PPARγ alleviates preeclampsia development by regulating lipid metabolism and ferroptosis.

The study aims to explore the effect of PPARγ signaling on ferroptosis and preeclampsia (PE) development. Serum and placental tissue are collected from healthy subjects and PE patients. The PPARγ and Nrf2 decreases in the PE. Rosiglitazone intervention reverses hypoxia-induced trophoblast ferroptosis and decreases lipid synthesis by regulating Nfr2 and SREBP1. Compared to the Hypoxia group, the migratory and invasive abilities enhance after rosiglitazone and ferr1 treatment. Rosiglitazone reduces the effect of hypoxia and erastin. The si-Nrf2 treatment attenuats the effects of rosiglitazone on proliferation, migration, and invasion. The si-Nrf2 does not affect SREBP1 expression. PPARγ agonists alleviates ferroptosis in the placenta of the PE rats. The study confirms that PPARγ signaling and ferroptosis-related indicators were dysregulated in PE. PPARγ/Nrf2 signaling affects ferroptosis by regulating lipid oxidation rather than SREBP1-mediated lipid synthesis. In conclusion, our study find that PPARγ can alleviate PE development by regulating lipid oxidation and ferroptosis.

The mediating role of AKT/ERK/JNK signaling on the malignant phenotype of microcystin-LR in gastric adenocarcinoma cells.

Microcystin-leucine arginine (MC-LR), a widely distributed and highly toxic environmental pollutant, plays crucial roles in cancer malignancy by activating characteristically toxic signaling pathways. Traditional animal-based toxicity evaluation methods have proven insufficient for identifying the specific role of these signaling pathways. Therefore, this study aimed to uncover the regulatory relationship between the toxic pathways and the progression of gastric cancer (GC). The findings provide novel avenues for conducting in vitro toxicity tests based on the investigated pathways. We found that MC-LR promoted the migration and invasion of SGC-7901 cells while simultaneously inhibiting their apoptosis in a dose-dependent manner. This observed cytotoxicity was primarily mediated through the AKT, JNK, and ERK signaling pathways. By using a mediation analysis model, we determined that AKT and ERK exhibited competitive effects in MC-LR-treated GC malignancy, while AKT and JNK acted independently from one another. This study establishes an in vitro toxicity test model of MC-LR based on toxicity-related pathways and underscores the pivotal roles of AKT, ERK, and JNK signaling in MC-LR toxicity. The findings offer a novel, fundamental framework for conducting chemical toxicity risk assessment.

Lipopolysaccharide exacerbates to the migration, invasion, and epithelial-mesenchymal transition of esophageal cancer cells by TLR4/NF-κB axis.

Previous studies have shown the role of bacterial lipopolysaccharide (LPS) in promoting tumor progression. Our previous study found that the community richness of LPS-producing bacteria was significantly increased in the fresh stool samples of esophageal cancer (EC) patients, but the relative LPS levels and underlying mechanism in EC progression remain unknown. In this study, an case-control study found that the content of LPS was higher in serum of EC patients. Functional experiments of CCK8 assay and transwell assay showed that LPS contributed to the proliferation, migration, invasion of EC109 cells. Meanwhile, LPS induced EC109 to secrete IL-6 and TGF-ß1. Western blot analysis revealed the level of TLR4 and NF-κB increased significantly after LPS treatment. Epithelial marker E-cadherin was significantly down-regulated and interstitial marker N-cadherin and Vimentin were up-regulated after LPS treatment. However, TAK242 (TLR4 inhibitor) or PDTC (NF-κB inhibitor) could eliminate the inflammatory and EMT-promoting effects of LPS. In total, our results suggested that LPS exacerbated to the migration, invasion, and epithelial-mesenchymal transition of EC109 cells by TLR4/NF-κB axis. High level LPS may have a critical effect on the occurrence and development of EC.

Progesterone Enhances the Invasion of Trophoblast Cells by Activating PI3K/AKT Signaling Pathway to Prevent Preeclampsia.

We aimed to explore whether the effect of progesterone on preeclampsia via the PI3K/AKT signaling pathway. First, we studied the role of progesterone in preeclampsia patients and HTR-8/Svneo cells by adding progesterone. Then PI3K inhibitor LY294002 was added. The effects of progesterone on preeclampsia were also studied in animals by constructing a preeclampsia rat model. CCK-8 and Transwell assay were applied to measure cell viability and invasion ability. ELISA was performed to measure progesterone, MMP-2, MMP-9, pro-inflammatory factors TNF-α, IL-1ß, and anti-inflammatory factors IL-4, IL-10, and IL-13 levels. HE staining was used to detect the pathological changes in uterine spiral artery. Western blot was performed to detect Cyclin D1, PCNA, MMP-2, MMP-9, inflammatory factors TNF-α, IL-1ß, IL-4, IL-10, IL-13, and PI3K/AKT signaling pathway related proteins AKT, p-AKT, PI3K, and p-PI3K expressions. Progesterone could reduce blood pressure and urine protein in pregnant women with preeclampsia. TNF-α and IL-1ß levels were decreased, but IL-4, IL-10, IL-13, cyclin D1, and PCNA levels were increased in pregnant women with preeclampsia after using progesterone. After the use of progesterone, the symptoms of the PE model group were improved. Among them, the lumen of the placental uterine spiral artery was enlarged, and the fibrinoid necrosis of the uterine wall and acute atherosclerotic lesions were relieved. In addition, progesterone promoted HTR-8/Svneo cells proliferation and invasion. However, high expression of MMP-2, MMP-9, p-AKT, and p-PI3K in Normal and preeclampsia groups caused by progesterone was weakened after adding LY294002, indicating that progesterone could activate PI3K/AKT signaling pathway to regulate HTR-8/Svneo cells. Progesterone decreased urine protein and blood pressure of preeclampsia rats in a concentration-dependent manner. Moreover, progesterone activated the PI3K/AKT signaling pathway and inhibited the inflammatory response in preeclampsia rats.

Comprehensive proteomic and phosphoproteomic reveal that Microcystin-LR contributed to the malignant progression of gastric cancer by estrogenic potency.

The widespread cyanotoxins in drinking water pose a threat to public health induced by Microcystins (MCs). MC-LR, a predominant toxic form of MCs, has been found to play critical roles in cancer progression. The role of MC-LR in hepatocarcinogenesis has attracted extensive attention. However, as a critical digestive organ, the precise mechanism of MC-LR-induced gastric cancer is still unclear. We found that 100 nM MC-LR promoted the proliferation, migration, invasion, and anti-apoptosis of SGC-7901 cells. Quantitative proteome and phosphoproteome analysis identified differential expression patterns and aberrant pathways of SGC-7901 cells exposed to MC-LR. The results indicated that 48,109 unique peptides from 6320 proteins and 1375 phosphoproteins with 3473 phosphorylation sites were detected after 24 h treatment of MC-LR. Proteome and phosphoproteome conjoint analysis indicated estrogen signaling pathway might play an essential step in MC-LR-treated molecular events. The mechanism underlying these changes may involve MC-LR excessively activating the estrogen signaling pathway by reducing Hsp90 phosphorylation, which results in nucleus translocation of activated ERα and Krt16 overexpression in gastric cells. In general, our results indicate multiple crucial signals triggered by MC-LR, among which MC-LR may promote the development of gastric cancer by exerting estrogenic potency.

Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data.

This study investigated the implication of monitoring hypertensive disorders in pregnancy (HDP) to prevent preeclampsia (PE) in pregnant women of advanced maternal age. Between January 2016 and April 2021, 262 consecutive pregnant women aged ≥40 years were recruited. Extensive monitoring of hypertensive disorders in pregnancy, including blood hypercoagulability screening and subsequent interventions, was performed in 129 pregnant women in our university hospital. The remaining 133 patients from other centres, who did not receive antenatal maternal pregnancy screening and preventive intervention during the same period, constituted the non-intervention group enabling comparison to mimic a trial. The incidences of hypertensive disorders, mild and severe PE, eclampsia, and chronic hypertension complicated by PE in the intervention group were significantly lower than in the non-intervention group (10.08 versus 20.30%, 8.52 versus 18.80%, 7.75 versus 21.05%, 0 versus 3.01%, and 3.86 versus 15.04%, respectively; P < 0.05). Premature birth, low birth weight, and foetal loss were significantly rarer in the intervention group than in the non-intervention group (6.98 versus 24.81%, 7.75 versus 21.80%, and 0.78 versus 14.29% respectively; P < 0.001). The comparison of MP with routine blood coagulation biochemical examination found that the MP detection system of Beijing Yes Medical Devices Co., Ltd., had similar sensitivity as thromboelastogram. Still, it was significantly better than the routine biochemical indicators (P < 0.01). Based on MP parameters, early anticoagulant treatment with low-molecular-weight heparin or low-dose aspirin in pregnant women with hypercoagulability can effectively prevent the occurrence of PE and significantly improve the prognosis of both mothers and infants.

A novel small molecule inhibitor of human Drp1.

Mitochondrial dynamin-related protein 1 (Drp1) is a large GTPase regulator of mitochondrial dynamics and is known to play an important role in numerous pathophysiological processes. Despite being the most widely used Drp1 inhibitor, the specificity of Mdivi-1 towards human Drp1 has not been definitively proven and there have been numerous issues reported with its use including off-target effects. In our hands Mdivi-1 showed varying binding affinities toward human Drp1, potentially impacted by compound aggregation. Herein, we sought to identify a novel small molecule inhibitor of Drp1. From an initial virtual screening, we identified DRP1i27 as a compound which directly bound to the human isoform 3 of Drp1 via surface plasmon resonance and microscale thermophoresis. Importantly, DRP1i27 was found to have a dose-dependent increase in the cellular networks of fused mitochondria but had no effect in Drp1 knock-out cells. Further analogues of this compound were identified and screened, though none displayed greater affinity to human Drp1 isoform 3 than DRP1i27. To date, this is the first small molecule inhibitor shown to directly bind to human Drp1.

Visual analysis of the research trend and status on the association between vitamin D and immunity: From 2012 to 2021.

Objective: We conducted this study to visualize hot spots and trends in the correlation between vitamin D and immunity over the past decade with bibliometric analysis. Methods: We collected relevant articles in the Web of Science Core Collection from 2012 to 2021 as the data source, and then used CiteSpace software to perform the data analysis. Some graphics were done with Graphpad software. Results: A total of 1,656 articles were retrieved, with an average citation count of 25.2 times. The United States (439 articles, 26.51%) has the top number of published articles, followed by China (164 articles, 9.90%), England (135 articles, 8.15%), Italy (114 articles, 6.88%), and India (82 articles, 4.95%). The most literature is found in areas of Immunology (337 articles, 20.35%) and Biochemistry Molecular Biology (179 articles, 10.81%). In terms of institutions, the top five institutions with the highest number of publications all belong to Europe. Among them, the League of European Research Universities (LERU) (121, 7.31%) has a greater proportion of output articles. The United States Department of Health Human Services (225, 13.59%) and National Institutes of Health United States (223, 13.47%) funded most articles. The leading five authors with the largest number of publications were Hewison M (19, 1.15%), Bergman P (14, 0.85%), Agerberth B (13, 0.76%), Carlberg C (12, 0.73%), and White JH (12, 0.73%). The top five keywords with the highest co-occurrence frequency are "vitamin d" (367), "d deficiency" (217), "expression" (195), "association" (151), and "d receptor" (132). Among the 17 keyword clusters, the largest cluster is #0 "diet." Despite cluster #13 "covid-19," most of the clusters were conducted the studies before 2012. Conclusion: The overall development of research in this field is promising. Western developed countries made outstanding contributions in this area and still take the leading role. But the participation of developing and low-income countries is also impressive. The potential therapeutic effects of vitamin D in immune-related diseases have been noted, especially in multiple sclerosis, COVID-19, etc. This is also the focus and frontier of current research. However, there is still no consensus conclusion in this field. Further research is needed in the future.

miR-2115-3p inhibits ferroptosis by downregulating the expression of glutamic-oxaloacetic transaminase in preeclampsia.

INTRODUCTION: Recently, ferroptosis has been reported to be closely related to preeclampsia (PE). However, the mechanisms associated with ferroptosis in PE have been poorly studied. METHODS: A PE rat model was established via reduced uterine perfusion pressure (RUPP) surgery. A Ferroptosis inhibitor was used to treat the model rats. Blood pressure, urine protein, sFlt-1, GSH, GSH-PX, MDA, total Fe, Fe (II), and Fe (Ⅲ) levels were detected. Placenta morphological changes and fetal survival rate were observed and counted, respectively. miRNA sequencing and bioinformatical analysis were conducted to establish the ferroptosis-related interaction network of miRNAs-mRNAs in PE. After hypoxia treatment, cells were silenced glutamic-oxaloacetic transaminase1 (GOT1) or overexpressed miR-2115-3p/GOT1. Cellular proliferation, invasion, and reactive oxygen species (ROS) were determined. The ferroptosis-related factors levels (ACSL4, TfR1, GPX4, SCL7A11, GSH, GSH-PX, Fe (II), and MDA) were quantified. RESULTS: In vivo, ferrostatin-1 attenuated ferroptosis in the PE models, significantly increasing fetal survivability. The miR-2115-3p/GOT1 pathway was screened for possible association with abnormal ferroptosis in PE. miR-2115-3p was discovered to interact with the mRNA of GOT1. Inhibition of GOT1 and overexpression of miR-2115-3p reversed the decrease in cell proliferation capacity, GSH, GSH-PX, and GPX4 levels, and the increase in ROS, ACSL4, TfR1, MDA, total Fe, and Fe (II) levels induced by hypoxia. However, simultaneous overexpression of miR-2115-3p and GOT1 reversed the above results of overexpression of miR-2115-3p. DISCUSSION: miR-2115-3p might interact with the GOT1 mRNA to downregulate its expression, further inhibiting the hypoxia-promoted ferroptosis in a PE model.

Mitochondrial Dynamin-Related Protein Drp1: a New Player in Cardio-oncology.

PURPOSE OF REVIEW: This study is aimed at reviewing the recent progress in Drp1 inhibition as a novel approach for reducing doxorubicin-induced cardiotoxicity and for improving cancer treatment. RECENT FINDINGS: Anthracyclines (e.g. doxorubicin) are one of the most common and effective chemotherapeutic agents to treat a variety of cancers. However, the clinical usage of doxorubicin has been hampered by its severe cardiotoxic side effects leading to heart failure. Mitochondrial dysfunction is one of the major aetiologies of doxorubicin-induced cardiotoxicity. The morphology of mitochondria is highly dynamic, governed by two opposing processes known as fusion and fission, collectively known as mitochondrial dynamics. An imbalance in mitochondrial dynamics is often reported in tumourigenesis which can lead to adaptive and acquired resistance to chemotherapy. Drp1 is a key mitochondrial fission regulator, and emerging evidence has demonstrated that Drp1-mediated mitochondrial fission is upregulated in both cancer cells to their survival advantage and injured heart tissue in the setting of doxorubicin-induced cardiotoxicity. Effective treatment to prevent and mitigate doxorubicin-induced cardiotoxicity is currently not available. Recent advances in cardio-oncology have highlighted that Drp1 inhibition holds great potential as a targeted mitochondrial therapy for doxorubicin-induced cardiotoxicity.

Bibliometric analysis of the global research status and trends of the association between Vitamin D and infections from 2001 to 2021.

Objective: The objective of this study was the visualization of hot spots and evolving trends in research on the association between vitamin D and infections through the use of bibliometric analysis. Methods: Based on 3046 relevant articles collected in the Web of Science Core Collection for the period of 2001-2021, the data were processed using CiteSpace software. GraphPad software was used for some of the graphics. Results: A total of 3,046 literature were retrieved, with an average citation frequency of 27.89 times. The number of published papers in the direction of "Immunology" (453 articles, 14.9%) and "Infectious diseases" (312 articles, 10.2%) is much higher. The United States presents the highest publication count (890, 29.2%) and shows a strong leadership in this field. Country burst shows that since 2015, many developing countries and low-income countries have carried out enthusiastic research in this regard, including China, Pakistan, and Iran. As for institutions, the League of European Research Universities produces a larger proportion of articles (220, 7.2%). In terms of authors, Martineau AR and Camargo CA have the highest number of published articles, contributing 30 (0.99%) and 28 articles (0.92%), respectively. Major studies are supported by the United States Department of Health Human Services funding (394, 12.9%). According to the keyword co-occurrence diagram, the 10 most frequent keywords from 2001 to 2021 are "vitamin D", "infection", "d deficiency", "risk", "association", "expression", "disease", "d supplementation", "vitamin d deficiency", and "children". The top 10 cited articles in 2021 are all related to COVID-19, suggesting it is a hotspot in recent times. Conclusion: Research on the association between vitamin D and infection has grown rapidly since 2012 and is generally developing well. While developed Western countries continue to be leading roles in this field, research trends in developing countries are also very promising. It is demonstrated that the relationship between vitamin D and respiratory infections, especially respiratory viruses and the more recently COVID-19, has received a lot of attention in the last two decades, suggesting that this is the hotspot and frontier of research issue.

Diverse viromes in polar regions: A retrospective study of metagenomic data from Antarctic animal feces and Arctic frozen soil in 2012-2014.

Antarctica and the Arctic are the coldest places, containing a high diversity of microorganisms, including viruses, which are important components of polar ecosystems. However, owing to the difficulties in obtaining access to animal and environmental samples, the current knowledge of viromes in polar regions is still limited. To better understand polar viromes, this study performed a retrospective analysis using metagenomic sequencing data of animal feces from Antarctica and frozen soil from the Arctic collected during 2012-2014. The results reveal diverse communities of DNA and RNA viruses from at least 23 families from Antarctic animal feces and 16 families from Arctic soils. Although the viral communities from Antarctica and the Arctic show a large diversity, they have genetic similarities with known viruses from different ecosystems and organisms with similar viral proteins. Phylogenetic analysis of Microviridae, Parvoviridae, and Larvidaviridae was further performed, and complete genomic sequences of two novel circular replication-associated protein (rep)-encoding single-stranded (CRESS) DNA viruses closely related to Circoviridae were identified. These results reveal the high diversity, complexity, and novelty of viral communities from polar regions, and suggested the genetic similarity and functional correlations of viromes between the Antarctica and Arctic. Variations in viral families in Arctic soils, Arctic freshwater, and Antarctic soils are discussed. These findings improve our understanding of polar viromes and suggest the importance of performing follow-up in-depth investigations of animal and environmental samples from Antarctica and the Arctic, which would reveal the substantial role of these viruses in the global viral community.

Alterations in the Gut Microbiome of Individuals With Tuberculosis of Different Disease States.

Objective: There is evidence that the gut microbiota play a regulatory role in the occurrence and progression of tuberculosis. The purpose of the current study was to explore the alterations in gut microbiome under different tuberculosis disease stages in the Uyghur population, clarify the composition of microbial taxonomy, search for microbial biomarkers and provide innovative ideas for individual immune prevention and for control strategies. Design: A case-control study of Uyghur individuals was performed using 56 cases of pulmonary tuberculosis (PTB), 36 cases of latent tuberculosis infection (LTBI) and 50 healthy controls (HC), from which stool samples were collected for 16S rRNA gene sequencing. Results: The results showed that the alpha diversity indexes of the PTB group were lower than those of the other two groups (P <0.001), while only observed species were different between LTBI and HC (P <0.05). Beta diversity showed differences among the three groups (P = 0.001). At the genus level, the relative abundance of Bifidobacterium and Bacteroides increased, while Roseburia and Faecalibacterium decreased in the PTB group, when compared with the other two groups, but the changes between the LTBI and HC groups were not significant. The classifier in the test set showed that the ability of the combined genus to distinguish between each two groups was 81.73, 87.26, and 86.88%, respectively, and the validation efficiency was higher than that of a single screened genus. Conclusion: The gut microbiota of PTB patients was significantly disordered compared with LTBI and HC, while the changes of LTBI and HC were not significant. In the future, gut microbiota could be used as a non-invasive biomarker to assess disease activity.

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance.

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.

Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series.

In this study, a treatment method was assessed for the prevention and treatment of postpartum bleeding after combined surgery in patients having late pregnancy with the complication of acute Stanford type A aortic dissection. The clinical records of ten patients receiving treatment at the Second Xiangya Hospital of Central South University between March 2012 and March 2021 were retrospectively analysed. All patients were diagnosed with acute Stanford type A aortic dissection according to computed tomography angiography of the thoracic and abdominal aorta. Aortic valve function was assessed using two-dimensional echocardiography. All patients experienced uterine-incision delivery under systemic anaesthesia. During the operation, intrauterine Bakri balloon tamponade and cervical cerclage were performed. Postpartum bleeding was effectively controlled for all patients. The extracorporeal circulation time was 230-295 min, the postpartum 24 h bleeding volume was 500-870 mL, the volume of physiological saline injected into the balloon was 290-515 mL, and the intrauterine balloon compression time was 28-51 h. No postpartum bleeding occurred. A 42-days follow-up showed no late postpartum bleeding, poor uterine incision healing, or puerperal infection, and no uterine removal was performed. Intrauterine Bakri balloon tamponade plus cervical cerclage can effectively prevent intra- and postoperative postpartum bleeding in pregnant patients with aortic dissection.

Tumor purity as a prognosis and immunotherapy relevant feature in cervical cancer.

BACKGROUND: Tumor purity plays a vital role in the biological process of solid tumors, but its function in gynecologic cancers remains unclear. This study explored the correlation between tumor purity and immune function of gynecological cancers and its reliability as a prognostic indicator of immunotherapy. METHODS: Gynecological cancer-related datasets were downloaded from The Cancer Genome Atlas (TCGA). Tumor purity was calculated by the ESTIMATE algorithm. A LASSO Cox regression analysis was performed to construct the risk score model. A Kaplan-Meier Plotter was used to explore the relationships between tumor purity and cancer prognosis. We performed the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) to explore the pathways in the subgroups. A nomogram was used to quantitatively assess the cancer prognosis. RESULTS: Tumor purity was negatively correlated with B cell infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Approximately 420 genes were positively associated with B cell infiltration and CESC prognosis and were enriched in immune-related signaling pathways. There were 11 key genes used to construct a risk score model. The low-risk group had a higher immune score and better prognosis than the high-risk group. A nomogram based on risk score, T stage, and clinical-stage had good predictive value in quantitatively evaluating CESC prognosis. CONCLUSIONS: This study is the first to reveal the correlation between tumor purity and immunity in CESC and suggests that low-risk patients may be more sensitive to immunotherapy. This provides a theoretical basis for the clinical treatment of CESC.

Association of gut microbiomes with lung and esophageal cancer: a pilot study.

Gut microbiota, especially human pathogens, has been shown to be involved in the occurrence and development of cancer. Esophageal squamous cell carcinoma and lung cancer are two malignant cancers, and their relationship with gut microbiota is still unclear. Virulence factor database (VFDB) is an integrated and comprehensive online resource for curating information about human pathogens. Here, based on VFDB database, we analyzed the differences of bacteria at genus level in the gut of patients with esophageal squamous cell carcinoma, lung cancer, and healthy controls. We proposed the possible cancer-associated bacteria in gut and put forward their possible effects. Apart from this, principal coordinate analysis (PCoA) and analysis of similarities (ANSOIM) suggested that some bacteria in the gut can be used as potential biomarkers to screen esophageal squamous cell carcinoma and lung cancer, and their effectiveness was preliminary verified. The relative abundance of Klebsiella and Streptococcus can be used to distinguish patients with esophageal squamous cell carcinoma and lung cancer from healthy controls. The absolute abundance of Klebsiella can further distinguish patients with esophageal squamous cell carcinoma from patients with lung cancer. In particular, the relative abundance of Fusobacterium can directly distinguish between patients with esophageal squamous cell carcinoma and healthy controls. Additionally, the absolute abundance of Haemophilus can distinguish lung cancer from healthy controls. Our study provided a new way based on VFDB database to explore the relationship between gut microbiota and cancer, and initially proposed a feasible cancer screening method.

Driving after alcohol consumption: A qualitative analysis among Chinese male drunk drivers.

In China, alcohol-related impaired driving has been perceived as a crucial contributor to traffic accidents. However, the topic of driving after alcohol consumption is still understudied in the country. To fill this void, the aim of this study was to find out male drivers' unique experiences of drunk driving in China. A qualitative analysis was adopted based on semi-structured interviews with 38 Chinese male drunk drivers who were serving community corrections. The findings of this study revealed that, being regular alcohol consumers, Chinese male drunk drivers had very little knowledge of the impairment caused by alcohol intake on driving. They mostly underestimated alcohol's negative influence on their driving ability and were overconfident that they would have a safe drive and would not be involved in any traffic accidents after consuming alcohol. In addition, most participants of this study reported that there was very little possibility that they would be arrested after fully assessing the situation and implementing strategies to avoid detection by traffic police. All these reasons affected these men's decision to drive drunk. Several criminological theories are applied to explain the findings and implications are finally recommended to reduce the possibility of drunk driving among Chinese men.

Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195).

The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.