Objectives
To explore the associations between higher antibiotic use rates (AURs) and adverse outcomes in very-low-birth-weight (VLBW) infants without culture-proven sepsis or necrotizing ...enterocolitis (NEC) in a multicenter of China.
Methods
A prospective cohort study was performed on VLBW infants admitted to 24 neonatal intensive care units from January 1, 2018, to December 31, 2018. AUR was calculated as calendar days of antibiotic therapy divided by total hospital days. The composite primary outcome was defined as mortality or severe morbidity, including any of the following: severe neurologic injury, bronchopulmonary dysplasia (BPD), and stage 3 or higher retinopathy of prematurity.
Results
A total of 1,034 VLBW infants who received antibiotics without culture-proven sepsis or NEC were included in this study. The overall AUR of eligible VLBW infants was 55%, and the AUR of each eligible VLBW infant ranged from 3 to 100%, with a median of 56% (IQR 33%, 86%). After generalized propensity score and logistic regression analysis of 4 groups of VLBW infants with different AUR range, infants in the higher quartile AUR, (Q3, 0.57~0.86) and (Q4, 0.87~1.00), had higher odds of composite primary outcome (adjusted OR: 1.81; 95% CI: 1.23–2.67; adjusted OR 2.37; 95% CI: 1.59–3.54, respectively) and BPD (adjusted OR: 3.09; 95% CI: 1.52–6.57; adjusted OR 3.17; 95% CI: 1.56–6.57, respectively) than those in the lowest AUR (Q1).
Conclusions
Antibiotic overexposure in VLBW infants without culture-proven sepsis or NEC was associated with increased risk of composite primary outcome and BPD. Rational empirical antibiotic use in VLBW infants is urgently needed in China.
Purpose
This study aimed to investigate the value of
99m
technetium-three polyethylene glycol spacers-arginine-glycine-aspartic acid (
99m
Tc3PRGD
2
) imaging in diagnosis and staging of breast ...cancer compared with 2-deoxy-2-
18
Ffluoro-D-glucose (
18
FFDG) imaging, and to explore the expression of integrin α
v
β
3
in tumor vascular endothelial cells.
Procedures
Forty-two women with suspected breast cancer underwent both
99m
Tc3PRGD
2
imaging and
18
FFDG imaging. Visual analysis was used to assess primary breast lesion, axillary lymph node, and distant metastasis. The tumor-blood (T/B) ratios from
99m
Tc3PRGD
2
imaging and the maximum standardized uptake value (SUVmax) from
18
FFDG imaging were analyzed for breast lesions. Integrin α
v
β
3
was analyzed through immunohistochemistry.
Results
Forty-five breast lesions were found (malignant,
n
= 38; benign,
n
= 7). The sensitivity, specificity, and accuracy of
99m
Tc3PRGD
2
and
18
FFDG imaging in visual analysis for the breast lesion were 97.4, 87.5, and 95.6 % and 97.4, 71.4, and 93.3 %, respectively (
P
> 0.05). For semi-quantitative analysis, no significant difference of the area under the curves (AUC) was found in the imaging using the two radiopharmaceuticals (0.880 and 0.955;
Z
= 0.88,
P
> 0.05). The sensitivity, specificity, and accuracy for axillary lymph node metastasis with
99m
Tc3PRGD
2
and
18
FFDG were 78.05, 99.36, and 94.92 % and 85.37, 98.72, and 95.64 %, respectively (
P
> 0.05). Nine patients with distant metastases were all detected with the two radiopharmaceuticals. The expression of integrin α
v
β
3
was correlated with
99m
Tc3PRGD
2
uptake (
r
= 0.582,
P
= 0.001), which were significantly higher in the HER2-positive and stage III–IV patients (
P
< 0.05).
Conclusions
The prospective study demonstrated that
99m
Tc3PRGD
2
imaging seems to be valuable for diagnosis of breast cancer and its staging. It may be less sensitive for detecting small lymph node metastatic lesions when compared with
18
FFDG imaging. Integrin α
v
β
3
in tumor microvessels was associated with the breast cancer subtype and its staging.
Objectives. Many patients with papillary thyroid cancer (PTC) have a high recurrence risk and poor prognosis, and the main obstacle to the clinical diagnosis and treatment of PTC is lack of effective ...predictive molecular markers. The purpose of this study was to investigate the clinicopathological and prognostic implications of WW domain binding protein 5 (WBP5) expression in PTC. Materials and Methods. Immunohistochemistry of WBP5 was performed using tissue microarrays of 131 patients with PTC who underwent surgery during January 2006 and January 2010 in the Zhejiang Cancer Hospital. Statistical analyses were conducted to evaluate the association between WBP5 expression and the clinicopathological features and to analyze the disease-free survival (DFS) and prognostic factors. Results and Conclusion. The positive expression rate of WBP5 in PTC and the adjacent normal tissues was 42.75% (56/131) and 45.45% (10/22), respectively. WBP5 expression was significantly correlated with bilaterality, capsule invasion, and N-stage, and it was a favorable factor of DFS. Moreover, patients with a high WBP5 expression exhibited reduced risk of disease recurrence compared with that in patients with low WBP5 expression in the univariate analysis, whereas the multivariate analysis suggested that WBP5 was not an independent prognostic factor. Our results indicate that WBP5 might be a favorable prognosis indicator of PTC.
Flavonoids are important plant natural products with variable structures and bioactivities. All known plant flavonoids are generated under the catalysis of a type III polyketide synthase (PKS) ...followed by a chalcone isomerase (CHI) and a flavone synthase (FNS). In this study, the biosynthetic gene cluster of chlorflavonin, a fungal flavonoid with acetolactate synthase inhibitory activity, was discovered using a self‐resistance‐gene‐directed strategy. A novel flavonoid biosynthetic pathway in fungi was revealed. A core nonribosomal peptide synthetase‐polyketide synthase (NRPS‐PKS) is responsible for the generation of the key precursor chalcone. Then, a new type of CHI catalyzes the conversion of a chalcone into a flavanone by a histidine‐mediated oxa‐Michael addition mechanism. Finally, the desaturation of flavanone to flavone is catalyzed by a new type of FNS, a flavin mononucleotide (FMN)‐dependent oxidoreductase.
Plant flavonoids are synthesized by type III PKS followed by chalcone isomerase (CHI) and flavone synthase (FNS). Now a unique flavonoid biosynthesis mechanism has been identified in fungi by genome mining. The chalcone skeleton is assembled by an NRPS‐PKS hybrid enzyme, and subsequent conversion into a flavone is catalyzed by new types of CHI and FNS. This finding provides new insight into the microbial production of valuable plant flavonoids.
LepI is a novel multifunctional enzyme that catalyzes stereoselective dehydration, Diels-Alder reaction, and retro-Claisen rearrangement. Here we report the crystal structure of LepI in complex with ...its co-factor
S
-adenosyl methionine (SAM). LepI forms a tetramer
via
the N-terminal helical domain and binds to a SAM molecule in the C-terminal catalytic domain. The binding modes of various LepI substrates are investigated by docking simulations, which suggest that the substrates are bound
via
both hydrophobic and hydrophilic forces, as well as cation-π interactions with the positively charged SAM. The reaction starts with a dehydration step in which H133 possibly deprotonates the pyridone hydroxyl group of the substrate, while D296 might protonate an alkyl-chain hydroxyl group. Subsequent pericyclization may be facilitated by the correct fold of the substrate's alkyl chain and a thermodynamic driving force towards σ-bonds at the expense of π-bonds. These results provide structural insights into LepI catalysis and are important in understanding the mechanism of enzymatic pericyclization.
Crystal structure of LepI, a SAM-dependent enzyme which can catalyze seteroselective dehydration, Diels-Alder reaction, and retro-Claisen rearrangement.
Antagonized functions between a heat shock and calcium-binding protein affects both preinvasion and postinvasion phases of defense responses.
The plant immune system consists of multiple layers of ...responses targeting various phases of pathogen infection. Here, we provide evidence showing that two responses, one controlling stomatal closure and the other mediated by intracellular receptor proteins, can be regulated by the same proteins but in an antagonistic manner. The HEAT SHOCK COGNATE70 (HSC70), while previously known as a negative regulator of stomatal closure, is a positive regulator of immune responses mediated by the immune receptor protein SUPPRESSOR OF NPR1-1, CONSTITUTIVE1 (SNC1) as well as basal defense responses. In contrast to HSC70, a calcium-binding protein, BONZAI1 (BON1), promotes abscisic acid- and pathogen-triggered stomatal closure in addition to and independent of its previously known negative role in
SNC1
regulation. BON1 likely regulates stomatal closure through activating SUPPESSOR OF THE G2 ALLELE OF SKP1 VARIANT B and inhibiting HSC70. New functions of
BON1
and
HSC70
identified in this study thus reveal opposite effects of each of them on immunity. The opposing roles of these regulators at different phases of plant immune responses exemplify the complexity in immunity regulation and suggest that immune receptors may guard positive regulators functioning at stomatal closure control.
1. The exposed level of vitamin A in plasma might be exceeded due to the both inadvertent and clinical utilization. The adverse effects of vitamin A have been frequently reported, however, the ...mechanism remains unclear. The inhibition of vitamin A on the activity of UDP-glucuronosyltransferases (UGTs) was determined using in vitro incubation system to explain the adverse effects of vitamin A from a new perspective.
2. UGT supersomes catalyzed glucuronidation of 4-methylumbelliferone (4-MU), trifluoperazine (TFP), and cotinine was used as the probe reaction to evaluate the inhibition of vitamin A toward UGT isoforms, and 100 μM of vitamin A significantly inhibited the activity of all the tested UGT isoforms. Vitamin A exerted competitive inhibition on the activity of UGT1A1, 2B4, 2B7, and 2B15, and the inhibition kinetic parameters (K
i
) were calculated to be 31.1, 16.8, 2.2, and 11.6 μM for UGT1A1, 2B4, 2B7, and 2B15. In silico docking method was used to try to elucidate the inhibition mechanism of vitamin A toward UGT2B7. The results showed the significant contribution of hydrogen bonds and hydrophobic interaction on the UGT2B7 inhibition by vitamin A.
3. The present study provides a new perspective for the adverse effects of vitamin A through reporting the inhibition of vitamin A on the activity of important phase II drug-metabolizing enzymes UGTs, which benefits our deep understanding of mechanism of vitamin A's adverse effects when high exposure of vitamin A occurs.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Amyloid aggregation of pathological proteins is closely associated with a variety of neurodegenerative diseases, and α-synuclein (α-syn) deposition and Tau tangles are considered hallmarks of ...Parkinson's disease and Alzheimer's disease, respectively. Intriguingly, α-syn and Tau have been found to co-deposit in the brains of individuals with dementia and parkinsonism, suggesting a potential role of cross-talk between these two proteins in neurodegenerative pathologies. Here we show that monomeric α-syn and the two variants of Tau, Tau23 and K19, synergistically promote amyloid fibrillation, leading to their co-aggregation in vitro. NMR spectroscopy experiments revealed that α-syn uses its highly negatively charged C terminus to directly interact with Tau23 and K19. Deletion of the C terminus effectively abolished its binding to Tau23 and K19 as well as its synergistic effect on promoting their fibrillation. Moreover, an S129D substitution of α-syn, mimicking C-terminal phosphorylation of Ser
in α-syn, which is commonly observed in the brains of Parkinson's disease patients with elevated α-syn phosphorylation levels, significantly enhanced the activity of α-syn in facilitating Tau23 and K19 aggregation. These results reveal the molecular basis underlying the direct interaction between α-syn and Tau. We proposed that this interplay might contribute to pathological aggregation of α-syn and Tau in neurodegenerative diseases.
![Comparison of [99mTc]3PRGD2...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1536-1632/small "Comparison of [99mTc]3PRGD2 Imaging and [18F]FDG PET/CT in Breast Cancer and Expression of Integrin αvβ3 in Breast Cancer Vascular Endothelial Cells")
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