Identification of potential biomarkers for idiopathic pulmonary arterial hypertension using single-cell and bulk RNA sequencing analysis.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and severe cardiopulmonary disease with a challenging prognosis, and its underlying pathogenesis remains elusive. A comprehensive understanding of IPAH is crucial to unveil potential diagnostic markers and therapeutic targets. In this study, we investigated cellular heterogeneity and molecular pathology in IPAH using single-cell RNA sequencing (scRNA-seq) analysis. Our scRNA-seq results revealed significant alterations in three crucial signaling pathways in IPAH: the hypoxia pathway, TGF ß pathway, and ROS pathway, primarily attributed to changes in gene expression within arterial endothelial cells. Moreover, through bulk RNA sequencing analysis, we identified differentially expressed genes (DEGs) enriched in GO and KEGG pathways, implicated in regulating cell adhesion and oxidative phosphorylation in IPAH lungs. Similarly, DEGs-enriched pathways in IPAH arterial endothelial cells were also identified. By integrating DEGs from three IPAH datasets and applying protein-protein interaction (PPI) analysis, we identified 12 candidate biomarkers. Subsequent validation in two additional PAH datasets led us to highlight five potential biomarkers (CTNNB1, MAPK3, ITGB1, HSP90AA1, and DDX5) with promising diagnostic significance for IPAH. Furthermore, real-time quantitative polymerase chain reaction (RT-qPCR) confirmed significant differences in the expression of these five genes in pulmonary arterial endothelial cells from PAH mice. In conclusion, our findings shed light on the pivotal role of arterial endothelial cells in the development of IPAH. Furthermore, the integration of single-cell and bulk RNA sequencing datasets allowed us to pinpoint novel candidate biomarkers for the diagnosis of IPAH. This work opens up new avenues for research and potential therapeutic interventions in IPAH management.

Identification and validation of the clinical prediction model and biomarkers based on chromatin regulators in colon cancer by integrated analysis of bulk- and single-cell RNA sequencing data.

Background: Chromatin regulators (CRs) are implicated in the development of cancer, but a comprehensive investigation of their role in colon adenocarcinoma (COAD) is inadequate. The purpose of this study is to find CRs that can provide recommendations for clinical diagnosis and treatment, and to explore the reasons why they serve as critical CRs. Methods: We obtained data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted Gene Co-Expression Network Analysis (WGCNA) screened tumor-associated CRs. LASSO-Cox regression was used to construct the model and to screen key CRs together with support vector machine (SVM), the univariate Cox regression. We used single-cell data to explore the expression of CRs in cells and their communication. Immune infiltration, immune checkpoints, mutation, methylation, and drug sensitivity analyses were performed. Gene expression was verified by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Pan-cancer analysis was used to explore the importance of hub CRs. Results: We finally obtained 32 tumor-associated CRs. The prognostic model was constructed based on RCOR2, PPARGC1A, PKM, RAC3, PHF19, MYBBP1A, ORC1, and EYA2 by the LASSO-Cox regression. Single-cell data revealed that the model was immune-related. Combined with immune infiltration analysis, immune checkpoint analysis, and tumor immune dysfunction and exclusion (TIDE) analysis, the low-score risk group had more immune cell infiltration and better immune response. Mutation and methylation analysis showed that multiple CRs may be mutated and methylated in colon cancer. Drug sensitivity analysis revealed that the low-risk group may be more sensitive to several drugs and PKM was associated with multiple drugs. Combined with machine learning, PKM is perhaps the most critical gene in CRs. Pan-cancer analysis showed that PKM plays a role in the prognosis of cancers. Conclusions: We developed a prognostic model for COAD based on CRs. Increased expression of the core gene PKM is linked with a poor prognosis in several malignancies.

Literature review and prospect on oral cognition and disease diagnosis and treatment between Han and Tang dynasties.

Chinese medicine entered a significant period from foundation to maturity between Han and Tang dynasties when the Chinese traditional stomatology was a key stage. Sorting and analysis of existing literature and research outcomes have showed that current research on stomatology between Han and Tang dynasties focuses on oral physiology, pathology, diagnosis and treatment, and health care. It also involves stomatology history and explanation of termino-logies related to mouth and teeth recorded in medical books, use of simple methods, and thinking with citation and analysis of literature simply listed and reasoning preliminarily deducted. From the macro perspective, current research has not unveiled the whole picture of stomatology between the two dynasties and left a series of key issues unresolved. Thus, new methods should be developed and employed to carry out medical research on stomatology between Han and Tang dynasties given that is has a prosperous future.

Pharmacokinetics and tissue distribution of five bioactive components in the Corydalis yanhusuo total alkaloids transdermal patch following Shenque acupoint application in rats assessed by ultra-performance liquid chromatography-tandem mass spectrometry.

The purpose of this study was to evaluate the pharmacokinetics and tissue distribution of the Corydalis yanhusuo total alkaloids transdermal patch (CTTP) following Shenque acupoint application in rats. The concentrations of corydaline, tetrahydropalmatine, tetrahydrocolumbamine, protopine, and dehydrocorydaline in rat plasma and various tissues were simultaneously detected by ultra-performance liquid chromatography-tandem mass spectrometry after Shenque acupoint administration of CTTP. Plasma, heart, liver, spleen, lung, and kidney tissue samples were collected at specific times and separated by gradient elution on an ACQUITY UPLC HSS T3 column (1.8 µm, 100 mm × 2.1 mm) with a mobile phase of 0.01% formic acid aqueous solution and acetonitrile-0.01% formic acid. The methodological results showed that the selectivity, linear range, accuracy, precision, stability, matrix effect, and extraction recovery of the established method met the requirements of biological sample analysis. The results indicated that CTTP following Shenque acupoint administration rapidly delivered adequate drug into rat blood and maintained an effective plasma level for a significantly longer time than non-acupoint administration. Furthermore, CTTP effectively reached the liver through Shenque acupoint administration and showed tissue selectivity. The data obtained could provide a prospect for the treatment of chronic pain with CTTP following Shenque acupoint application.

An integrated fecal microbiome and metabolome in rats reveal variations in gut microbiota and fecal metabolic phenotype of Semen Euphorbiae and Semen Euphorbiae Pulveratum.

Semen Euphorbiae (SE) is a toxic traditional Chinese medicine made from the dry or mature seed of Euphorbia lathyris L. Research demonstrates that the toxic side-effects from eating SE are associated with intestinal disturbance. By processing to produce Semen Euphorbiae Pulveratum (SEP), the toxicity is reduced, and diarrhea is attenuated. However, there are minimal studies on the differential effects between SE and SEP on microbiota and fecal metabolites. In this study, 16S rDNA sequencing and UPLC-Q-TOF/MS were interpreted with PCA and OPLS-DA multivariate analysis to understand the effect of SE and SEP on the gut microbiota and fecal metabolic phenotype in rats. Compared to the blank control group, the results showed that both SE and SEP were associated with increased microbes from the phylum Firmicutes and decreased Bacteroidetes, but the change was not as strong in the SEP administration group. Meanwhile, the fecal metabolism of rats also changed significantly, since 17 additional metabolites were detected in both groups, including amino acid metabolites, bacterial metabolites, and lipid metabolites. Our results indicate that the SEP administration group may reduce toxicity by differentially influencing intestinal metabolites and flora.

Construction of magnetic drug delivery system and its potential application in tumor theranostics.

Magnetic nanoparticles(NPs) are characterized by a rich variety of properties. Because of their excellent physical and chemical properties, they have come to the fore in biomedicine and other fields. The magnetic NPs were extensively studied in magnetic separation of cells, targeted drug delivery, tumor hyperthermia, chemo-photothermal therapy, magnetic resonance imaging (MRI) and other biomedical fields. Magnetic NPs are increasingly used in magnetic resonance imaging (MRI) based on their inherent magnetic targeting, superparamagnetic enzyme-like catalytic properties and nanoscale size. Poly(lactic-co-glycolic acid) (PLGA) is a promising biodegradable material approved by FDA and EU for drug delivery. Currently, PLGA-based magnetic nano-drug delivery systems have attracted the attention of researchers. Herein, we achieved the effective encapsulation of sized-controlled polyethylene glycol-3,4-dihydroxy benzyl-amine-coated superparamagnetic iron oxide nanoparticles (SPIO NPs) and euphorbiasteroid into PLGA nanospheres via a modified multiple emulsion solvent evaporation method (W1/O2/W2). NPs with narrow size distribution and acceptable magnetic properties were developed that are very useful for applications involving cancer therapy and MRI. Furthermore, SPIO-PLGA NPs enhanced the MRI T2 relaxation properties of tumor sites.The prepared SPIO NPs and magnetic PLGA nanospheres can be promising magnetic drug delivery systems for tumor theranostics. This study has successfully constructed a tumor-targeting and magnetic-targeting smart nanocarrier with enhanced permeability and retention, multimodal anti-cancer therapeutics and biodegradability, which could be a hopeful candidate for anti-tumor therapy in the future.

Characterization of diterpene metabolism in rats with ingestion of seed products from Euphorbia lathyris L. (Semen Euphorbiae and Semen Euphorbiae Pulveratum) using UHPLC-Q-Exactive MS.

Previous pharmacological studies have indicated that diterpenoids are the primary effective chemical cluster in the seeds of Euphorbia lathyris L. The seed products are used in traditional Chinese medicine in the forms of Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP). However, the metabolism of the plant's diterpenoids has not been well elucidated, which means that the in vivo metabolite products have not been identified. The current study screened the physiological metabolites of six diterpenes [Euphorbia factor L1 (L1), L2 (L2), L3 (L3), L7a (L7a), L7b (L7b), and L8 (L8)] in feces and urine of rats after oral administration of SE and SEP using UHPLC-Q-Exactive MS. A total of 22 metabolites were detected in feces and 8 in urine, indicating that the major elimination route of diterpenoids is via the colon. Hydrolysis, methylation, and glucuronidation served as the primary metabolic pathways of these diterpenoids. In sum, this study contributed to the elucidation of new metabolites and metabolic pathways of SE and SEP, and the new chemical identities can be used to guide further pharmacokinetic studies.

Research on adaption to air pollution in Chinese cities: Evidence from social media-based health sensing.

Air pollution seriously threats to human health. Understanding the health effects of air pollution is of great importance for developing countermeasures. However, little is known about the real-time impacts of air pollution on the human heath in a comprehensive way in developing nations, like China. To fill this research gap, the Chinese urbanites' health were sensed from more than 210.82 million Weibo (Chinese Twitter) data in 2017. The association between air pollution and the health sensing were quantified through generalized additive models, based on which the sensitivities and adaptions to air pollution in 70 China's cities were assessed. The results documented that the Weibo data can well sense urbanites' health in real time. With the different geographical characteristics and socio-economic conditions, the Chinese residents have adaption to air pollution, indicated by the spatial heterogeneity of the sensitivities to air pollution. Cities with good air quality in South China and East China were more sensitive to air pollution, while cities with worse air quality in Northwest China and North China were less sensitive. This research provides a new perspective and methodologies for health sensing and the health effect of air pollution.

Metabonomics analysis of semen euphorbiae and semen Euphorbiae Pulveratum using UPLC-Q-TOF/MS.

Semen Euphorbiae (SE), the dry and mature seed of Euphorbia lathyris L., a common traditional Chinese medicine, has significant pharmacological activity. However, its toxicity limits its clinical application, and less toxic Semen Euphorbiae Pulveratum (SEP) is often used clinically. To explore the possible mechanism of SE frost-making and attenuation, this study used ultrahigh-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry to perform a comprehensive metabolomics analysis of serum and urine samples from rats treated with SE and SEP, and performed histopathological evaluation of liver, kidney and colon tissues. Meanwhile, the different metabolites were visualized through multivariate statistical analysis and the HMDB and KEGG databases were used to distinguish the differential metabolites of SE and SEP to reveal related metabolic pathways and their significance. In total, 32 potential biomarkers, 14 in serum and 18 in urine, were identified. The metabolic pathway analysis revealed that arachidonic acid metabolism, sphingolipid metabolism, tyrosine and tryptophan biosynthesis, the tricarboxylic acid cycle and seven other metabolic pathways were significantly altered. Importantly, compared with SE, SEP reduced the metabolic disorder related to endogenous components. The mechanism may be related to the regulation of lipid metabolism, intestinal flora metabolites, amino acid metabolism and energy metabolism. This study provided new insights into the possible mechanism of SE freezing and attenuation.

The relationship between social support and Internet addiction among Chinese college freshmen: A mediated moderation model.

Purpose: Internet addiction has become a worldwide mental health problem, and this problem is particularly prominent in China. Although current studies have shown that social support is closely related to Internet addiction, the mechanism of the relationship between the two is not clear at present. This study aimed to find out the influencing factors and the mechanism of Internet addiction among college freshmen, and to form scientific prevention and intervention plan on this basis. Method: This study adopts the cluster sampling method to select 322 college freshmen in a typical postsecondary school in Shandong Province, using Chinese Internet Addiction Scale (CIAS), Social Support Rating Scale (SSRS), and Network-related Maladaptive Cognition Scale (NRMCS) to investigate the relationship between social support, network-related maladaptive cognition, gender, and the degree of Internet addiction. Results: The findings of this study are as follows: (1) After controlling age and family location, social support had a significant negative predictive effect on Internet addiction; (2) Gender acted as a moderator between the relationship of social support and Internet addiction; and (3) Additionally, the moderating effect of gender was completely mediated by network-related maladaptive cognition. Conclusion: There is a mediated moderating effect between social support and Internet addiction. That is, gender plays a moderating role between social support and Internet addiction, and this moderating effect is mediated by network maladaptive cognition.

Correction: PSC-derived Galectin-1 inducing epithelial-mesenchymal transition of pancreatic ductal adenocarcinoma cells by activating the NF-κB pathway.

[This corrects the article DOI: 10.18632/oncotarget.21212.].

Ligand-modified homologous targeted cancer cell membrane biomimetic nanostructured lipid carriers for glioma therapy.

The main treatment measure currently used for glioma treatment is chemotherapy; the biological barrier of solid tumors hinders the deep penetration of nanomedicines and limits anticancer therapy. Furthermore, the poor solubility of many chemotherapeutic drugs limits the efficacy of antitumor drugs. Therefore, improving the solubility of chemotherapeutic agents and drug delivery to tumor tissues through the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) are major challenges in glioma treatment. Nanostructured lipid carriers (NLCs) have high drug loading capacity, high stability, and high in vivo safety; moreover, they can effectively improve the solubility of insoluble drugs. Therefore, in this study, we used solvent volatilization and ultrasonic melting methods to prepare dihydroartemisinin nanostructured lipid carrier (DHA-NLC). We further used the glioma C6 cancer cell (CC) membrane to encapsulate DHA-NLC owing to the homologous targeting mechanism of the CC membrane; however, the targeting ability of the CC membrane was weak. We accordingly used targeting ligands for modification, and developed a bionanostructured lipid carrier with BBB and BBTB penetration and tumor targeting abilities. The results showed that DHA-loaded NGR/CCNLC (asparagine-glycine-arginine, NGR) was highly targeted, could penetrate the BBB and BBTB, and showed good anti-tumor effects both in vitro and in vivo, which could effectively prolong the survival time of tumor-bearing mice. Thus, the use of DHA-loaded NGR/CCNLC is an effective strategy for glioma treatment and has the potential to treat glioma.

Comparison of Pharmacokinetics and Tissue Distribution Characteristics of Three Diterpenoid Esters in Crude and Prepared Semen Euphorbiae.

BACKGROUND: Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP) have a long history of medicinal use. SEP is the processed product of SE; both ancient and modern studies have shown that SEP has a lower toxicity compared to SE. To clarify the influence of processing on the pharmacological properties of SE and SEP, a study was carried out to compare the pharmacokinetics and distribution characteristics of three active compounds after oral administration of SE and SEP extracts. METHODS: A UPLC-MS/MS method was established to simultaneously determine the contents of Euphorbia factors L1, L2, and L3 in rat plasma and mouse tissues after an oral administration of crude and processed SE with approximately the same dosage. Plasma and heart, liver, spleen, lung, kidney, and colon tissue samples were treated with ethyl acetate and separated by gradient elution on a C18 column with a mobile phase of 0.1% formic acid and methanol. RESULTS: The established method had good selectivity, linear range, accuracy, precision, stability, matrix effect, and extraction recovery. The area under the concentration time curve, time to maximum concentration, maximum concentration, half-life of elimination, and mean retention time of plasma samples in SEP-treated group decreased, and the clearance in SEP-treated group increased. Moreover, the active component concentrations in colon, liver, and kidney tissues were more followed by those in the heart, lungs, and spleen. CONCLUSION: These results indicate that the processing could influence the pharmacokinetics and tissue distribution of Euphorbia factors L1, L2, and L3 after oral administration of crude and processed SE. The data obtained may lay a foundation for the clinical use of SE and for further study on the processing mechanism of SE.

Mapping the exposure and sensitivity to heat wave events in China's megacities.

The rising temperature makes the weather becoming more extreme. Understanding how extreme hot temperature-heat wave events (HWEs)-are likely to alter individual heat exposure and sensitivity is crucial for developing climate change mitigation and adaptation strategies. Despite the importance, little is known about the real-time impacts of HWEs on individual daily life in developing nations, like China. To fill this gap, we adopt over 1544 thousand Weibo (Chinese Twitter) social media data, coupled with meteorological conditions people face when posting, to assess the heat exposure and people's sensitivity to HWEs across 31 mega-cities in China. The results show the hotspot of Weibo heat is coincident with the extremely hot temperature, with a correlation of 0.7 (p < 0.05). The intensities, frequencies, and durations of HWEs in both geographical and social media space have high spatial heterogeneity. Its spatial variation can be explained by the type of climate zone and the unique geographical environment. The cities with extreme hot weather are more likely to adapt to the heatwave and less sensitivity to HWEs. The proposed framework, which integrates the real-time social media semantic analysis, statistical method, and spatial techniques, provides a new paradigm to assess the HWEs exposure and sensitivity analysis in China.

[Balloon Eustachian tuboplasty for treatment of Eustachian tube dysfunction: A systematic review and Meta-analysis].

Objective:To sysetematically evaluate the efficacy, compliance and collaborative operation of Balloon Eustachian tuboplasty（BET） for treatment of Eustachian tube dysfunction via Meta-analysis. Method:The PubMed, OVID, Embase, Cochrane Library, ProQuest, Web of Science, Chinese biomedical literature database, VIP database, WanFang database, CNKI were searched for papers on autoinflation for treatment of chronic otitis media with effusion in children（up to March 2020）. Statistical analysis was performed by using Cochrane tools and RevMan5.2. Result:A total of 14 articles were included. The results of Meta-analysis showed that the effective rate of the BET was 86%（95%CI: 0.79-0.94）, and had statistical significance. The tubomanometry, ETS, ETDQ-7 of postoperative BET was better than that of the control group, and had statistical significance. Heterogeneity of tubomanometry,ETS was relatively small, which is I²=51%（OR 3.57, 95%CI ：1.95 - 6.55） and I²=59%（SMD 1.33, 95%CI ：0.98-1.67） respectively. There was no statistical significance between BET plus tympanic paracentesis compared with those treated with BET alone. The recurrence rate of the included literature was 5.37% and the complication rate was only 0.33%. Conclusion:Balloon Eustachian tuboplastycan be a safe and effective treatment for adult Eustachian tube dysfunction. However, in terms of collaborative surgery and evaluation methods, we still need more homogeneous, multi-center randomized controlled studies to obtain more accurate conclusions to guide clinical practice.

Intestinal microbiota: a new force in cancer immunotherapy.

Cancer displays high levels of heterogeneity and mutation potential, and curing cancer remains a challenge that clinicians and researchers are eager to overcome. In recent years, the emergence of cancer immunotherapy has brought hope to many patients with cancer. Cancer immunotherapy reactivates the immune function of immune cells by blocking immune checkpoints, thereby restoring the anti-tumor activity of immune cells. However, immune-related adverse events are a common complication of checkpoint blockade, which might be caused by the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. In this context, the intestinal microbiota has shown great potential in the immunotherapy of cancer. The intestinal microbiota not only regulates the immune function of the body, but also optimizes the therapeutic effect of immune checkpoint inhibitors, thus reducing the occurrence of complications. Therefore, manipulating the intestinal microbiota is expected to enhance the effectiveness of immune checkpoint inhibitors and reduce adverse reactions, which will lead to new breakthroughs in immunotherapy and cancer management. Video abstract.

Clinical nomogram for lymph node metastasis in pathological T1 esophageal squamous cell carcinoma: a multicenter retrospective study.

BACKGROUND: Endoscopic resection is increasingly used to treat pathological T1 (pT1) esophageal cancer (EC) patients. However, the procedures are limited by lymph node metastasis (LNM) and remain controversial. We aimed to construct a nomogram to predict the risk of LNM in patients with pT1 esophageal squamous cell carcinoma (ESCC). METHODS: A total of 243 patients with pT1 ESCC who underwent esophagectomy and lymph node dissection at two different institutes between February 2013 and June 2019 were analyzed retrospectively. Patients were categorized into the negative group and the positive group according to whether there was LNM. Risk factors for LNM were evaluated by univariate and multivariate analyses. The nomogram was used to estimate the individual risk of LNM. RESULTS: Forty-six (18.9%) of the 243 patients with pT1 ESCC exhibited LNM. The LNM rate in patients with stage T1a disease was 5.7% (5/88), and the rate in patients with stage T1b disease was 26.5% (41/155). Multivariable logistic regression analysis showed that tumor differentiation [odds ratio (OR) =1.942, 95% confidence interval (CI): 1.067-3.536, P=0.030], the T1 sub-stage (OR =4.750, 95% CI: 1.658-13.611, P=0.004), the preoperative alanine aminotransferase/aspartate aminotransferase ratio (LSR) (OR =5.371, 95% CI: 1.676-17.210, P=0.005), and the high-density lipoprotein cholesterol (HDL-C) level (OR =5.894, 95% CI: 1.917-18.124, P=0.002) were independent risk factors for LNM. The nomogram had relatively high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.803 (95% CI: 0.732-0.873). The calibration curve showed that the predicted probability of LNM was in good agreement with the actual probability. CONCLUSIONS: Clinicopathological and hematological parameters of tumor differentiation, the T1 sub-stage, the preoperative LSR, and the HDL-C level may predict the risk of LNM in T1 ESCC. The risk of LNM can be predicted by the nomogram.

[Identification of SDHD c.170-1G>T variant in pedigree affected with carotid body tumor].

OBJECTIVE: To carry out genetic testing for a pedigree affected with carotid body tumor (CBT). METHODS: Members of the pedigree were enrolled and underwent physical examination, ultrasonography and CT scan. Genomic DNA of the proband was extracted from peripheral blood sample and subjected to exome sequencing. Candidate variants were predicted using bioinformatic tools and verified among members from his pedigree. RESULTS: A c.170-1G>T splicing variant of the SDHD gene was detected in 15 individuals from the pedigree. Physical examination and imaging confirmed that 9 of them had CBT and hypertension, while the remaining 6 died of cardiovascular and cerebrovascular diseases. CONCLUSION: The c.170-1G>T variant of the SDHD gene probably underlies the CBT in this pedigree. Genetic testing should be considered for CBT patients with CBT in addition to conventional clinical examination.