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2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Bailing Chen ◽  
Yulong Li ◽  
Meilin Tian ◽  
Hao Su ◽  
Wei Sun ◽  
...  

AbstractR. esculentum is a popular seafood in Asian countries and an economic marine fishery resource in China. However, the genetic linkage map and growth-related molecular markers are still lacking, hindering marker assisted selection (MAS) for genetic improvement of R. esculentum. Therefore, we firstly used 2b-restriction site-associated DNA (2b-RAD) method to sequence 152 R. esculentum specimens and obtained 9100 single nucleotide polymorphism (SNP) markers. A 1456.34 cM linkage map was constructed using 2508 SNP markers with an average interval of 0.58 cM. Then, six quantitative trait loci (QTLs) for umbrella diameter and body weight were detected by QTL analysis based on the new linkage map. The six QTLs are located on four linkage groups (LGs), LG4, LG13, LG14 and LG15, explaining 9.4% to 13.4% of the phenotypic variation. Finally, 27 candidate genes in QTLs regions of LG 14 and 15 were found associated with growth and one gene named RE13670 (sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1-like) may play an important role in controlling the growth of R. esculentum. This study provides valuable information for investigating the growth mechanism and MAS breeding in R. esculentum.


2021 ◽  
Author(s):  
Paula González-López ◽  
Carla Ares-Carral ◽  
Andrea R. López-Pastor ◽  
Jorge Infante-Menéndez ◽  
Tamara Gonzalez-Illanes ◽  
...  

Abstract Background: Cardiovascular diseases (CVDs) are the main cause of death in first world countries, being atherosclerosis, a recurring process underlying their apparition. MicroRNAs (miRNAs) are small non-coding RNAs that modulate the expression of their target proteins. Therefore, they have emerged as key players in diseases like cancer, diabetes, or CVDs.Methods: Apolipoprotein E-deficient (ApoE-/-) mice fed a standard type diet (STD) or high fat diet (HFD) for 8 and 18 weeks was compared to wild type (WT) STD-fed groups for the same time. 18 miRNAs were selected (from pubmed and GEO database) for their possible role in promoting atherosclerosis and were analysed by RT-qPCR in the aorta from the experimental model. Afterwards, the altered miRNAs in the aorta from 18 weeks-ApoE-/- mice were studied in human healthy aortic samples, human early aortic atherosclerotic plaques, and human advanced carotid atherosclerotic plaques. Results: From the 18 miRNAs analyzed, miR-155-5p was overexpressed and miR-143-3p was downregulated in mouse and human atherosclerotic lesions. In addition, a significant decrease of protein kinase B (AKT), target of miR-155-5p, and an increase of insulin-like growth factor type II receptor (IGF-IIR), target of miR-143-3p, were noted in aortic roots from ApoE-/- mice and in carotid plaques from ACA patients. Finally, both miRNAs were studied on vascular endothelial and smooth muscle cell lines. The overexpression of miR-155-5p reduced AKT levels and its phosphorylation in vascular smooth muscle cells. MiR-143-3p overexpression decreased IGF-IIR reducing apoptosis in vascular cells. Conclusions: Our results suggest that miR-155-5p and miR-143-3p may be implicated in insulin resistance and plaque instability by the modulation of their targets AKT and IGF-IIR, contributing to the progression of experimental and human atherosclerosis.Trial Registration: authorization numbers PFS09-007 and PI1442016.


2021 ◽  
Author(s):  
Lang Yang ◽  
Kai Li ◽  
Weizhao Li ◽  
Chaohu Wang ◽  
Yi Liu ◽  
...  

Introduction Insulin-like growth factor type 1 receptor (IGF1R) is overexpressed in various malignant tumors, which relates to their transformation and recurrence. Craniopharyngioma is a benign tumor with malignant results, often accompanied by a severe inflammatory reaction. However, the relationship between IGF1R expression and the inflammatory response of craniopharyngioma is unclear. Methods We enrolled 85 patients with adamantinomatous craniopharyngioma (ACP) in a study to explore the relationship between IGF1R expression and clinical features of this disease. Results Patients in the IGF1R high expression group had a significantly higher incidence of hypopituitarism, higher recurrence rate and lower progression-free survival. Beta-catenin can further regulate expression of the stem cell marker, CD44, by regulating IGF1R. Using immunofluorescence, we found that tumor stem cell–like cells did not express phosphorylated (p)-ERK, although p-ERK activation was evident in the surrounding cells. Picropodophyllin, a specific inhibitor of IGF1R, increased the expression of p-ERK protein, and decreased the transcription level of interleukin-6. Conclusions High expression of IGF1R might promote inflammation of ACP, which might be an unfavorable factor for pituitary function and prognosis. The high expression of IGF1R in tumor cell stem-like cells might inhibit the expression of p-ERK and promote the generation of inflammatory factors. Insulin-like growth factor type 1 receptor plays a stemness maintenance role in ACP and regulates the production of inflammatory factors through a p-ERK pathway, which suggests that targeting IGF1R and p-ERK might provide a new direction for alleviating tumor inflammation.


2021 ◽  
Author(s):  
Shahan Mamoor

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding sushi, von Willebrand factor type A, EGF and pentraxin domain-containing 1, SVEP1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SVEP1 was also differentially expressed in the brain metastases of patients with metastatic breast cancer. SVEP1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SVEP1 in primary tumors of the breast was correlated with distant metastasis-free survival in patients with normal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. SVEP1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.


Author(s):  
Nina Gillis-Germitsch ◽  
Tobias Kockmann ◽  
Lars M. Asmis ◽  
Lucienne Tritten ◽  
Manuela Schnyder

Angiostrongylus vasorum is a cardiopulmonary nematode of canids and is, among others, associated with bleeding disorders in dogs. The pathogenesis of such coagulopathies remains unclear. A deep proteomic characterization of sex specific A. vasorum excretory/secretory proteins (ESP) and of cuticular surface proteins was performed, and the effect of ESP on host coagulation and fibrinolysis was evaluated in vitro. Proteins were quantified by liquid chromatography coupled to mass spectrometry and functionally characterized through gene ontology and pathway enrichment analysis. In total, 1069 ESP (944 from female and 959 from male specimens) and 1195 surface proteins (705 and 1135, respectively) were identified. Among these were putative modulators of host coagulation, e.g., von Willebrand factor type D domain protein orthologues as well as several proteases, including serine type proteases, protease inhibitors and proteasome subunits. The effect of ESP on dog coagulation and fibrinolysis was evaluated on canine endothelial cells and by rotational thromboelastometry (ROTEM). After stimulation with ESP, tissue factor and serpin E1 transcript expression increased. ROTEM revealed minimal interaction of ESP with dog blood and ESP did not influence the onset of fibrinolysis, leading to the conclusion that Angiostrongylus vasorum ESP and surface proteins are not solely responsible for bleeding in dogs and that the interaction with the host’s vascular hemostasis is limited. It is likely that coagulopathies in A. vasorum infected dogs are the result of a multifactorial response of the host to this parasitic infection.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A231-A231
Author(s):  
Jenny Zilberberg ◽  
Amelia Zellander ◽  
Kenneth Kirby ◽  
Christopher Uhl ◽  
Christopher Cultrara ◽  
...  

BackgroundIGV-001 is a novel immunotherapy that combines irradiated, patient-derived glioblastoma tumor cells and an antisense oligonucleotide against insulin-like growth factor type 1 receptor (IMV-001) in biodiffusion chambers (0.1-micron pore size). We recently evaluated IGV-001 in patients with newly diagnosed glioblastoma.1 In a subgroup of IGV-001-treated, Stupp-eligible patients2 with methylated O6-methylguanine–DNA methyl-transferase (MGMT) promoter, median progression free survival was 38.4 months1 compared with 8.3 months in historical standard-of-care-treated patients (p=0.0008).2 We utilized the GL261-Luciferase (-Luc) glioblastoma orthotopic murine model and conducted in vitro immunological assays using patient-derived GBM tumor cells and matched peripheral blood mononuclear cells (PBMC) to unravel the potential mechanisms associated with the activity of IGV-001.MethodsBiodiffusion chambers containing phosphate-buffered saline (PBS) alone or IGV-001 prepared with 1x106 GL261-Luc cells were implanted in the flanks of C57BL/6 albino mice and explanted 48 hours later, as per the clinical protocol. GL261-Luc intracranial tumor challenge was conducted 28 days after chamber implantation. Mice were monitored for survival and tumor growth, as determine by bioluminescence intensity (BLI). For in vitro experiments, IGV-001 prepared with patient tumor cells were co-cultured with patient-derived PBMC to evaluate activated and memory T cell subsets and responses. To elucidate the immunostimulatory underpinnings of IGV-001, ATP release assay was conducted as a surrogate measure of immunogenic cell death.Results59% of IGV-001 treated mice were alive and continued to gain weight at the termination of the study, 58 days post–intracranial tumor challenge. In comparison, there were no survivors in the PBS group by day 24 (p<0.001). Fluorospot assays demonstrated enhanced T cell IFN-gamma responses to tumor cell antigens. In IGV-001 treated mice, serum IL-6 was positively correlated with BLI, meaning that treated mice with lower BLI signal had less circulating IL-6 (p<0.01). Fluorospot assays demonstrated enhanced T cell IFN-gamma responses to tumor cell antigens. Tumor co-culture studies showed elevated percentage of activated CD4 and CD8 T cells as well as increased central and effector memory phenotypes in both T cell subsets compared to IMV-001-treated PBMC controls. Lastly, tumor cells treated with IMV-001 released significantly more (p<0.01) ATP than untreated or sense oligonucleotide-treated controls.ConclusionsThese data support the antitumor activity of IGV-001 in newly diagnosed glioblastoma, as evidenced in the phase 1 study. Th1 anti-tumor T cell activity was demonstrated. The ATP results suggest a possible immunogenic conversion by which IGV-001 stimulates the immune system and suppresses tumor growth, which can be quantified via circulating IL-6.ReferencesAndrews DW, Judy KD, Scott CB, Garcia S, Harshyne LA, Kenyon L, Talekar K, Flanders A, Atsina KB, Kim L, Martinez N, Shi W, Werner-Wasik M, Liu H, Prosniak M, Curtis M, Kean R, Ye DY, Bongiorno E, Sauma S, Exley MA, Pigott K, Hooper DC. Phase Ib clinical trial of IGV-001 for patients with newly diagnosed glioblastoma. Clin Cancer Res 2021 April 1;27(7):1912–1922. doi: 10.1158/1078-0432.CCR-20-3805. Epub 2021 Jan 26. PMID: 33500356.Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005 March 10;352(10):987–96. doi: 10.1056/NEJMoa043330. PMID: 15758009.Ethics ApprovalEthical consent was obtained for all human biospecimens with the appropriate IRB approval.ConsentInformed consent was obtained for all human biospecimens with the appropriate IRB approval.


Author(s):  
Richard J Auchus ◽  
Kyriakie Sarafoglou ◽  
Patricia Y Fechner ◽  
Maria G  Vogiatzi ◽  
Erik A Imel ◽  
...  

Abstract Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Design Open-label, phase 2 study, with sequential cohort design (NCT03525886). Setting United States (6 centers). Participants Men and women, 18-50 years, with 21OHD. Interventions Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in &gt;1 cohort. Main Outcomes Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: Cohort 1 (n=8), Cohort 2 (n=7), Cohort 3 (n=8), Cohort 4 (n=8). Mean age was 31 years; 94% were white. Median percent reductions were &gt;60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios. Conclusions Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.


Endocrinology ◽  
2021 ◽  
Author(s):  
Deyana Ivanova ◽  
Xiao-Feng Li ◽  
Caitlin McIntyre ◽  
Yali Liu ◽  
Lingsi Kong ◽  
...  

Abstract Psychosocial stress disrupts reproduction and interferes with pulsatile LH secretion. The posterodorsal medial amygdala (MePD) is an upstream modulator of the reproductive axis and stress. Corticotropin-releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in the MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on LH pulses in ovariectomised mice. Next, we delivered Astressin2B, a selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting MePD Ucn3 neurons while exposing mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone release. Administration of Ucn3 into the MePD dose-dependently inhibited LH pulses and administration of Astressin2B blocked the suppressive effect of TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses and corticosterone release. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and corticosterone secretion. Ucn3 signalling in the MePD plays a role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the interaction between the reproductive and stress axes.


PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0255755
Author(s):  
Dorota Mirosław-Świątek ◽  
Paweł Popielski ◽  
Piotr Śliwiński ◽  
Tomasz Cwalina ◽  
Zdzisław Skutnik

River embankments are the basic and the oldest measures of protecting areas potentially subjected to flooding, and at the same time pose a serious threat to their environment in the event of damage or failure. The technical condition of the levees and its regular evaluation is a key element of their safety. A general assessment of the technical condition of a levee is the result of many interacting factors and parameters that depend on each other to a varying degree. Therefore, it is necessary to consider the cause-and-effect links between the interrelationships of numerous parameters and sensors of significant impact. In this article the decision-making trial and evaluation laboratory (DEMATEL) method was applied to develop a cause-and-effect model for factors impacting the condition and safety of levees. Effective factors impacting the technical condition of a levee were identified; relationships between these factors were determined; a cause-and-effect model was developed based on identified factors; factors were categorized based on the dependence scale and influential indicators of each factors used in the DEMATEL method. The obtained results demonstrate that three following factors: hydrological factor, type and condition of soils in levee body and condition of levee areas (inter-levee and landside) play the most important role for levee safety. The results of this study can support traditional assessments of hydrotechnical structure or assist entities managing levees.


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