Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic ...tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
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•AIM2 is required to mediate protection against colorectal cancer•AIM2 suppresses overt proliferation in enterocytes•AIM2 inhibits expansion of the intestinal stem cell population•Transfer of healthy microbiota dampens tumor development in Aim2-deficient mice
The cytosolic DNA sensor AIM2 regulates stem cell proliferation in the intestinal mucosa in an inflammasome-independent fashion, contributing to a decrease in the likelihood of colorectal cancer development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
β-lactam antibiotics are the most frequently used drugs and the most common drugs that cause allergic reactions in pediatrics. The occurrence of some allergic reactions can be predicted by skin ...testing, especially severe adverse reactions such as anaphylactic shock. Thus, penicillin and cephalosporin skin tests are widely used to predict allergic reactions before medication in pediatrics. However, false-positive results from skin tests were more often encountered in pediatrics than in adults. In fact, many children labeled as allergic to β-lactam are not allergic to the antibiotic, leading to the use of alternative antibiotics, which are less effective and more toxic, and the increase of antibiotic resistance. There has been controversy over whether β-lactam antibiotics should be tested for skin allergies before application in children. Based on the great controversy in the implementation of β-lactam antibiotic skin tests, especially the controversial cephalosporin skin tests in pediatrics, the mechanism and reasons of anaphylaxis to β-lactam antibiotics, the significance of β-lactam antibiotic skin tests, the current state of β-lactam antibiotic skin tests at home and abroad, and the problems of domestic and international skin tests were analyzed to determine a unified standard of β-lactam antibiotic skin tests in pediatrics to prevent and decrease adverse drug reactions, avoid waste of drugs, and a large amount of manpower and material resource consumption.
Cancer stem cells are remarkably similar to normal stem cells: both self-renew, are multipotent and express common surface markers, for example, prominin 1 (PROM1, also called CD133). What remains ...unclear is whether cancer stem cells are the direct progeny of mutated stem cells or more mature cells that reacquire stem cell properties during tumour formation. Answering this question will require knowledge of whether normal stem cells are susceptible to cancer-causing mutations; however, this has proved difficult to test because the identity of most adult tissue stem cells is not known. Here, using an inducible Cre, nuclear LacZ reporter allele knocked into the Prom1 locus (Prom1C-L), we show that Prom1 is expressed in a variety of developing and adult tissues. Lineage-tracing studies of adult Prom1+/C-L mice containing the Rosa26-YFP reporter allele showed that Prom1+ cells are located at the base of crypts in the small intestine, co-express Lgr5 (ref. 2), generate the entire intestinal epithelium, and are therefore the small intestinal stem cell. Prom1 was reported recently to mark cancer stem cells of human intestinal tumours that arise frequently as a consequence of aberrant wingless (Wnt) signalling. Activation of endogenous Wnt signalling in Prom1+/C-L mice containing a Cre-dependent mutant allele of -catenin (Ctnnb1lox(ex3)) resulted in a gross disruption of crypt architecture and a disproportionate expansion of Prom1+ cells at the crypt base. Lineage tracing demonstrated that the progeny of these cells replaced the mucosa of the entire small intestine with neoplastic tissue that was characterized by focal high-grade intraepithelial neoplasia and crypt adenoma formation. Although all neoplastic cells arose from Prom1+ cells in these mice, only 7% of tumour cells retained Prom1 expression. Our data indicate that Prom1 marks stem cells in the adult small intestine that are susceptible to transformation into tumours retaining a fraction of mutant Prom1+ tumour cells.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • Study comparing the effect of proton pump inhibitors (PPIs) on voriconazole pharmacokinetics. • Physiologically based pharmacokinetic (PBPK) model was used to predict pharmacokinetic ...profiles. • PBPK model used to assess the drug–drug interaction potential of voriconazole with PPIs. • Omeprazole was the most potent CYP2C19 inhibitor tested; rabeprazole had no influence on voriconazole. • Dosage adjustment of voriconazole is unnecessary regardless of which PPI was co-administered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background & Aims Invasive pancreatic ductal adenocarcinoma is thought to originate from duct-like lesions called pancreatic intraepithelial neoplasia (PanIN). PanINs progress from low grade ...(PanIN-1) to high grade (PanIN-3) as the cells attain molecular alterations to key regulatory genes, including activating mutations in the KRAS protooncogene. Despite a well-documented progression model, our knowledge of the initiator cells of PanINs and the transcriptional networks and signaling pathways that impact PanIN formation remains incomplete. Methods In this study, we examined the importance of the acinar-restricted transcription factor Mist1 to KrasG12D -induced mouse PanIN (mPanIN) formation in 3 different mouse models of pancreatic cancer. Results In the absence of Mist1 ( Mist1 KO ), Kras G12D -expressing mice exhibited severe exocrine pancreatic defects that were rescued by ectopic expression of Mist1 in acinar cells. mPanIN development was greatly accelerated in Mist1 KO / Kras G12D/+ pancreata, and in vitro assays revealed that Mist1 KO acinar cells were predisposed to convert to a ductal phenotype and activate epidermal growth factor receptor (EGFR) and Notch-signaling pathways. Conclusions We propose that convergence of EGFR, Notch, and Kras pathways in acinar cells lacking Mist1 leads to enhanced mPanIN formation.
Botryosphaeria dothidea
is a major pathogen responsible for postharvest kiwifruit soft rot. This study aimed to determine the influence of hydrogen sulfide (H
2
S) on postharvest resistance to ...kiwifruit soft rot and the antifungal role of H
2
S against
B. dothidea
. The results indicated that H
2
S (20 μl L
−1
) restricted the lesion area following inoculation with
B. dothidea
. H
2
S enhanced the production of shikimic acid, tyrosine, tryptophan, and phenylalanine while also increasing the total phenols, flavonoids, and lignin. H
2
S upregulated the expression of
AcDHQS, AcSDH, AcSK, AcPAL, AcCAD
, and
AcCHS
. Additionally, sodium hydrosulfide (NaHS)-released H
2
S inhibited mycelial growth. NaHS concentrations of 20 and 40 mmol L
−1
significantly decreased the mycelial weight and malondialdehyde content (MDA) content while increasing cell membrane conductivity and membrane leakage. The results indicate that H
2
S induces resistance in kiwifruit
via
a microbicidal role and amino acid metabolism involved in postharvest kiwifruit disease resistance.
A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the ...small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on Kras G12D expression, we took advantage of LSL-Kras G12D /+ / p48 Cre /+ mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinar-ductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that Kras G12D -induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this paper, the method of speed control for 3D biped robots is addressed. First, the primary principle of speed control by regulation of input energy is studied, the feature of which is to ...regulate the speed and the step length synchronically. The method of Poincaré mapping is used to prove the stability of speed control in the common range. Second, a method of speed control for an 18 DOFs bipedal 3D robot, which is characterized by the two-point-foot, is proposed. The method is developed on the basis of the 3D walking pattern proposed previously, with the new function of speed regulation being added in. The simulations show that the performances of regular walking, acceleration, and deceleration are effective and stable, and therefore verify the feasibility of the proposed method. Furthermore, some walking features, such as the walking efficiency and lateral control, are demonstrated.
•Speed control method with adaptive regulation of step length.•Speed control principle by regulation of input energy, which is implemented by regulation of the force of ground-push.•Walking planning by kinematics extension from simplified model to complete model.•Planning and control method for dynamic walking of 3D biped robots.•Simulation on 3D biped robots.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Asn-Gly-Arg (NGR) motifs have vasculature-homing properties via interactions with the aminopeptidase N (CD13) expressed on tumor neovasculature. Numerous NGR peptides with different molecular ...scaffolds have been exploited for targeted delivery of different compounds for imaging and therapy. When conjugated with NGR, complexes recognize the CD13 receptor expressed on the tumor vasculature, which improves the specificity to tumor and avoids systematic toxic reactions. Both preclinical and clinical studies performed with these products suggest that NGR-mediated vascular targeting is an effective strategy for delivering bioactive amounts of cytokines to tumor endothelial cells. For molecular imaging, radiolabeled peptides have been the most successful approach and have been translated into clinic. This review describes current data on radiolabeled tumor vasculature-homing NGR peptides for imaging and therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
This work investigates the role of hydrogen sulfide (H
2
S) in the browning and regulating the antioxidant defensive system in fresh-cut Chinese water chestnuts. The samples were fumigated with 0, ...10, and 15 μl L
−1
of H
2
S and stored at 10°C for 8 days. The results indicated that the H
2
S treatment significantly inhibited the browning of fresh-cut Chinese water chestnuts, reduced superoxide anion (
O
2
·
-
) production rate and H
2
O
2
content accumulation, promoted the increase of total phenol content, and enhanced activities of catalase (CAT), superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR) (
P
< 0.05). On the other hand, phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and peroxidase (POD) activities remained at a low level in the H
2
S treatment (
P
< 0.05). This result suggested that H
2
S treatment might be a promising approach to inhibit browning and prolong the shelf life by enhancing oxidation resistance and inhibiting browning enzyme activity of fresh-cut Chinese water chestnuts during storage. Among them, the 15 μl L
−1
H
2
S treatment had the best effect on fresh-cut Chinese water chestnuts.
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