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Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.
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Objective To investigate the characteristics of intestinal microbiota in neonates on the first and third day after birth.Methods A total of 50 healthy singleton neonates who were born between June 15,2016 and August 3,2016 in Shanghai First Maternity and Infant Hospital were enrolled.Their stool samples were collected on the first and third day after birth and the samples were labeled according to the time of collection (D1 and D3 groups,n=50 each).Illumina NexSeq high-throughput sequencing platform was used to sequence the variable region 4 and 5 of all bacterial 16S rRNA genes in the samples.The composition of intestinal microbial communities was determined and the differences between the two groups were compared by Metastats analysis.Results (1) A total of 100 stool samples were sequenced and the retrieved sequences were from 25 bacterial phyla,119 families,227 genera and 159 species.(2) Major phyla in the two groups were the same,namely,Proteobacteria,Frimicutes,Bacteroidetes and Actinobacteria.The relative abundances of Frimicutes (0.27 ± 0.03 vs 0.41 ± 0.05) and Bacteroidetes (0.07 ± 0.01 vs 0.09 ± 0.03) increased over time,while that of Actinobacteria (0.10±0.01 vs 0.01 ±0.00) decreased on day 3.No significant difference in the relative abundance of Proteobacteria (0.51 ±0.03 vs 0.49± 0.05) was observed between D1 and D3 groups.There were significant difference in relative abundances of Frimicutes and Actinobacteria between the two groups (both q=-0.01,both P＜0.05).(3) Among the top ten most abundant families,Enterobacteriaceae,Staphylococcaceae,Enterococcaceae,Streptococcaceae and Lachnospiraceae were detected in both of the two groups.The relative abundances of Enterobacteriaceae (0.25 ± 0.02 vs 0.46 ± 0.06),Staphylococcaceae (0.07 ± 0.02 vs 0.12 ± 0.03),Enterococcaceae (0.04±0.02 vs 0.10±0.04),Streptococcaceae (0.03 ±0.02 vs 0.06±0.01) increased over time,while that of Lachnospiraceae (0.03 ± 0.01 vs 0.02 ± 0.02) decreased on day 3.Only the relative abundance of Enterobacteriaceae had statistical difference between the two groups (q=0.00,P＜0.05).(4) Among the top ten most abundant genera,Staphylococcus,Enterococcus,Streptococcus,Bacteroides and Pseudomonas were detected in both groups.The relative abundances of aerobic and facultative anaerobic bacteria which belonged to genera of Stenotrophomonas,Propionibacterium,Acinetobacter,Bacillus,Sphingomonas and so on decreased on day 3 as compared with those on day 1 (0.00±0.00 vs 0.07±0.02,0.00±0.00 vs 0.06±0.01,0.00±0.00 vs 0.03±0.01,0.00±0.00 vs 0.02±0.01,0.00±0.00 vs 0.02±0.00,all q=0.00,all P＜0.05).However,the relative abundances of anaerobic bacteria which belonged to Bacteroides,Veillonella,Parabacteroides and so on increased on day 3 (0.01 ±0.00 vs 0.08±0.03,0.00±0.00 vs 0.03±0.02,0.00±0.00 vs 0.01 ±0.00,q=0.01,0.01 and 0.00,all P＜0.05).(5) The most abundant species in intestinal microbiota was escherichia coli in both groups.Three less abundant species including lactobacillus gasseri,lactobacillus animalis and bifidobacterium bifidum were detected in both groups.(6) Regardless of the mode of delivery,Staphylococcus,was the highest predominant genera in meconium samples,followed by stenotrophomonas.Stool samples collected on the third day after birth were divided into four groups based on deliver modes and feeding patterns.Neonates who were born abdominally with exclusive breastfed thereafter were different from those of the other three groups in predominant intestinal bacteria,but the difference was not statistically significant.Bifidobacterium and Subdoligranulum were only detected in the vaginally born neonates.Conclusions Meconium is not sterile.Although the intestinal microbiota on the first day of life is different from that on the third day of life,the dominant bacteria are common.During the first three days of life,the relative abundances of aerobic and facultative anaerobic bacteria decreased significantly over time,while the relative abundance of anaerobic bacteria increased.
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Objective To establish a reference range of cancellous bone ultrasonic backscatter coefficient (BSC) in term neonates,and to determine the significance of BSC in bone nutritional status in term newborns and infants.Methods Six hundred and sixty-five term newborns,who were born in Shanghai First Maternity and Infant Hospital from July 2014 to August 2014,were enrolled.On the third day and the 42nd day after birth,all infants underwent ultrasonic measurement of the calcaneum bone using a broadband-non-focus ultrasonic transducer at three frequencies (2.25,3.5 and 5 MHz).MATLAB software was used to analyze the backscatter signals.Clinical data of the infants,including gestational age,birth weight and birth age,were recorded at the same time.Statistical analyses of the data included variance analysis,Tukey's test,rank sum test,Dunn test and Pearson or Spearman correlation analysis.Results (1) Of the 665 infants,335 were male.The mean gestational age at birth was (38.0± 1.9) weeks,and the mean birth weight was (3 1524±226) g.(2) On the third day,there were significant differences in BSC values acquired at 2.25 and 3.5 MHz among the groups with different gestational ages or birth weights (2.25 MHz:H=9.842 and 17.271;3.5 MHz:H=6.275 and 21.450,respectively,all P＜0.05).At 3.5 and 2.25 MHz,BSC values were positively correlated with gestational age (r=0.047 and 0.035,respectively,both P＜0.05) and birth weight (r=0.125 and 0.186,both P＜0.05).(3) On the 42nd day,significant differences in BSC were observed at each frequency among the groups with different gestational ages or birth weights (gestational age:H=76.832,16.498 and 32.756;birth weight:H=70.014,18.095 and 34.126;all P＜0.01).Gestational age and birth weight were positively correlated with BSC value acquired at each frequency (r=0.397,0.286 and 0.272 for gestational age,0.451,0.223 and 0.196 for birth weight;all P＜0.01).Conclusions A preliminary BSC reference percentile in term-born infants is established.There are positive correlations between BSC value and newborn gestational age and birth weight at certain frequencies,which can reflect the status of the newborn's cancellous bone.Determination of BSC value should be performed during the follow-up period to assess the nutritional status of neonatal bone.
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Objective To investigate the effect of persistent hypoglycemia on the cerebral oxidative stress and matrix metalloproteinase-2 (MMP-2) activity of newborn rats and to explore the potential mechanism of hypoglycemia-induced brain injury of newborn.MethodsSeven-day-old rats were injected insulin subcutaneously to induce persistent hypoglycemia.Cerebral cortex,hippocampus and thalamus were collected after 36 hours' observation and stored in -80 ℃.Glutathione (GSH)and glutathione disulfide (GSSG) were detected by commercial kit and GSSG/GSH was calculated.MMP-2 activity was detected by gelatin zymography. The data were analyzed by t test,one or two-wayanalysis of variance and Pearson correlation analysis.Six rats were set as the normal glucose group. ResultsThirty-six hours after induction of hypoglycemia, the cerebral GSSG and GSSG/GSH of hypoglycemic pups elevated about 1.5 times higher than those of control group [GSSG:(15.89 ± 5.46) vs (6.15 ± 3.42) mg/g protein,t =3.704,P =0.004; GSSG/GSH:(5.58± 1.79) ％ vs (2.79±1.76) ％,t =2.712,P=0.022].The GSSG and GSSG/GSH in thalamus of hypoglycemia were significantly higher than those of control [GSSG:(15.93 ± 5.75) mg/g protein vs (5.03±5.14)mg/g protein,P＜0.05; GSSG/GSH:(6.50±3.25) ％ vs (2.41±3.12) ％,P＜0.05],whereas there were no significant differences in the cortex ard hippocampus.The total MMP-2 activity of hypoglycemic animals (2.22±0.59) was significantly higher than that of control (1.21± 0.17)(t=4.064,P=0.002),and significant differences were found between the two groups in cortex (2.14 ± 0.5 vs 1.17± 0.27),hippocampus (2.31± 0.72 vs 1.22 ± 0.37) and thalamus (2.22±0.68 vs 1.24±0.18) with all P＜0.01].The activity of MMP-2 was positively related to GSSG (r=0.575,P=0.0002) and GSSG/GSH (r=0.484,P=0.0003).ConclusionsOxidative stress might play an important role in the persistent hypoglycemia induced brain injury of 7-day-old rat pups and thalamus might be most vulnerable to hypoglycemia.Hypoglycemia might also elevate MMP-2 activity which is positively related to GSSG level and GSSG/GSH of the brain.