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IntroductionPrevious studies have indicated that activity of fatty acid desaturase 1 (FADS1), is involved in cardiometabolic risk. Recent experimental data have shown that FADS1 knockdown can promote lipid accumulation and lipid droplet formation in liver cells. In this study, we aimed to characterize whether different FADS1 genotypes affect liver fat content, essential fatty acid content and free oxylipin mediators in the blood.MethodsWe analyzed the impact of FADS1 single-nucleotide polymorphisms (SNPs) rs174546, rs174547, and rs174550 on blood fatty acids and free oxylipins in a cohort of 85 patients from an academic metabolic medicine outpatient center. Patients were grouped based on their genotype into the homozygous major (derived) allele group, the heterozygous allele group, and the homozygous minor (ancestral) allele group. Omega-3 polyunsaturated fatty acids (n-3 PUFA) and omega-6 polyunsaturated fatty acids (n-6 PUFA) in the blood cell and plasma samples were analyzed by gas chromatography. Free Oxylipins in plasma samples were analyzed using HPLC–MS/MS. Liver fat content and fibrosis were evaluated using Fibroscan technology.ResultsPatients with the homozygous ancestral (minor) FADS1 genotype exhibited significantly lower blood levels of the n-6 PUFA arachidonic acid (AA), but no significant differences in the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There were no significant differences in liver fat content or arachidonic acid-derived lipid mediators, such as thromboxane B2 (TXB2), although there was a trend toward lower levels in the homozygous ancestral genotype group.DiscussionOur findings suggest that FADS1 genotypes influence the blood levels of n-6 PUFAs, while not significantly affecting the n-3 PUFAs EPA and DHA. The lack of significant differences in liver fat content and arachidonic acid-derived lipid mediators suggests that the genotype-related variations in fatty acid levels may not directly translate to differences in liver fat or inflammatory lipid mediators in this cohort. However, the trend towards lower levels of certain lipid mediators in the homozygous ancestral genotype group warrants further investigation to elucidate the underlying mechanisms of different FADS1 genotypes and potential implications for cardiometabolic risk.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHAderived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP-metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHAderived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy. [ABSTRACT FROM AUTHOR]

ObjectiveIn patients with complex coronary artery disease (CAD) undergoing cardiac surgery, myocardial protection might be impaired due to microvascular obstruction, resulting in myocardial injury and subsequent biomarker release. Therefore, this study investigated the correlation between the complexity of CAD, reflected by the SYNTAX Score, and the release of cardiac biomarkers after CABG.MethodsIn a consecutive series of 919 patients undergoing isolated CABG SYNTAX scores I and II were calculated to assess the complexity of CAD. Levels of high sensitivity cardiac troponin T (hs-cTnT) and creatine kinase-myocardial band (CK-MB) were routinely measured once before and serially after surgery. Patients were divided into tertiles according to their SYNTAX Scores I and II. Spearman correlations and regression models were performed to measure the degree of association between the release of hs-cTnT and CK-MB and the SYNTAX Scores.ResultsPatients with a higher SYNTAX Score I had more comorbidities reflected in a higher EuroSCORE II. Preoperatively, higher levels of cardiac biomarkers were found in patients with higher SYNTAX Score II. No correlation was observed between hs-cTnT, CK-MB and SYNTAX Score I or II. Regression models did not show any association between cardiac biomarkers and the complexity of CAD.ConclusionThe complexity of CAD is not associated with the release of cardiac biomarkers after CABG. Factors influencing postoperative biomarker release need to be elucidated in future trials to include postoperative biomarker release into risk stratification models predicting outcome after cardiac surgery.

BackgroundLong-term outcomes of elderly and frail patients with secondary mitral valve regurgitation (MR) are inconclusive. Especially in patients with co-morbidities such as atherosclerosis who are suffering from heart failure, optimal medical therapy (OMT) is the preferred therapy relative to surgical or percutaneous interventions. It remains challenging to identify the most successful therapy to improve symptoms and increase life expectancy. To reduce surgical trauma for these patients, minimally invasive mitral valve surgery (MIMVS) was developed; this has shown promising medium-term results, but there is still a lack of evidence regarding long-term results. The aim of this investigation was to describe the long-term outcomes of less invasive mitral valve surgery (MVS) in elderly patients.MethodsIn this longitudinal retrospective analysis, 67 patients (aged ≥70 years) with secondary MR who underwent MV repair ± tricuspid valve repair (TVR) were identified. MVS was performed via minithoracotomy (MT) in most cases (n = 54); in patients with contraindications for MIMVS, partial upper sternotomy (PS) was the preferred route for surgical access (n = 13). The appropriate access route was chosen according to the patient's clinical condition and comorbidities. We analyzed reoperation-free long-term survival, combined operative success (lack of residual MR, conversion to MV replacement, or larger thoracic incisions), and perioperative safety (at 30 days: mortality, re-thoracotomy, ECMO, pacemaker implantation, dialysis, longer ventilation, stroke, myocardial infarction). In a subgroup analysis, we compared long-term survival in MVS patients with and without TVR.ResultsThe median age of patients (62.7% female) was 74 years (interquartile range: 72–76 years), with a median EuroSCORE2 of 2.8% (1.5%–4.6%) and N-terminal pro-brain natriuretic peptide plasma levels of 1,434 ng/L (1035–2149 ng/L). The median follow-up period was 5.6 years (2.7–8.5 years). The reoperation-free long-term survival rate up to 10 years was 66.2%. Combined operative success and perioperative safety were achieved in 94% and 76% of patients, respectively. Additional TVR was performed in 56.7% of patients, without any significant difference in survival rates compared to the group without TVR (p = 0.417; HR 1.473, 95% CI 0.578–3.757).ConclusionLess invasive MV repair for secondary MR shows excellent operative success and safety in selected patients. Freedom from significant MR and from the need for reoperation indicates long-lasting efficacy. These results should be considered in heart team discussions regarding allocation of patients to surgical mitral procedures.

Both arbuscular mycorrhizal fungi (AMF) and phytohormones collectively regulate plant growth and root development, but their individual and combined effects on tea [Camellia sinensis (L.) O. Kuntze] cutting seedings remain unclear. This study examined the individual and combined effects of two species of AMF (Rhizophagus intraradices, RI and Funneliformis mosseae, FM) and two types of palnt hormones (strigolactones, SLs; polyamines, PAs) on tea cutting seedings, by evaluating the growth and physiobiochemical characteristics of plants treated with the AMFs and/or hormones. The results showed that inoculation with either AMF individually or hormones treatment alone could significantly enhanced mycorrhizal colonization, growth target and physiobiochemical characteristics of tea cutting seedlings. Interestingly, the addition of a combination of AMFs and hormones showed superior effects, while SL and RI exhibited the most improvements to the colonization rate, plant growth, root-morphological traits, root DHA activity, photosynthesis, chlorophyll content, soluble sugar content in leaves, and the activities of antioxidant enzymes (SOD, POD, and CAT), compared to other treatment combinations (SL + FM, PA + RI, and PA + FM). Correlation analyses revealed a significantly (p < 0.05) positive correlation of root AMF colonization with root-related traits (e.g., DHA, root total length, surface area, and volume) and leaf-related traits (e.g., leaf area, shoot biomass, total chlorophyll, and antioxidant enzyme activities). This study demonstrated that while the apllication of individual AMF or plant hormones had a certain good effects on most growth and physiobiochemical characteristics parameters of tea cutting seedings, the additive effect was from specific combined of AMF and plant hormones. These results highlight the possibility for combined of AMF and plant hormones to improve the asexual reproduction of tea plants via cuttings.

IntroductionRecent advances in machine learning provide new possibilities to process and analyse observational patient data to predict patient outcomes. In this paper, we introduce a data processing pipeline for cardiogenic shock (CS) prediction from the MIMIC III database of intensive cardiac care unit patients with acute coronary syndrome. The ability to identify high-risk patients could possibly allow taking pre-emptive measures and thus prevent the development of CS.MethodsWe mainly focus on techniques for the imputation of missing data by generating a pipeline for imputation and comparing the performance of various multivariate imputation algorithms, including k-nearest neighbours, two singular value decomposition (SVD)—based methods, and Multiple Imputation by Chained Equations. After imputation, we select the final subjects and variables from the imputed dataset and showcase the performance of the gradient-boosted framework that uses a tree-based classifier for cardiogenic shock prediction.ResultsWe achieved good classification performance thanks to data cleaning and imputation (cross-validated mean area under the curve 0.805) without hyperparameter optimization.ConclusionWe believe our pre-processing pipeline would prove helpful also for other classification and regression experiments.

Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) can visualize the spatial distribution characteristics of molecules in tissues in situ, in which the matrix plays a key role. In this paper, we propose a platinum nanomaterial pre-coated matrix, which can be prepared in bulk by sputtering platinum nanoparticles onto slides using an ion sputterer and then used for MALDI-MS analysis by placing tissue sections on the matrix. We used this matrix for MALDI-MS imaging analysis of corn kernels and germinated wheat sections, and the results show that triacylglycerides were mainly distributed in the embryo of corn kernels and germinated wheat, and sugars were mainly distributed in the endosperm, with the highest content of disaccharides.It provides a simple and reliable experimental condition for analyzing the distribution of oligosaccharide and lipid components in plant tissues.

BackgroundSevere traumatic cervical spinal cord injury (tcSCI) is a disastrous event for patients and families. Maximizing spinal cord function recovery has become the primary therapeutic goal. This study investigated the effect of early extensive posterior decompression on spinal cord function improvement after severe tcSCI.MethodsA retrospective review of 83 consecutive patients who underwent extensive open-door laminoplasty decompression within 24 h after severe tcSCI (American Spinal Injury Association (ASIA) impairment scale (AIS) grade A to C) between 2009 and 2017 at our institution was performed. The patient clinical and demographic data were collected. Neurological functional recovery was evaluated according to the Japanese Orthopaedic Association (JOA) score system, ASIA motor score (AMS) and AIS grade.ResultsAmong the 83 patients initially included, the baseline AIS grade was A in 12, B in 28, and C in 43. Twenty-three patients (27.7%) had a high cervical injury. Cervical spinal stenosis (CSS) was identified in 37 patients (44.6%). The mean intramedullary lesion length was 59.6 ± 20.4 mm preoperatively and 34.2 ± 13.3 mm postoperatively (p

Purpose: This is the first study to compare the pharmacokinetics, safety and, immunogenicity of QL1209, a biosimilar of Perjeta®.Methods: This study was a randomized, double-blind, parallel-controlled clinical trial evaluating the biosimilarity between QL1209 (specification: 420 mg:14 ml, single use via, manufacturer: Qilu Pharmaceutical Co., Ltd., batch number: 201808001KJL) and Perjeta® (specification: 420 mg: 14 ml, single use via, manufacturer: Roche Pharma AG, batch number: H0309H02). The trial period was 99 days (blood samples for PK were collected 99 days after infusion). Serum concentrations were determined using a validated assay. PK parameters were calculated using a non-compartmental model and analyzed statistically. Anti-drug antibody (ADA)-positive samples were further tested for the presence of neutralization antibody detection (NAb).Results: A total of 137 healthy subjects were administrated. The subjects were randomized 1:1 to receive QL1209 or Perjeta® 420 mg intravenously. The geometric mean ratio (GMRs) for QL1209 versus Perjeta® are 104.14%, 104.09%, and 110.59% for Cmax, AUC0-t, and AUC0-∞, respectively, and their 90% confidence interval (CIs) all fell within the predefined bioequivalence margin 80.00–125%. The incidence of drug-related adverse events was 95.6% and 95.5% in the QL1209 and Perjeta® groups, respectively, also comparable between the two groups.Conclusion: The results of this comparative clinical pharmacology study demonstrated the PK similarity of QL1209 (420 mg: 14 ml) and Perjeta® (420 mg: 14 ml) and there was no significant difference in safety and immunogenicity between QL1209 and Perjeta® manufactured by Roche Pharma AG.

Long non-coding RNAs (lncRNAs) widely regulate gene expression and play important roles in the pathogenesis of human diseases, including malignant tumors. However, the functions of most lncRNAs remain to be elucidated. In order to study and screen novel lncRNAs with important functions in the carcinogenesis of nasopharyngeal carcinoma (NPC), we constructed a lncRNA expression profile of 10 NPC tissues and 6 controls through a gene microarray. We identified 1,276 lncRNAs, of which most are unknown, with different expression levels in the healthy and NPC tissues. In order to shed light on the functions of these unknown lncRNAs, we first constructed a co-expression network of lncRNAs and mRNAs using bioinformatics and systematic biological approach. Moreover, mRNAs were clustered and enriched by their biological functions, and those lncRNAs have similar expression trends with mRNAs were defined as functional molecules with potential biological significance. The module may help identify key lncRNAs in the carcinogenesis of NPC and provide clues for in-depth study of their functions and associated signaling pathways. We suggest the newly identified lncRNAs may have clinic value as biomarkers and therapeutic targets for NPC diagnosis and treatment.

Thyroglobulin (Tg) is secreted by thyroid follicular cells and stored in the thyroid follicular lumen as a component of thyroid hormone. It is known that both benign and well-differentiated malignant thyroid tissue can secrete Tg. In recent years, growing lines of evidence have shown that Tg plays an important role in the diagnosis and metastasis of preoperative differentiated thyroid carcinoma (DTC). The levels of Tg, whether in the serum or in a fine-needle aspiration washout fluid, are usually viewed as an excellent indicator in the monitoring of postoperative DTC, including the guidance and evaluation of radioactive iodine ablation. Nevertheless, some factors limit the application of Tg, such as the method used to measure Tg and the presence of Tg antibodies. This review aimed to summarize the role of Tg in the preoperative and postoperative evaluation of patients with DTC, and the factors influencing Tg. This review could provide a reference for a more accurate application of Tg in patients with DTC.

Over the past decades, shockwave therapy (SWT) has gained increasing interest as a therapeutic approach for regenerative medicine applications, such as healing of bone fractures and wounds. More recently, pre-clinical studies have elucidated potential mechanisms for the regenerative effects of SWT in myocardial ischemia. The mechanical stimulus of SWT may induce regenerative effects in ischemic tissue via growth factor release, modulation of inflammatory response, and angiogenesis. Activation of the innate immune system and stimulation of purinergic receptors by SWT appears to enhance vascularization and regeneration of injured tissue with functional improvement. Intriguingly, small single center studies suggest that SWT may improve angina, exercise tolerance, and hemodynamics in patients with ischemic heart disease. Thus, SWT may represent a promising technology to induce cardiac protection or repair in patients with ischemic heart disease.

Inflammasomes are multiprotein complexes that can sense danger signals and activate caspase-1 to mediate pro-inflammatory cytokines release and pyroptotic cell death. There are two main canonical and non-canonical signaling pathways that trigger inflammasome activation. Inflammasomes are expressed and assembled in parenchymal and nonparenchymal cells in response to liver injury in the liver. Additionally, the hepatocytes, biliary epithelial cells (cholangiocytes), hepatic stellate cells (HSCs), hepatic macrophages, and liver sinusoidal endothelial cells (LSECs) contribute to liver fibrosis via different mechanisms. However, the underlying mechanism of the inflammasome and pyroptosis in these liver cells in liver fibrosis remains elusive. This review summarizes the activation and function of inflammasome complexes and then discusses the association between inflammasomes, pyroptosis, and liver fibrosis. Unlike other similar reviewers, we will focus on the effect of inflammasome activation and pyroptosis in the various liver cells during the development of liver fibrosis. We will also highlight the latest progress of pharmacological intervention in inflammasome-mediated liver fibrosis.

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children.Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-μg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 μg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 μg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 μg and 100 μg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3.Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 μg, whereas the Fabs was tolerated to only 28.9%–32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%–89.0%. A severe adverse event was found in Part 2. In Part 3 (100 μg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly.Conclusion: Using the optimized nasal spray method, a single dose of 20/100 μg of the test drug was safe and tolerable, and 100 μg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

Genomic instability and amplification are intrinsically important traits determining the development and heterogeneity of tumors. The role of extrachromosomal circular DNA (eccDNA) in tumors has recently been highlighted. EccDNAs are unique genetic materials located off the chromosomal DNA. They have been detected in a variety of tumors. This review analyzes the mechanisms involved in the formation of eccDNAs and their genetic characteristics. In addition, the high-copy number and transcriptional levels of oncogenes located in eccDNA molecules contribute to the acceleration of tumor evolution and drug resistance and drive the development of genetic heterogeneity. Understanding the specific genomic forms of eccDNAs and characterizing their potential functions will provide new strategies for tumor therapy. Further research may yield new targets and molecular markers for the early diagnosis and treatment of human cancer.

BackgroundThe prevalence of thyroid carcinoma (TC) and Hashimoto’s thyroiditis (HT) has been increasing dramatically over the past decades. We investigated the relationship between HT and TC.MethodsWe followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for carrying out and reporting this meta-analysis. The literature from January 1, 2010 to December 31, 2020, regardless of region and publication type, was searched comprehensively in PubMed, Embase, Web of Science, and Cochrane Library databases. After careful selection and data extraction, the pooled odds ratio of various clinical characteristics in 39 studies were calculated. Publication bias was analyzed using funnel plots.ResultsMeta-analysis of 39 original research articles showed HT to be a risk factor of TC (pooled odds ratio = 1.71; 95% confidence interval, 1.57–1.80; p < 0.00001) and papillary thyroid carcinoma (1.67, 1.51–1.85,

Chronic liver disease (CLD) represents a global health problem, accounting for the heavy burden of disability and increased health care utilization. Epigenome alterations play an important role in the occurrence and progression of CLD. Histone modifications, which include acetylation, methylation, and phosphorylation, represent an essential part of epigenetic modifications that affect the transcriptional activity of genes. Different from genetic mutations, histone modifications are plastic and reversible. They can be modulated pharmacologically without changing the DNA sequence. Thus, there might be chances to establish interventional solutions by targeting histone modifications to reverse CLD. Here we summarized the roles of histone modifications in the context of alcoholic liver disease (ALD), metabolic associated fatty liver disease (MAFLD), viral hepatitis, autoimmune liver disease, drug-induced liver injury (DILI), and liver fibrosis or cirrhosis. The potential targets of histone modifications for translation into therapeutics were also investigated. In prospect, high efficacy and low toxicity drugs that are selectively targeting histone modifications are required to completely reverse CLD and prevent the development of liver cirrhosis and malignancy.

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been basically under control in China since March 2020, but the import of domestic SARS-CoV-2 has begun to increase. This study reported the first case of asymptomatic SARS-CoV-2 infection imported from Spain into Sichuan Province, China, on March 11, 2020. The infected male had a body temperature of 37.5°C, normal blood oxygen saturation levels, and a computed tomography (CT) examination showed that his lungs had no shadows. However, a throat swab from the subject tested positive for SARS-CoV-2 using qPCR assay. In this study, we conducted transcriptome sequencing on respiratory throat swabs from the subject and found that the dominant SARS-CoV-2 sequence (Gene Bank ID: MW301121) was a spike protein D614G mutant strain, which is currently popular throughout world. We downloaded and analyzed SARS-CoV-2 sequences collected from cases in China and Spain for comparison and tracing purposes. After March 11, 2020, the Chinese domestic clade was naturally divided into the imported SARS-CoV-2 D614G mutant strain and evolutionarily-related similar sequences and that of sequences collected in the original Wuhan area. The sequence reported in this study was located on a small branch, far from the evolution of Wuhan sequences. As expected, the identified sequence was closely related to the evolution of the SARS-CoV-2 D614G mutant strain circulating in Spain.

In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.

Breast cancer is the most common malignant tumor in women, and its incidence is increasing each year. To effectively treat breast cancer, it is important to identify genes involved in its occurrence and development and to exploit them as potential drug therapy targets. Here, we found that potassium channel subfamily K member 6 (KCNK6) is significantly overexpressed in breast cancer, however, its function in tumors has not been reported. We further verified that KCNK6 expression is upregulated in breast cancer biopsies. Moreover, overexpressed KCNK6 was found to enhance the proliferation, invasion, and migration ability of breast cancer cells. These effects may occur by weakening cell adhesion and reducing cell hardness, thus affecting the malignant phenotype of breast cancer cells. Our study confirmed, for the first time, that increased KCNK6 expression in breast cancer cells may promote their proliferation, invasion, and migration. Moreover, considering that ion channels serve as therapeutic targets for many small molecular drugs in clinical treatment, targeting KCNK6 may represent a novel strategy for breast cancer therapies. Hence, the results of this study provide a theoretical basis for KCNK6 to become a potential molecular target for breast cancer treatment in the future.

Circular RNAs (circRNAs) are a novel type of non-coding RNAs. Because of their characteristics of a closed loop structure, disease- and tissue-specificity, and high conservation and stability, circRNAs have the potential to be biomarkers for disease diagnosis. Head and neck cancers are one of the most common malignant tumors with high incidence rates globally. Affected patients are often diagnosed at the advanced stage with poor prognosis, owing to the concealment of anatomic sites. The characteristics, functions, and specific mechanisms of circRNAs in head and neck cancers are increasingly being discovered, and they have important clinical significance for the early diagnosis, treatment, and prognosis evaluation of patients with cancer. In this study, the generation, characteristics, and functions of circRNAs, along with their regulatory mechanisms in head and neck cancers have been summarized. We report that circRNAs interact with molecules such as transcription and growth factors to influence specific pathways involved in tumorigenesis. We conclude that circRNAs have an important role to play in the proliferation, invasion, metastasis, energy and substance metabolism, and treatment resistance in cancers.

Stress is an inevitable part of life. Chronic stress on account of reasons like adversity, depression, anxiety, or loneliness/social isolation can endanger human health. Recent studies have shown that chronic stress can induce tumorigenesis and promote cancer development. This review describes the latest progress of research on the molecular mechanisms by which chronic stress promotes cancer development. Primarily, chronic stress activates the classic neuroendocrine system [the hypothalamic-pituitary-adrenal (HPA) axis] and the sympathetic nervous system (SNS) and leads to a decline and dysfunction of the prefrontal cortex and the hippocampus under stress. Stress hormones produced during the activation of both the HPA axis and the SNS can promote tumorigenesis and cancer development through a variety of mechanisms. Chronic stress can also cause corresponding changes in the body's immune function and inflammatory response, which is significant because a long-term inflammatory response and the decline of the body's immune surveillance capabilities are implicated in tumorigenesis. Stress management is essential for both healthy people and cancer patients. Whether drugs that limit the signaling pathways downstream of the HPA axis or the SNS can suppress chronic stress-induced cancers or prolong patient survival deserves further study.

The intestinal tract is the largest digestive organ in the human body. It is colonized by, and consistently exposed to, a myriad of microorganisms, including bifidobacteria, lactobacillus, Escherichia coli, enterococcus, clostridium perfringens, and pseudomonas. To protect the body from potential pathogens, the intestinal tract has evolved regional immune characteristics. These characteristics are defined by its unique structure, function, and microenvironment, which differ drastically from those of the common central and peripheral immune organs. The intestinal microenvironment created by the intestinal flora and its products significantly affects the immune function of the region. In turn, specific diseases regulate and influence the composition of the intestinal flora. A constant interplay occurs between the intestinal flora and immune system. Further, the intestinal microenvironment can be reconstructed by probiotic use or microbiota transplantation, functioning to recalibrate the immune homeostasis, while also contributing to the treatment or amelioration of diseases. In this review, we summarize the relationship between the intestinal flora and the occurrence and development of diseases as an in-turn effect on intestinal immunity. We also discuss improved immune function as it relates to non-specific and specific immunity. Further, we discuss the proliferation, differentiation and secretion of immune cells, within the intestinal region following remodeling of the microenvironment as a means to ameliorate and treat diseases. Finally, we suggest strategies for improved utilization of intestinal flora.

Background and Objective: Inhibition of thrombosis and platelet aggregation through a thromboxane synthetase inhibitor proved to be an effective and promising treatment for cardiovascular and/or cerebrovascular disease (CCVD) patients. This phase I study evaluated the safety, tolerability, and pharmacokinetics of sodium pyragrel, a novel thromboxane A2 synthetase inhibitor, in healthy volunteers.Methods: A total of 84 healthy Chinese volunteers were enrolled in the study and randomized into one of five dosing regimens of intravenous pyragrel, which were single ascending dose (30 to 300 mg), multiple doses (pyragrel 180 mg once daily on Day 1 and Day 6, twice daily from Day 2 to Day 5), 3×3 Latin square crossover (60, 120, 240 mg), and a continuous dose (360 mg in 24 h), respectively. Plasma concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis.Results: The maximum plasma concentrations of pyragrel were essentially reached at the end of the 3 h infusion. The pharmacokinetic process of pyragrel and two main metabolites (BBS and BJS) is linear over the 30–300 mg dose range, with no significant accumulation on multiple doses. The urinary excretion of pyragrel accounted for more than 70% of the total drug amount. Preliminary pharmacodynamic results demonstrated that the production of urinary 11-D-HTXB2 was time- and dose-dependently inhibited by single i.v. dose of pyragrel.Conclusions: Pyragrel was well tolerated after single ascending doses up to 300 mg, multiple doses of 180 mg, and continuous administration of 360 mg within 24 h. No drug-related, serious adverse drug reactions occurred during the five-part study. The most common pyragrel-related adverse events (AEs) were total bilirubin (TB)/direct bilirubin (DB) elevations with a relatively low incidence rate and seemed to be dose independent. Given the acceptable safety and appropriate pharmacokinetic properties of sodium pyragrel proven in this study, continued clinical development is warranted. The study was registered at http://www.chictr.org.cn (ChiCTR-IID-16010159).

Brain-derived neurotrophic factor (BDNF) is essential for cognitive and memory functions. Abnormal BDNF expression in the central nervous system may impair these functions. Anaesthesia and surgery can induce perioperative neurocognitive disorders (PND). Clinical studies show that BDNF expression is decreased in patients presenting with cognitive impairment after anaesthesia and surgery. However, the molecular mechanism is still unclear. Epigenetic regulation plays an important role in cognition. The hypermethylation of H3K9 is crucial for transcriptional silencing and the onset of cognitive disorders. Here, we hypothesised that H3K9 trimethylation repressed BDNF expression and impaired memory formation or recall during anaesthesia and surgery. Laparotomy under isoflurane inhalation anaesthesia, behavioural tests, Western blotting, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation (ChIP), and immunohistochemistry were used in this study. BDNF expression was decreased in the hippocampus after anaesthesia and surgery. Cognitive impairment affected memory formation but not recall. The trimethylation of H3K9 downregulated BDNF expression. The overexpression of BDNF or use of exogenous BDNF improved the impairment of memory formation caused by anaesthesia and surgery. Therefore, inhibiting H3K9 trimethylation and increasing the expression of BDNF may help prevent PND in the clinical setting.