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Uterine fibroids (UFs) are the most common benign gynecological tumor and greatly affect reproductive health in women of reproductive age. Some studies have indicated an association between UFs and several cardiovascular disease (CVD) risk factors. To determine whether UFs are associated with increased blood pressure, we performed a cross-sectional study and meta-analysis. In the cross-sectional study, 8401 participants who underwent a physical examination at the First Affiliated Hospital of Shantou University Medical College from June 2011 to June 2013 were divided into a uterine fibroid group (1617 cases) and a control group (6784 cases) to assess the relationship between UFs and blood pressure. Then, we conducted a systematic review to confirm the results. The cross-sectional study showed that UFs were associated with an increased rate of elevated blood pressure [OR = 1.35, 95% confidence interval (CI): 1.016-1.792]. The meta-analysis revealed a significant association between UFs and the prevalence of hypertension [pooled OR = 1.44, 95% CI: 1.17-1.75, P = 0.0004; I

Background: Recent studies have demonstrated a correlation between intestinal flora and the severity of myocardial infarction as well as post-myocardial infarction repair. However, few studies have investigated whether probiotics reduce mortality and improve cardiovascular outcomes in patients with acute myocardial infarction. In this study, we will conduct a randomized controlled trial (RCT) to evaluate the effect of probiotics on in-hospital mortality and incidence of major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). Methods: This is an open-label, randomized, controlled, superiority clinical trial involving 2594 adult patients who diagnosed with acute myocardial infarction. Patients will be randomized to (1)receive bifidobacteria triple viable capsule (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) 840 mg, twice a day, plus standard treatment strategy during the hospital stay , for a maximum of 30 days, or (2)receive the standard treatment strategy and will not take the bifidobacterium triple live capsule. The primary outcome was in-hospital all-cause mortality. Discussion: The purpose of this clinical trial is to determine whether probiotics can reduce in-hospital mortality and improve prognosis in patients with AMI, and the results will provide evidence for probiotics as a complementary treatment for AMI. Trial registration: Chinese Clinical Trials Registry ChiCTR2000038797. Registered on 2 October 2020.

SummaryAs drilling sections become deeper and longer, transferring more weight downhole to improve rate of penetration is the primary concern for the operator. Drillstring dynamics and buckling are some primary limiters for drilling efficiency. Aggressive drilling parameters may lead to severe downhole dynamics, which leads to cutter breakage and tool damage. When axial compression exceeds a certain threshold, the drillstring buckles sinusoidally inside the wellbore first, followed by helical buckling. Buckling leads to accelerated joint wear, tool fatigue failures, and lower drilling efficiency. To better manage drillstring dynamics and buckling, we propose a method of simulating drillstring dynamics motion and postbuckling state using an advanced transient dynamics model.An analysis methodology was developed on the basis of the finite element transient dynamics model. The model captures the enriched physics of drillstring dynamics and loading: the large deformation of buckled drillstring, the strong nonlinearity of contact and friction forces, and the dynamically triggered instability caused by drilling rotation. Transient dynamics simulations are conducted for drillstring with the actual well trajectory and rotation speed. The weight on bit (WOB) is ramped up gradually, and the drillstring deformation is monitored to detect the onset of buckling or dynamics instability.To conduct the model validation, the buckling inception loads predicted by the model are compared against the analytical equation of critical buckling loads. A field extended reach drilling (ERD) job was simulated by the model. The downhole weight and torque data from the measurement-while-drilling (MWD) tool was used to validate the weight transfer prediction by the model. Most existing buckling theories use the analytical equations of critical buckling load, which were normally derived on the basis of the idealized assumptions, such as perfect wellbore shape and uniform tubular geometry. The proposed method simulates the drillstring behaviors in the field drilling conditions and aims to capture effects of wellbore friction and string rotation. The transient dynamics model is capable of simulating drillstring dynamics movement (whirling and snaking) and weight lockup under severe helical buckling. An automatic method is proposed to interpret the drillstring behaviors from the simulation results. Using the transient dynamics model, the procedure presented in this article can simulate the dynamics and buckling behaviors of drillstring and help mitigate associated risks in well-planning and execution phases.

Prophenoloxidase (PPO), an important immunity protein in insects, is mainly produced by hemocytes and released into the hemolymph upon cell lysis. In addition, PPO can also be produced by epidermal cells in the foregut to detoxify the toxic plant secondary metabolites and in the hindgut to kill pathogens through PPO-induced melanization. Previously, we noticed a pair of tubes extended from the larval hindgut became melanized upon staining in dopamine dissolved in 30% ethanol. However, the structure and function of these tubes are largely unknown. In this study, we performed staining of the tubes and the neighboring Malpighian tubule for further confirmation. Eventually, we detected PPO inside epidermal cells of the tubes, and called them as PPO-positive tubes. We observed that the PPO-positive tubes are physically derived from the hindgut but strongly adhere to the Malpighian tubule. Inside the PPO-positive tubes, there is an acellular peritrophic membrane to protect the epidermal cells. Furthermore, the PPO-positive tubes act like a doorkeeper to firstly detoxify the metabolite wastes collected by the Malpighian tubule from the hemolymph.

John Lee, Rongbing Chen, T Mohanakumar, Ross Bremner, Sumeet Mittal, Timothy P Fleming Norton Thoracic Institute, St. Joseph Hospital, Phoenix, AZ, USACorrespondence: Timothy P FlemingSt. Joseph’s Hospital and Medical Center, Norton Thoracic Institute, 124 W. Thomas Road, Suite 105, Phoenix, AZ, 85013, USATel +1 314-960-2331Email Timothy.Fleming@commonspirit.orgIntroduction: Esophageal cancer (EC) is an aggressive cancer type that is increasing at a high rate in the US and worldwide. Extensive sequencing of EC specimens has shown that there are no consistent driver mutations that can impact treatment strategies. The goal of this study was to identify activated tyrosine kinase receptors (TKRs) in EC samples as potential targets in the treatment of EC.Methods: Activated tyrosine kinase receptors were detected using a dot-blot array for human TK receptors. Human esophageal cancer cell lines were transplanted into immunocompromised mice, and tumor xenografts were subjected to tyrosine kinase inhibitors based on the dot-blot array data.Results: Using the OE33 esophageal cancer cell line, we identified activated EGF receptor (EGFR), as well as ErbB2 and ErbB3. Treatment of this cell line with erlotinib, a specific inhibitor of EGFR, did not impact the growth of this tumor cell line. Treating the OE33 cell line with afatinib, a pan-EGFR family inhibitor resulted in the growth inhibition of OE33, indicating that the ErbB2 and ErbB3 receptors were contributing to tumor cell proliferation. Afatinib treatment of mice growing OE33 tumors inhibited growth of the OE33 tumor cells.Discussion: Activated tyrosine kinase receptors were readily detected in both cancer cell lines and human esophageal cancer samples. By identifying the activated receptors and then using the appropriate tyrosine kinase inhibitors, we can block tumor growth in vitro and in animal xenografts. We propose that identifying and targeting activated TKRs can be used as a personalized EC tumor treatment strategy.Keywords: tyrosine phosphorylation, tyrosine kinase receptors, esophageal cancer, treatment, kinase inhibitors

As the drilling sections become deeper and longer, transferring more weight downhole to improve ROP is the primary concern to the operator. Drillstring buckling is a primary concern when using very aggressive drilling parameters. Buckling is a phenomenon where the drillstring suddenly loses stability as axial compression exceeds a certain threshold. The drillstring first buckles sinusoidally inside the wellbore which is then followed by helical buckling. Buckling leads to accelerated joint wear, tool fatigue failures, and lower drilling efficiency. To better manage the buckling risk, this paper proposes a method of simulating drillstring buckling inception and post-buckling state using an advanced transient dynamics model. A buckling and post-buckling analysis methodology was developed based on the finite element transient dynamics model. The model captures the enriched physics involved in the buckling phenomenon: the large deformation of buckled drillstring, the strong non-linearity of contact and friction forces, and the dynamically triggered buckling due to drilling rotation. Transient dynamics simulations are conducted for drillstring with the actual well trajectory and rotation speed. Weight on bit (WOB) is ramped up gradually, and the drillstring deformation is monitored to detect the onset of buckling. The post-buckling state is examined to evaluate drilling efficiency and string reliability. To conduct the model validation, an extended reach drilling (ERD) job was analyzed by the model. A measurement while drilling (MWD) tool was deployed in BHA to measure the downhole weight and torque. The simulation implies the helical buckling occurs in drill-pipe and captures the drilling weight and torque loss due to buckled string. Most existing buckling theories use the analytical equations of critical buckling load, which were normally derived based on the idealized assumptions, such as perfect wellbore shape and uniform tubular geometry, but neglect friction and string rotation. The proposed method simulates the drillstring buckling in the actual field drilling conditions. It gives more realistic predictions of buckling inception load and post-buckling configuration. The transient dynamics model is capable of simulating drillstring whirl and weight lockup under the severe helical buckling. Based on the simulated the post buckling configuration of the string, an automatic interpretation method was proposed to detect the buckling mode and location along the drillstring. Using the transient dynamics model, the simulation procedure presented in this paper can significantly improve drillstring buckling and post-buckling predictions and help mitigate buckling risk in well planning and execution phases.

The extensive use of neonicotinoids (NEOs) has caused the release of wide-ranging of residues to the environment and food, and their potential health risks are now receiving more attention. In this study, three surveys were conducted to obtain the overall profiles of NEO residue levels (seven NEOs and one metabolite) in Chinese tea over a period of seven years. A total of 726 tea samples were tested, and nearly 87% of the samples were found to have detectable NEO residues. The overall average detection frequency of acetamiprid was the highest, reaching 73%. Imidacloprid residues in 4.6% of the samples exceeded the Chinese maximum residue limits, whereas clothianidin and nitenpyram had been detected in Chinese tea samples since 2014. The applications of thiacloprid and thiamethoxam gradually increased, and some tea samples with high residue levels appeared in China. These findings signal the replacement of new and old varieties of NEOs in China. Both long- and short-term cumulative exposures to NEOs were calculated based on optimistic and pessimistic models recommended in the EFSA guidelines. In the three survey periods, the average total imidacloprid-equivalent concentrations were 484.63, 1713.36, and 1148.34 μg/kg, respectively. Combined with the refined point estimates and probabilistic models used in this study, the hazard quotients of NEO residues in tea for Chinese tea consumers were found to be low and within the bounds of safety.

In this work, we evaluated two lead compounds, referred to as SG410 and SG430, obtained from a screen of sulfur benzoylphenylurea analogues, against in vitro and in vivo models of pancreas cancer. Both drugs showed a similar mechanism of action profile, with SG410 being more potent as an inhibitor of tubulin assembly. We determined the best in vivo administration schedule and tested SG410 and SG430 in nine cases of a novel platform of direct pancreas cancer xenografts. Both compounds had antiproliferative activity in vitro in the low nanomolar range, but only SG410 showed significant activity in vivo. Administration of SG410 resulted in significant tumor growth delay in five of nine groups tested. In a direct comparison in three of the cases, SG410 was at least as efficacious as docetaxel. We also sought markers that would be predictive of the efficacy of these agents, and we found such a marker in microtubule-associated protein tau (MAPT). This protein enhances the assembly and stability of microtubules. In both the cell lines and the direct human xenografts, MAPT mRNA and protein levels correlated well. There was also a statistically significant inverse correlation between MAPT expression and sensitivity to the tested agents. In summary, the novel sulfur benzoylphenylurea SG410 showed activity inversely related to MAPT expression in a preclinical model of pancreatic cancer comparable with that observed with docetaxel, another microtubule-targeting agent. [Mol Cancer Ther 2007;6(5):1509–16]

In difficult drilling environments, a critical aspect for success is BHA design optimization in the pre-job phase. In previous operations, modeling and run simulations have proven valuable at helping operators improve drilling efficiency (reduce NPT; increase footage/day), produce high-quality log data and properly position the wellbore to increase contact with the reservoir. To further improve modeling accuracy/reliability, a dynamic modeling system was used for BHA analysis. The FEA (finite element analysis)-based system enables engineers to leverage the team's combined expertise and full suite of drilling tools to optimize a BHA for a specific application. Four criteria are used to evaluate BHA performance during simulations: stability; robustness/reliability; measurement quality; steerability. Simulations are run to determine each configuration's potential for axial, lateral/torsional vibration and identify the root cause and dominant mode. To ensure maximum BHA robustness, the loading on BHA components is mapped/rated allowing refinements to increase BHA service life and reduce the potential for costly NPT. Simulations are run to observe the potential for MWD/LWD tool deformation and sag angle to determine the adverse effect sensor motion could have on measurement quality. To mitigate steerability issues, build/walk tendencies are simulated to determine how the BHA will respond to steering command from RSS/PDM. A wide-range of factors can be considered in this procedure. Various cutting structures and steering tools are analyzed and modified as required. The type and location of BHA components are also modeled and re-positioned for optimization purposes. Various drilling scenarios and operating parameters are fed into the system including RPM/WOB, sliding/rotating time, back-reaming and rotating off bottom. Formation characteristics including rock types, friction factor, heterogeneity/homogeneity, degree/amount of interbedding can all be varied to investigate the BHA's corresponding directional implications and vibrational response. All potential BHA designs are evaluated under a set of pre-defined drilling scenarios. A comparative analysis is performed to investigate BHA responses against each specific criterion to identify the optimum BHA configuration. Operating conditions are analyzed for each BHA and an optimal parameter window of minimized BHA shock and vibration is generated with a range of RPM/WOB recommendations. The authors will present several conclusive case studies that document the method's effectiveness and cost reducing capabilities.

This paper provides an efficient approach to classify individual radio-frequency interference in high-frequency radars. By employing empirical mode decomposition as signal pre-process method, stable chaotic characteristics of individual radio-frequency interference are extracted. Based on these stable characteristics and treelike assembly classifier, individual radio-frequency interference can be effectively classified. Detailed real data experiments are finally provided to demonstrate the effectiveness of the proposed method.

Although interleukin 13 (IL-13) is an important mediator of asthma and allergic diseases, the molecular mechanisms regulating IL-13 gene expression are not well understood. This study was designed to define the molecular mechanisms governing IL-13 gene expression in T cells. IL-13 expression was examined in human peripheral blood T cells and in the EL-4 T-cell line by enzyme-linked immunosorbent assay and reverse-transcription polymerase chain reaction. An IL-13 promoter deletion analysis was performed using luciferase-based reporter plasmids transiently transfected into EL-4 cells by electroporation. DNA binding factors were investigated using electrophoretic mobility shift assays. In contrast to IL-4 expression, which required concomitant activation of calcium- and protein kinase C- (PKC-) dependent signalling pathways, PKC activation alone was sufficient for IL-13 protein secretion in mitogen-primed (but not resting) peripheral blood T cells, and for IL-13 mRNA expression and promoter activity in EL-4 T cells. Promoter deletion analysis localized a phorbol 12-myristate 13-acetate (PMA) -sensitive element to a proximal promoter region between −109 and −79 base pairs upstream from the IL-13 transcription start site. This promoter region supported the binding of both constitutive and PMA-inducible nuclear factors in gel shift assays.

Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid with wide-ranging effects on multiple lung cells including airway epithelial and smooth muscle cells. LPA can augment migration and cytokine synthesis in lymphocytes, but its potential effects on Th2 cytokines have not been well studied. We examined the effects of physiological concentrations of LPA on IL-13 gene expression in human T cells. The Jurkat T cell line and human peripheral blood CD4+ T cells were incubated with LPA alone or with 1) pharmacological agonists of different signaling pathways, or 2) antibodies directed against the T cell receptor complex and costimulatory molecules. Luciferase-based reporter constructs driven by different lengths of the human IL-13 promoter were transfected by electroporation in Jurkat cells treated with and without LPA. The effects of LPA on IL-13 mRNA stability were examined using actinomycin D to halt ongoing transcription. Expression of mRNA encoding LPA2and LPP-1 increased with T cell activation. LPA augmented IL-13 secretion under conditions of submaximal T cell activation. This was observed using pharmacological agonists activating intracellular calcium-, PKC-, and cAMP-dependent signaling pathways, as well as antibodies directed against CD3 and CD28. LPA only slightly prolonged IL-13 mRNA half-life in submaximally stimulated Jurkat cells. In contrast, LPA significantly enhanced transcriptional activation of the IL-13 promoter via regulatory elements contained within proximal 312 bp. The effects of LPA on IL-13 promoter activation appeared to be distinct from those mediated by GATA-3. LPA can augment IL-13 gene expression in T cells, especially under conditions of submaximal activation.

The mechanism by which glucocorticoids (GC) inhibit IL-4 gene expression is currently unknown. In T lymphocytes, IL-4 gene expression is regulated at the level of transcription by increases in intracellular calcium concentration and by the calcium-activated phosphatase calcineurin. In this paper we report that dexamethasone (Dex) inhibits calcium ionophore-induced activation of the human IL-4 promoter in transiently transfected Jurkat T cells. Inhibition of the promoter by Dex is dependent on expression of the GC receptor (GR), because it does not occur in GR-deficient cells. Dex also represses activation of the promoter induced by cotransfecting cells with a constitutively active mutant of calcineurin. Using a series of deletion constructs, we show that the proximal 95 bp of the IL-4 promoter contain a Dex-sensitive regulatory element. This region contains the P1 sequence, a proximal binding site for NF-AT. A calcium-induced but Dex-inhibited nuclear complex containing NF-AT binds to the P1 element in EMSA. Using immunoprecipitation under nondenaturing conditions, we found that the GRα isoform coprecipitates with NF-ATc in nuclear extracts of calcium ionophore- and Dex-treated cells. Taken together, our results show that GC inhibit IL-4 gene expression by interfering with NF-AT-dependent transactivation of the proximal human IL-4 promoter.

The differentiation of naive T-helper (Th) cells into cytokine-secreting effector Th cells requires exposure to multiple signals, including exogenous cytokines. Interleukin-4 (IL-4) plays a major role in this process by promoting the differentiation of IL-4–secreting Th2 cells. In Th2 cells, IL-4 gene expression is tightly controlled at the level of transcription by the coordinated binding of multiple transcription factors to regulatory elements in the proximal promoter region. Nuclear factor of activated T cell (NFAT) family members play a critical role in regulating IL-4 transcription and interact with up to five sequences (termed P0 through P4) in the IL-4 promoter. The molecular mechanisms by which IL-4 induces expression of the IL-4 gene are not known, although the IL-4–activated transcription factor signal transducer and activator of transcription 6 (Stat6) is required for this effect. We report here that Stat6 interacts with three binding sites in the human IL-4 promoter by electrophoretic mobility shift assays. These sites overlap the P1, P2, and P4 NFAT elements. To investigate the role of Stat6 in regulating IL-4 transcription, we used Stat6-deficient Jurkat T cells with different intact IL-4 promoter constructs in cotransfection assays. We show that, whereas a multimerized response element from the germline IgE promoter was highly induced by IL-4 in Stat6-expressing Jurkat cells, the intact human IL-4 promoter was repressed under similar conditions. We conclude that the function of Stat6 is highly dependent on promoter context and that this factor promotes IL-4 gene expression in an indirect manner.

Publisher Summary The knowledge of IL-4 transcriptional regulation comes from studies of a relatively restricted region (approximately 300 bp) within the 12,500 bp intergene segment located between the IL-13 and IL-4 gene coding regions. This IL-4 proximal upstream region is indeed sufficient to confer Th2 cell specificity on heterologous gene transcription. A recent report on IL-4-1uciferase and TCR-αβ double transgenic mice demonstrates that an extended 800 bp IL-4 upstream region is preferentially activated in Th2 cells, while a lower degree of Th2 cell specificity was attained in transgenics for reporter constructs driven by an artificial promoter made of three copies of the P1/OAP40 region placed upstream of the IL-4 minimal promoter (up to bp -58). However, luciferase mRNA expression in Th2 cells was very low when compared with expression of the native IL-4 gene, implicating a role for an as yet unidentified enhancer region outside the IL-4 promoter region. Possible IL-4 enhancers might reside somewhere in the IL-13/IL-4 intergene region, downstream of the IL-4 gene, or, in an untranslated area within the coding region of the IL-4 gene.

Atopy, which predisposes individuals to develop asthma, severe systemic anaphylaxis, and atopic dermatitis, is usually associated with dramatically elevated total serum IgE levels and is thought to be controlled by a major susceptibility gene and multiple minor susceptibility genes. A recent sib-pair analysis revealed a tight linkage between markers on 5q31.1 and a major susceptibility gene controlling total serum IgE levels. Due to its location within this cluster and its biologic role in Ig class switching and Th2 cell differentiation, the IL-4 gene has emerged as one major candidate for the atopy gene. In one model, polymorphisms within IL-4 regulatory elements might result in overexpression of the gene, amplifying Th2 cell differentiation and class switching to IgE. In support of this model, we report that the human IL-4 promoter exists in multiple allelic forms that exhibit distinct transcriptional activities in IL-4-positive T cells. A particular allele has an unusually high transcriptional activity. A nucleotide substitution within a recently described OAP40 element located just upstream of an NF-AT site (P sequence) appears to be largely responsible for the increased promotor strength of this particular allelic form of the IL-4 promoter. In EMSAs, this substitution results in a markedly enhanced affinity for sequence-specific complexes exhibiting an AP-1 specificity. The identification of allelic nucleotides, which results in overexpression of the IL-4 gene, provides specific targets for a comprehensive screening of atopic and nonatopic individuals and may provide a clue for genetic predisposition for atopy.