respiratory diseases) and that obesity decreases the risk of bronchiectasis.

ß-Glucans in particulate and solubilized forms elicit varied immunomodulatory and apoptosis effects in teleost macrophages in a dosedependent manner.

ß-Glucans are a group of heterogeneous glucose polymers that possess immunomodulatory activities. The complex nature of their structures, uncertainty regarding the doses, and variable immune effects pose a challenge to comprehensive understanding. In this study, we investigated the immune responses and apoptosis effects in Nile tilapia (Oreochromis niloticus) head kidney macrophages (MФ) upon exposure to two ß-Glucans (Paramylon and Laminarin) at low and high doses. Our results demonstrate that Paramylon elicits more robust immune responses than Laminarin, albeit with a dose-limiting effect. We also observed that the high-dose Paramylon induces apoptosis, whereas no such effect was detected in Laminarin treatment. Mechanistically, high-dose Paramylon activates the intrinsic apoptosis pathway, with significantly up-regulation of intrinsic apoptosis-related genes and impaired mitochondrial function. On the other hand, Laminarin triggers metabolic reprogramming in MФ, resulting in the enrichment of the metabolite α-Ketoglutarate, which protects the MФ from apoptosis. Overall, our findings highlight the importance of identifying the optimal dose range for ß-Glucans, based on sources or structures, to achieve maximal immunomodulatory effects. These results have important implications for the design and optimization of ß-Glucans-based drugs or adjuvants in immunotherapies.

The germline HLA-A02B62 supertype is associated with a PD-L1-positive tumour immune microenvironment and poor prognosis in stage I lung cancer.

Background: Germline HLA class I molecule supertypes are shown to correlate with response to anti-PD-1 therapy. Here, we investigate the significance of germline HLA-A and HLA-B supertypes in tumour microenvironment of non-small-cell lung cancer. Methods: Totally 278 NSCLC patients were collected retrospectively. HLA genotyping was conducted using next-generation sequencing. The evaluation of tumour-infiltrating lymphocytes was performed by multiplex immunohistochemistry assay. Correlations among HLA supertypes, tumour infiltrating lymphocytes, and clinicopathological characteristics were assessed. Results: HLA-A03 and HLA-B62 were the supertypes with the highest proportions, at 69.1% and 52.2%, respectively. HLA-A02 or HLA-B62, but not HLA-A03, associated with higher PD-L1+ tumour and stromal cells levels, CD68+ cells, and CD68+PD-L1+ cells. Patients with both HLA-A02 and HLA-B62 supertypes displayed significantly higher PD-L1+ cells, CD68+ cells, and CD8+ cells levels than patients with other supertypes (P = 0.0301, P = 0.0479, P = 0.0192). These cells collectively constitute a hot but immunosuppressive tumour microenvironment. Accordingly, patients with both HLA-A02 and HLA-B62 supertypes had short progression-free survival after surgery (HR = 2.27, P = 0.0373). Conclusions: The HLA-A02B62 supertype could serve as a possible indicator of poor prognosis in early-stage lung cancer. However, it may also act as a favorable prognostic factor for immunotherapy, given its association with a PD-L1-positive tumour microenvironment.

Nomogram for predicting survival after lymphatic metastasis in esophageal cancer: A SEER analysis.

Lymphatic metastasis (LM) is a significant mechanism for the spread of esophageal cancer (EC) and predicts the poor prognosis of EC patients. This research aimed to assess the survival of patients with LM from EC by developing a nomogram. In this retrospective study, EC patients with LM from 2004 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were divided by year of diagnosis into a training cohort and a validation cohort. Univariate and multivariate Cox regression analyses were employed to determine the prognostic factors of LM, and a nomogram was constructed. The discrimination and calibration of the nomogram were compared by the C-index, area under the curve value, and calibration plots. The survival time difference was compared using Kaplan-Meier curves. A total of 11,695 patients with EC were included in this analysis. LM occurred in 56.5% (n = 6614) of EC patients. In the post-propensity score matching (PSM) cohort, patients with LM had significantly lower median overall survival (OS) than those without LM. Multivariate Cox regression was used to identify the eleven independent prognostic factors. The C-index was 0.709 in both the training and test sets, revealing the good predictive performance of the nomogram. Based on the results of calibration plots and the receiver operating characteristic (ROC) curve, we demonstrate the great performance of the prognostic model. The survival time of EC patients with LM was remarkably lower than that of EC patients without LM. The nomogram model established in this study can precisely predict the survival of EC patients with LM.