Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis.

BACKGROUND: The efficacy and safety of anti-tumor necrosis factor-α (TNF-α) monoclonal antibody therapy [adalimumab (ADA) and infliximab (IFX)] with therapeutic drug monitoring (TDM), which has been proposed for inflammatory bowel disease (IBD) patients, are still controversial. AIM: To determine the efficacy and safety of anti-TNF-α monoclonal antibody therapy with proactive TDM in patients with IBD and to determine which subtype of IBD patients is most suitable for proactive TDM interventions. METHODS: As of July 2023, we searched for randomized controlled trials (RCTs) and observational studies in PubMed, Embase, and the Cochrane Library to compare anti-TNF-α monoclonal antibody therapy with proactive TDM with therapy with reactive TDM or empiric therapy. Pairwise and network meta-analyses were used to determine the IBD patient subtype that achieved clinical remission and to determine the need for surgery. RESULTS: This systematic review and meta-analysis yielded 13 studies after exclusion, and the baseline indicators were balanced. We found a significant increase in the number of patients who achieved clinical remission in the ADA [odds ratio (OR) = 1.416, 95% confidence interval (CI): 1.196-1.676] and RCT (OR = 1.393, 95%CI: 1.182-1.641) subgroups and a significant decrease in the number of patients who needed surgery in the proactive vs reactive (OR = 0.237, 95%CI: 0.101-0.558) and IFX + ADA (OR = 0.137, 95%CI: 0.032-0.588) subgroups, and the overall risk of adverse events was reduced (OR = 0.579, 95%CI: 0.391-0.858) according to the pairwise meta-analysis. Moreover, the network meta-analysis results suggested that patients with IBD treated with ADA (OR = 1.39, 95%CI: 1.19-1.63) were more likely to undergo TDM, especially in comparison with patients with reactive TDM (OR = 1.38, 95%CI: 1.07-1.77). CONCLUSION: Proactive TDM is more suitable for IBD patients treated with ADA and has obvious advantages over reactive TDM. We recommend proactive TDM in IBD patients who are treated with ADA.

Anti-hepatoma Effect of DC2.4 Cells Transfected with Tumor-Associated Antigen Cdc25C In Vitro.

OBJECTIVE: Cell division cyclin 25 homolog C (Cdc25C) is a tumor-associated antigen candidate gene, and this may be used as an effective target in cancer treatment. The present study aims to evaluate the lysis effect of cytotoxic T lymphocytes (CTLs) induced by dendritic cell line DC2.4 overexpressing Cdc25C, and the feasibility of Cdc25C as a component in hepatoma immunotherapy. METHODS: The mouse Cdc25C gene was ligated into a lentiviral vector, and transfected into DC2.4 cells. The DC2.4 cell phenotype and cytokine secretion were determined by flow cytometry and ELISA, respectively. CD8+ T cells were sorted from the spleens of C57BL/6 mice using a magnetic bead sorting kit obtained from Miltenyi Biotech, Germany, and co-cultured with DC2.4 cells for one week as effector cells. Then, IL-2, granzyme B and perforin were detected in the CTL culture medium by ELISA. Next, time-resolved fluorescence immunoassay was used to detect the immune killing effect of Cdc25C-specific CTLs on target cells. Meanwhile, the effect of blocking MHC-I sites on target cells with a monoclonal anti-MHC-I antibody was evaluated. RESULTS: The results revealed that Cdc25C could be stably overexpressed in DC2.4 cells by LV-Cdc25C infection. DC2.4 cells transfected with LV-Cdc25C secreted more IL-6, IL-12, TNF-α and IFN-γ, and had higher expression levels of CD40, CD86, CCR7 and MHC-II than unaltered DC2.4 cells. The elevated Cdc25C in dendritic cells also further increased the secretion of IL-2, granzyme B and perforin to elicit Cdc25C-specific CTLs, and induced the higher cytotoxicity in Hepa1-6 cell lines (P<0.05), but this had no effect on the target cells when MHC-I monoclonal antibodies were blocked. CONCLUSION: DC2.4 cells transfected with LV-Cdc25C can induce specific CTLs, and result in a strong cellular immune response. The dendritic cells that overexpress Cdc25C may be useful for hepatoma immunotherapy.

Comparative Analysis of Mitogenomes among Five Species of Filchnerella (Orthoptera: Acridoidea: Pamphagidae) and Their Phylogenetic and Taxonomic Implications.

Mitogenomes have been widely used for exploring phylogenetic analysis and taxonomic diagnosis. In this study, the complete mitogenomes of five species of Filchnerella were sequenced, annotated and analyzed. Then, combined with other seven mitogenomes of Filchnerella and four of Pamphagidae, the phylogenetic relationships were reconstructed by maximum likelihood (ML) and Bayesian (BI) methods based on PCGs+rRNAs. The sizes of the five complete mitogenomes are Filchnerella sunanensis 15,656 bp, Filchnerella amplivertica 15,657 bp, Filchnerella nigritibia 15,661 bp, Filchnerella pamphagoides 15,661 bp and Filchnerella dingxiensis 15,666 bp. The nucleotide composition of mitogenomes is biased toward A+T. All tRNAs could be folded into the typical clover-leaf structure, except that tRNA Ser (AGN) lacked a dihydrouridine (DHU) arm. The phylogenetic relationships of Filchnerella species based on mitogenome data revealed a general pattern of wing evolution from long wing to increasingly shortened wing.

Diversity of the gut microbiome in three grasshopper species using 16S rRNA and determination of cellulose digestibility.

BACKGROUND: Grasshoppers are typical phytophagous pests, and they have large appetites with high utilization of plants fibers, the digestion of which may depend on the microorganisms in their intestines. Grasshoppers have the potential to be utilized in bioreactors, which could improve straw utilization efficiency in the future. In this study, we describe the gut microbiome in three species of grasshoppers, Oedaleus decorus asiaticus, Aiolopus tamulus and Shirakiacris shirakii, by constructing a 16S rDNA gene library and analyzed the digestibility of cellulose and hemicellulose in the grasshoppers by using moss black phenol colorimetry and anthrone colorimetry. RESULTS: There were 509,436 bacterial OTUs (Operational Taxonomic Units) detected in the guts of all the grasshoppers sampled. Among them, Proteobacteria and Firmicutes were the most common, Aiolopus tamulus had the highest bacterial diversity, and Shirakiacris shirakii had the highest bacterial species richness. The intestinal microflora structure varied between the different species of grasshopper, with Aiolopus tamulus and Shirakiacris shirakii being the most similar. Meanwhile, the time at which grasshopper specimens were collected also led to changes in the intestinal microflora structure in the same species of grasshoppers. Klebsiella may form the core elements of the microflora in the grasshopper intestinal tract. The digestibility of cellulose/hemicellulose among the three species grasshoppers varied (38.01/24.99%, 43.95/17.21% and 44.12/47.62%). LEfSe analysis and Spearman correlation coefficients showed that the hemicellulosic digestibility of Shirakiacris shirakii was significantly higher than that of the other two species of grasshopper, which may be related to the presence of Pseudomonas, Stenotrophomonas, Glutamicibacter, Corynebacterium, and Brachybacterium in Shirakiacris shirakii intestinal tract. CONCLUSION: The intestinal microbial communities of the three grasshoppers species are similar on phylum level, but the dominant genera of different species grasshoppers are different. The cellulose digestibility of the three species of grasshoppers is relatively high, which may be correlated with the presence of some gut microbiome. Increasing the understanding of the structure and function of the grasshopper intestinal microflora will facilitate further research and the utilization of intestinal microorganisms in the future.

Impact of tyrosine kinase inhibitors on the statural growth in children with acute lymphoblastic leukemia.

PURPOSE: To investigate the effect of tyrosine kinase inhibitors (TKIs) on the statural growth in children with acute lymphoblastic leukemia (ALL). METHODS: We retrospectively collected data from 344 children with ALL younger than 17 years old at diagnosis identified in pediatric department of Peking University People's Hospital. The children were divided into three groups: conventional chemotherapy group, imatinib group and dasatinib group. Height was expressed as standard deviation score(HtSDS). In the three groups, we compared the HtSDS and △HtSDS at the start of treatment and during follow-up period and also compared the adult height and median parental height(MPH). We further compared the HtSDS classified by age and gender in imatinib group. At last, univariate analysis was used to analyze the influencing factors on the deceleration of height growth by imatinib. RESULTS: There were 298 children in conventional chemotherapy group, 39 in imatinib group and 7 in dasatinib group. In imatinib group, the mean HtSDS of children at follow-up time was significantly lower than that at the start of treatment (P < 0.05), regardless of age and gender. In imatinib group, the decrease of HtSDS in girls was more obvious than in boys(P = 0.031). The HtSDS gradually decreased in the first and the second year in imatinib group. After discontinuation of imatinib, the HtSDS had no obvious change. Multivariate analysis showed that the HtSDS at the start of imatinib was negatively correlated with severe growth impairment on imatinib therapy. The HtSDS in dasatinib group and conventional chemotherapy group maintained a high degree of consistency. CONCLUSION: Imatinib can affect growth velocity in children with ALL, regardless of age and gender. With the discontinuation of imatinib, the inhibitory effect will not continue. The lower HtSDS at the start of imatinib therapy, the more obvious effect of imatinib on growth impairment will be, and the effect will be more obvious in girls than boys.

Comparative analysis of mitogenomes among six species of grasshoppers (Orthoptera: Acridoidea: Catantopidae) and their phylogenetic implications in wing-type evolution.

The degree of wing development has a close relationship with insects' movement ability and range, and it should also be closely related to mitochondrial-related genes. The complete mitochondrial genomes of six species of Catantopidae were sequenced, annotated and analyzed. Then, combined with 37 mitogenomes of grasshoppers, the ratio of nonsynonymous substitution to synonymous substitution (Ka/Ks) of the combined sequences of protein coding genes (PCGs) was calculated by DnaSP5, and the phylogenetic relationships were reconstructed by maximum likelihood (ML) and Bayesian (BI) methods based on PCGs+rRNAs. The results showed that the sizes of the six complete mitogenomes are Stenocatantops mistshenkoi Willemse F., 1968, 15,573 bp; Traulia lofaoshana Tinkham, 1940, 15,645 bp; Sinopodisma rostellocerca You, 1980, 15,622 bp; Anapodisma miramae Dovnar-Zapolskij, 1932, 15,189 bp; Qinlingacris elaeodes Yin & Chou, 1979, 15,221 bp; and Eozubovskya planicaudata Zhang & Jin, 1985, 15,830 bp; their structures are the same as those of Acridoidea. The AT bias of the wing-degenerated group (lobiform and apterous) is higher than that of the longipennate group, and more nonsynonymous substitutions accumulated in the wing-degenerated group than in the longipennate group (P = 0.000), which indicates that the wing-degenerated group has undergone weaker evolutionary selection than the longipinnate group. The phylogenetic tree shows that the wing-degenerated group in the Catantopidae are multiorigin and present parallel evolution.

[Influence of dasatinib treatment on body height in children with acute myeloid leukemia].

OBJECTIVE: To study the influence of dasatinib treatment on body height in children with acute myeloid leukemia (AML). METHODS: A retrospective analysis was performed for the clinical data of 86 AML children aged <17 years. According to the treatment regimen, these children were divided into a conventional chemotherapy group and a dasatinib chemotherapy group. The 57 children in the conventional chemotherapy group were given conventional chemotherapy drugs without tyrosine kinase inhibitor, and the 29 children in the dasatinib chemotherapy group were given conventional chemotherapy drugs and dasatinib. The two groups were compared in terms of height standard deviation score (HtSDS) at the beginning of treatment and after treatment, as well as the change in HtSDS after 1 and 2 years of treatment. RESULTS: There was no significant difference in HtSDS between the conventional and dasatinib chemotherapy groups before treatment. Within the first two years of treatment, the dasatinib chemotherapy group had a similar change trend of HtSDS as the conventional chemotherapy group. Four children in the dasatinib chemotherapy group reached the final adult height during follow-up, which was significantly lower than the target height (P=0.044). In the conventional chemotherapy group, there was no significant difference between final adult height and target height. In the dasatinib chemotherapy group, the children in adolescence had a significant change in HtSDS after treatment (P=0.032). CONCLUSIONS: Dasatinib treatment may affect the final height of children with AML, and the use of dasatinib after the beginning of adolescence may lead to growth disorder, but dasatinib treatment has little effect on body height in the short-term treatment.

[Diagnostic value of the propranolol-exercise provocative test for growth hormone deficiency in children].

OBJECTIVE: To assess the diagnostic value of the propranolol-exercise provocative test for growth hormone deficiency (GHD) in children. METHODS: This study included 120 children who received both the insulin provocative test and the propranolol-exercise provocative test due to short stature between January 2009 and March 2013. Growth hormone (GH) levels in venous blood were measured before and after the provocative test. Peak GH <10 ng/mL was defined as negative stimulation, while peak GH ≥10 ng/mL was defined as positive stimulation. The children whose peak GH levels were <10 ng/ mL after both tests were diagnosed with GHD. RESULTS: Twenty-nine (24.2%) of the 120 children with short stature were diagnosed with GHD. The positive rate in the insulin provocative test was 48.3%, versus 65.8% in the propranolol-exercise provocative test. The overall coincidence rate and positive coincidence rate of the two tests were 62.5% and 79.3%, respectively. The peak GH after the propranolol-exercise provocative test was significantly higher than that after the insulin provocative test (P<0.01). Peak GH occurred mostly at 30-60 minutes after the insulin provocative test, while that occurred mostly at 120 minutes after the propranolol-exercise provocative test. No adverse effects were observed in the propranolol-exercise provocative test. CONCLUSIONS: Coincidence rates in stimulating the secretion of GH are high between the propranolol-exercise provocative test and the insulin provocative test. Compared with the insulin provocative test, the propranolol-exercise provocative test is more likely to stimulate the secretion of GH. GHD can be clinically diagnosed by the insulin provocative test combined with the propranolol-exercise provocative test.

[Effects of r-hGH replacement therapy on glucose and lipid metabolism and thyroid function in children with idiopathic short stature].

OBJECTIVE: To study the effects of recombinant human growth hormone (r-hGH) replacement therapy on glucose and lipid metabolism and thyroid function in children with idiopathic short stature (ISS). METHODS: Forty-seven ISS children with a mean age of 10±3 years treated between January 2009 and January 2013 were enrolled. All children underwent r-hGH replacement therapy for 3-24 months and were followed up once every 3 months. Fasting blood glucose (FBG), insulin (INS), blood lipids and thyroid function were measured before treatment and after 0-1 and 1-2 years of treatment. RESULTS: After treatment with r-hGH, there were no significant changes in FBG, INS, insulin sensitivity index (ISI), and FBG/INS ratio (FGIR), but the FGIR showed a declining trend. The percentage of patients with FGIR<7 (a marker of insulin resistance) was 13% before treatment compared to 18% 1-2 years after treatment. The atherosclerosis index decreased after r-hGH treatment, but there were no significant changes in total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and BMI. Furthermore, no significant change in thyroid function was observed after r-hGH therapy. CONCLUSIONS: r-hGH therapy can improve lipid metabolism, without significant impacts on thyroid function, FBG and INS. It seems to be a safe and reliable therapy for children with ISS. However, this therapy possibly reduces insulin sensitivity.

[Physiological changes in serum procalcitonin concentrations in premature infants early after birth].

OBJECTIVE: To investigate serum procalcitonin (PCT) concentrations in premature infants with different gestational ages at different times after birth. METHODS: A total of 217 neonates without infection, including 102 premature infants and 115 full-term infants, were enrolled in this study. The premature infants were further divided by gestational age into three subgroups: 30-32 weeks (n=30), 33-34 weeks (n=35) and 35-36 weeks (n=37). All the infants were studied to evaluate serum PCT concentrations at 0-12, 13-24, 25-36, 37-48, 49-72, 73-96, 97-120 and 121-144 hours after birth. RESULTS: In the newborns, serum PCT concentrations increased gradually after birth, reached peak values at about 24 hours after birth, and then gradually declined and dropped to normal values for children at about 96 hours after birth. In the premature infants, serum PCT concentrations reached peak values at about 36 hours after birth, later than in the full-term infants, then declined slowly and dropped to levels similar to the full-term infants at 96 hours after birth. Serum PCT concentrations in the 30-32 week subgroup remained at low levels after birth, and increased gradually, later than in other premature infants, at 37-48 hours after birth. CONCLUSIONS: Early after birth, neonates have a changing serum PCT concentration, increasing first and then decreasing. Peak serum PCT levels appear later in premature infants than in full-term infants. Serum PCT concentrations of premature infants with a gestational age of under 32 weeks remain at relatively low levels within 36 hours after birth.