Polyethylene glycol recombinant human growth hormone in Chinese prepubertal slow-growing short children: doses reported in a multicenter real-world study.

BACKGROUND: To evaluate the effectiveness of individualized-dose polyethylene glycol recombinant human growth hormone (PEG-rhGH) for short stature. METHODS: This real-world study enrolled children with short stature in 19 hospitals throughout China. They were treated with PEG-rhGH for 6 months. The starting dosage ranged from 0.10 to 0.20 mg/kg/week. The primary outcome was the change in height standard deviation score (ΔHt SDS). RESULTS: Five hundred and ten patients were included and grouped based on dosage as A (0.10-0.14 mg/kg/week), B (0.15-0.16 mg/kg/week), C (0.17-0.19 mg/kg/week), and D (0.20 mg/kg/week). The mean 6-month ΔHt SDS for the total cohort was 0.49 ± 0.27, and the means differed among the four dose groups (P = 0.002). The ΔHt SDS was lower in group A than in groups B (LSM difference [95%CI], -0.09 [-0.17, -0.01]), C (LSM difference [95%CI], -0.10 [-0.18, -0.02]), and D (LSM difference [95%CI], -0.13 [-0.21, -0.05]) after adjusting baseline covariates. There were no significant differences among groups B, C, and D. When the baseline IGF-1 was < -2 SDS or > 0 SDS, the △Ht SDS was not different among the four groups (P = 0.931 and P = 0.400). In children with baseline IGF-1 SDS of -2 ~ 0 SDS, a higher dosage was associated with a better treatment effect (P = 0.003), and the △Ht SDS was lower in older children than in younger ones (P < 0.001). CONCLUSIONS: PEG-rhGH could effectively increase height in prepubertal short children. When the baseline IGF-1 was < -2 SDS, 0.10 mg/kg/week could be a starting dose. In other IGF-1 statuses, 0.15-0.20 mg/kg/week might be preferred. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03249480 , retrospectively registered.

Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty.

BACKGROUND: To evaluate the efficacy of GH in improving FAH in ISS children in a multicenter study. METHODS: A real-world observation was carried out. Children with ISS in seven hospitals in China were enrolled. The height gains standard deviation score and the height gain over the target height were evaluated. RESULTS: There were 344 ISS patients (217 boys and 127 girls). The baseline average age of boys and girls was 12.7 and 11.7 years, with bone age of 11.7 and 10.1 years, respectively. The baseline height SDS of boys and girls was - 3.07 and - 2.74, and the FAH SDS was - 1.91 and - 1.38, respectively. Compared with the baseline height SDS, the FAH SDS was significantly increased in both boys and girls (both P = 0.0000). The FAH SDS was the highest (gain by 1.54 SD) in the ≥2y treatment course group. Two hundred eighteen patients (218/344, 63.4%) had a FAH SDS > - 2 SD. Among these patients, girls in the 1-2y treatment course group and ≥ 2y group had a FAH SDS higher than TH SDS. Even in the control group, a spontaneous catch-up growth of 1.16 SD was observed. A multivariate linear regression model was used to analyze the results, with FAH SDS as the dependent variable. It was found that the treatment course and baseline height SDS in the boys' model were statistically significant (P < 0.05), whereas the baseline height SDS and baseline bone age significantly affected the girls' FAH SDS (P < 0.05). CONCLUSIONS: Both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.

High prevalence of elevated serum liver enzymes in Chinese children suggests metabolic syndrome as a common risk factor.

AIM: This study investigated the pattern of liver enzymes in a large cohort of Chinese children and adolescents, including 16 383 individuals aged 4-18 years old recruited at six medical centres in China. METHODS: Clinical data were collected including weight, height, blood pressure, alanine aminotransferase, aspartate aminotransferase and fasting lipid panel. We used an unsupervised machine learning algorithm, the K-means clustering method, to identify different patterns of increased liver enzymes. RESULTS: Six clusters of elevated enzymes patterns were identified. The most common in 2.18% (325) of youth was elevated transaminases in the absence of features of metabolic syndrome(MetS), and they were thinner, and more likely to be from urban areas. The second cluster, with 1.47% (n = 220) youth had the most notable MetS features. They were older, obese and had central obesity, higher BP, triglycerides cholesterol and lower high-density lipoprotein cholesterol. Cluster 3 (0.6%, N = 90) had mild MetS, and cluster 4 (0.06%, N = 9), 5 (0.03%, N = 5) and 6 (0.007%, N = 1) were not related to MetS. CONCLUSIONS: We identified two distinct groups of children with both increased liver enzymes and MetS features in this population sample of Chinese children. One of the two groups had increased liver enzymes as the predominant clinical features at a younger age, suggesting genetic susceptibility to the condition. Further work to understand the increased MetS risk in cluster 2 is warranted.

U-shaped relationship between birth weight and childhood blood pressure in China.

BACKGROUND: The relationship between birth weight and blood pressure has not been well explored in Chinese children and adolescents. The aim of this study was to investigate the relationship between birth weight and childhood blood pressure in China. METHODS: A total of 15324 children and adolescents (7919 boys and 7405 girls) aged 7-17 years were stratified into six birth weight groups. Analysis of covariance and binary logistic regression were used to analyse the relationship between birth weight and blood pressure while controlling for potential confounding factors, including age, gestational age, season of birth and area of residence. RESULTS: The group with birth weights from 2500 to 2999 g had the lowest prevalence of hypertension (8.9%). Lower birth weight children (< 2000 g) had significantly higher systolic blood pressure (SBP) (106.00 ± 0.72, P = 0.017), and children with heavier birth weights also had higher SBP (3500-3999 g, 105.13 ± 0.17, P < .001; ≥ 4000 g, 105.96 ± 0.27, P < .001). No significant relationship was found between birth weight and diastolic blood pressure (DBP). The overall rate of hypertension was 10.8% (12.1% in boys and 9.4% in girls). The median weight group (2500-2999 g) had the lowest rate of hypertension (8.9%). Compared with children in the median weight group, children with lower birth weight had a higher prevalence of hypertension (< 2000 g, OR = 1.85, 95% CI = 1.25-2.74; 2000-2499 g, OR = 1.57, 95% CI = 1.15-2.13), and groups with higher birth weights also had higher risks of hypertension (3500-3999 g, OR = 1.22, 95% CI = 1.02-1.45; ≥ 4000 g, OR = 1.42, 95% CI = 1.16-1.74). CONCLUSIONS: Excluding the confounding effect of obesity, a U-shaped relationship between birth weight and risk of hypertension was found in children and adolescents in Chinese cities. Birth weight significantly influences SBP but has a minimal effect on DBP. Further basic research on foetal development and programming may shed light on this phenomenon.

IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling.

The assembly and maintenance of cilia depend on intraflagellar transport (IFT) proteins, which play an important role in development and homeostasis. IFT80 is a newly defined IFT protein and partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III, both characterized by abnormal skeletal development. However, the role and mechanism of IFT80 in the invasion of gastric cancer is unknown. We established SGC-7901 and MKN-45 gastric cancer cell lines that stably overexpressed IFT80, as verified by quantitative reverse transcription-PCR, Western blot, and immunofluorescence. Matrix metalloproteinase-9 (MMP9) plays an important role in tumor invasion, and its expression was assessed by quantitative reverse transcription-PCR, Western blotting, and immunofluorescence. The invasion ability of IFT80 on SGC-7901 and MKN-45 cells was examined by the Matrigel invasion assay. The relationship between p75NGFR, and the p75NGFR antagonists, PD90780 and IFT80, were detected by quantitative reverse transcription-PCR and Western blotting. We first detected an IFT80 expression pattern, and found that IFT80 was highly expressed in gastric cancer clinical samples. Overexpression of IFT80 in the gastric cancer cell lines, SGC-7901 and MKN-45, led to lengthening cilia. Additionally, overexpression of IFT80 significantly improved proliferation and invasion, but inhibited apoptosis, in gastric cancer cells. We further found that overexpression of IFT80 increased p75NGFR and MMP9 mRNA and protein expression. Treatment with the p75NGFR antagonist PD90780 inhibited the increased invasion ability resulting from overexpression of IFT80 in SGC-7901 and MKN-45 gastric cancer cells. Thus, these results suggest that IFT80 plays an important role in invasion of gastric cancer through regulating the ift80/p75NGFR/MMP9 signal pathways.

Metformin use improves the survival of diabetic combined small-cell lung cancer patients.

Metformin has been reported having potential anticancer effect on kinds of solid tumors, but its role in combined small-cell lung cancer (C-SCLC) remains indistinct. This study aimed to explore whether metformin use has a prognosis benefit in diabetic C-SCLC patients. A total of 259 C-SCLC patients with diabetes were enrolled in our study. The clinicopathological parameters and survival data were collected and analyzed. The correlation between metformin use and clinicopathological characters was analyzed. Univariate and multivariate analyses were performed to investigate the prognostic significance of metformin use for C-SCLC. The metformin was used in 120 (46.3 %) patients. Our data showed that the metformin use decreased C-SCLC recurrence rate (p = 0.001). The median overall survival (OS) and disease-free survival (DFS) were significantly better in the metformin use group compared to non-metformin group (OS 19.0 vs 11.5 months, p < 0.001; DFS 10.5 vs 7.0 months, p < 0.001). Multivariate analyses indicated that metformin use was an independent prognostic factor for OS and DFS (p = 0.001 vs p = 0.018). The metformin use improved the long-term outcome of C-SCLC patients with diabetes, which might be considered a potential useful prognostic indicator and anticancer drug.

The overexpression of MCPH1 inhibits cell growth through regulating cell cycle-related proteins and activating cytochrome c-caspase 3 signaling in cervical cancer.

MCPH1, initially identified as an hTERT repressor, has recently been implicated in mediating DNA damage response and maintaining chromosome integrity. This study is to investigate its potential role in the onset of cervical cancer. In the study, decreased expression of MCPH1 was observed in 19 of 31 cases (61.3%) at mRNA level and 44 of 63 cases (69.8%) at protein level of cervical tumor tissues compared with the paired nontumor tissues. Reduced MCPH1 protein expression was significantly associated with high-tumor grade (1 vs. 3 P = 0.013; 2 vs. 3 P = 0.047). In addition to inhibit SiHa cell migration and invasion, the overexpression of MCPH1 inhibited cervical cancer cells growth through inducing S phase arrest and mitochondrial apoptosis. Further analysis demonstrated cyclinA2/CDK2, CDC25C-cyclinB/CDC2, and p53/p21 pathways were involved in the MCPH1 overexpression-induced S phase arrest. Moreover, the overexpression of MCPH1 activated mitochondrial apoptosis through regulating several apoptosis-related proteins such as p53, Bcl-2, Bax, cytochrome c, caspase-3, and PARP-1. Our findings indicate that downregulated MCPH1 correlates with tumor progression in cervical cancer, and MCPH1 has an important role in regulating cell growth through regulating the cell cycle and apoptosis. Thus, it may be a crucial tumor suppressor gene and a novel candidate therapeutic target for cervical cancer.

[Epidemiologic study on current pubertal development in Chinese school-aged children].

OBJECTIVE: To survey the current status of pubertal development of Chinese children and to compare the precocious puberty prevalence of different regions. METHODS: A cross-sectional epidemiological study was conducted on 18 707 children and adolescents aged 6≊18 y with male/female ratio of 9 812/8 895 from 6 representative geographical areas in China, including Beijing, Tianjin, Hangzhou, Shanghai, Chongqing and Nanning. The height, weight, waist circumference (WC), hip circumference(HC) and sexual maturation states (Tanner stages: breast stages for girls and testicular volume for boys) of children and adolescents were measured. Probit analysis was used to calculate the median age and 95% confidence interval (CI) for onset of breast and testicular development. The prevalence of precocious puberty of different regions and BMI, waist circumference of different groups were compared. RESULTS: Breast development before 8 y was observed in 2.91% of girls, and testicular volume 4 ml or more before 9 y was observed in 1.74% of boys. The median age of onset of Tanner stages 2 for breast development in girls was 9.69 y (95% CI: 9.63≊ 9.75); the median age of onset of puberty as indicated by Tanner stages 2 for testicular development in boys was 11.25 y (95%CI:11.19≊ 11.30). The prevalence of precocious puberty (43 girls and 37 boys) was 0.43% (80/18 707). The prevalence of precocious puberty in northern region was higher than that in southwest region (0.736% compared with 0.282% P<0.05). There was no difference in onset age of precocious puberty in girls among three regions; but the onset age of precocious puberty in boys was earlier in east China [(7.4±0.28)y]. The SD values of BMI and waist-to-hip ratio (W/H) in precocious puberty children were higher than those in the peer normal children. There was no difference in BMI,waist circumference and waist-to-hip ratio in the precocious puberty children among different regions. CONCLUSION: The current diagnostic criteria of precocious puberty are suitable for the children in the survey areas. The prevalence and the onset age of precocious puberty are various in different regions. A positive association between obesity and precocious puberty is found both in boys and girls.

[Correlation between vaspin concentration and insulin sensitivity in the visceral adipose tissue of young obese rats].

OBJECTIVE: To investigate the correlation between visceral adipose tissue-derived serine protease inhibitor (vaspin) concentration and insulin sensitivity in the visceral adipose tissue of young obese Sprague-Dawley (SD) rats. METHODS: Twenty-four SD rats which had been weaned 3 weeks before were randomly divided into two groups (n=12 each) to receive a high-fat and normal diet. The weight and abdominal circumference (AC) of each rat were measured, the fasting plasma glucose (FPG) and fasting insulin (FINS) in blood from the angular vein were measured after 12 hours of fasting and blood glucose (BG) and insulin (INS) levels in blood from the angular vein were measured at 60 and 120 minutes after intraperitoneal injection of 50% glucose (2 g/kg). The rats were sacrificed, and their liver and visceral adipose tissue were weighed. The vaspin concentration of the visceral adipose tissue in each rat was measured using ELISA. Correlation analysis was performed on the vaspin concentration and other indices. RESULTS: Compared with the normal diet group, the high-fat diet group showed significantly higher weight, AC, weight of visceral adipose tissue, FPG, FINS, 120 minute INS level, vaspin concentration, homeostasis model assessment for insulin resistance (HOMA-IR) and homeostasis model assessment of ß cell function (HOMA-ß) (P<0.05) Insulin sensitivity index (ISI) was significantly lower (P<0.01). Vaspin concentration was positively correlated with visceral adipose tissue and liver weight, AC, 120 minute INS level, FPG, FINS, HOMA-IR and HOMA-ß (P<0.05), and negatively correlated with ISI (P<0.05). CONCLUSIONS: High expression of vaspin is associated with insulin resistance in young obese SD rats. Vaspin is presumably an adipocytokine that can increase insulin sensitivity, promote insulin secretion by islet ß-cells and improve glucose tolerance, and it may be involved in insulin resistance and the disturbance of carbohydrate metabolism.

The rational dose for MaXingShiGan decoction is crucial for its clinical effectiveness in treating bronchial pneumonia: three randomized, double-blind, dose-parallel controlled clinical studies.

Objective: Evaluate the impact of adjusting the overall dose, Gypsum Fibrosum [Mineral; Gypsum] (ShiGao, SG) dose, and Prunus armeniaca L. [Rosaceae; Semen Armeniacae Amarum] (KuXingRen, KXR) dose on the efficacy of MaXingShiGan Decoction (MXSG) in treating children with bronchial pneumonia (Wind-heat Blocking the Lung), in order to provide strategy supported by high-quality evidence for the selection of rational clinical doses of MXSG. Methods: Based on the basic dose of MXSG, we conducted three randomized, double-blind, dose parallel controlled, multicenter clinical trials, involving adjustments to the overall dose, SG dose, and KXR dose, and included 120 children with bronchial pneumonia (Wind-heat Blocking the Lung) respectively. And the patients were divided into low, medium, and high dose groups in a 1:1:1 ratio, with 40 cases in each group. The intervention period lasted for 10 days. The primary outcome was the clinical cured rate, while the secondary outcomes included the effectiveness in alleviating major symptoms of bronchial pneumonia (including fever, cough, dyspnea, and phlegm congestion). And the occurrence of adverse events was recorded. Results: We first recorded and analyzed the baseline characteristics of the three studies, including age, gender, height, and so on. The results indicated that there were no significant differences among the dose groups within each study. For the study adjusting the overall dose of MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher clinical cured rates compared to the low-dose group (Chi-square value 9.01, p = 0.0111). However, there was no significant benefit between the high-dose group and the medium-dose group (81.58% vs. 81.08%). Regarding phlegm congestion, excluding fever, cough, and dyspnea, both the medium-dose group and high-dose group had significantly higher clinical cured rates than the low-dose group (Chi-square value 6.31, p = 0.0426), and there was no significant benefit between the high-dose group and the medium-dose group (69.23% vs. 75.00%). A total of 5 adverse events were observed, of which only 1 case in the medium-dose group was possibly related to the experimental medication. For the study adjusted the SG dose in MXSG, the results showed that the high-dose group had the highest clinical cured rate, but the inter-group difference was not statistically significant (Chi-square value 3.36, p = 0.1864). The area under the curve (AUC) for cough in the medium-dose group was significantly lower than in the low-dose group and high-dose group (F-test value 3.14, p = 0.0471). Although no significant differences were observed in fever and dyspnea among the groups, the AUC in the high-dose group was lower than in the medium-dose and low-dose groups. In comparing the complete defervescence time, both the high-dose group (p < 0.0001) and the medium-dose group (p = 0.0015) achieved faster than the low-dose group. The high-dose group slightly outperformed the medium-dose group (0.50 (0.50, 0.80) vs. 0.80 (0.40, 1.40)), although the difference was not significant. In the medium-dose group, 1 adverse event was observed, but it was not related to the experimental medication. For the study adjusted the KXR dose in MXSG, the results showed that both the medium-dose group and high-dose group had significantly higher cured rates compared to the low-dose group (Chi-square value 47.05, p < 0.0001). However, there was no significant benefit comparing the high-dose group to the medium-dose group (90.00% vs. 92.50%). Regarding clinical symptoms, the results indicated that for cough (F-test value 3.16, p = 0.0460) and phlegm congestion (F-test value 3.84, p = 0.0243), the AUC for both the medium-dose group and high-dose group were significantly lower than in the low-dose group. Although there was benefit in the high-dose group compared to the medium-dose group, it was not statistically significant. No adverse events were observed during the study period. Conclusion: The synthesis of the three conducted clinical studies collectively indicates that for children with bronchial pneumonia (Wind-heat Blocking the Lung), the basic clinical dose of MXSG may represents an optimal intervention dose based on the accumulated clinical experience of doctors. If the dose is insufficient, the clinical effects might be compromised, but using a higher dose does not significantly enhance benefits. Concerning different symptoms, increasing the overall formula's dose has a favorable impact on improving phlegm congestion, increasing the SG is effective in improving symptoms such as fever, cough, and dyspnea, while higher dose of KXR is effective in alleviating cough and phlegm congestion. These findings suggest that for MXSG, achieving the optimal intervention dose is crucial to achieve better clinical efficacy. For the SG and KXR, if certain symptoms are more severe, increasing the dose can be considered within safe limits, can lead to significant clinical benefits in symptom improvement. This also explains why the dose of MXSG might vary among clinical doctors, while maintaining a balance between safety and effectiveness. Of course, our study is still exploratory clinical trials, and further studies are needed to confirm our findings. Clinical Trial Registration: https://www.chictr.org.cn/index.html; Identifier: ChiCTR-TRC-13003093, ChiCTR-TRC-13003099.

Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study.

CONTEXT: The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. OBJECTIVE: This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. DESIGN: A prospective, observational, posttrial study (NCT03290235). SETTING, PARTICIPANTS AND INTERVENTION: Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months. MAIN OUTCOMES MEASURES: Height SD score (Ht SDS) at 12, 24, and 36 months. RESULTS: A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. CONCLUSIONS: PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

Construction of Bifidobacterium infantis as a live oral vaccine that expresses antigens of the major fimbrial subunit (CfaB) and the B subunit of heat-labile enterotoxin (LTB) from enterotoxigenic Escherichia coli.

We sought to develop Bifidobacterium infantis (BI) as a vehicle for the expression of heterologous antigens. Two proteins of enterotoxigenic Escherichia coli (ETEC) were expressed in BI: CfaB, a major fimbrial subunit protein, and LTB, the B subunit of heat-labile enterotoxin. The expression of CfaB and LTB in BI was verified by electrophoretic analysis. Sprague-Dawley rats were then subjected to intragastric immunization with BI-CfaB and BI-LTB systems both separately and together. ELISA was used to characterize the serum and mucosal immune responses against ETEC antigens. The immunized rats were intraperitoneally challenged with wild-type ETEC H10407 to study the immune response in vivo. The serum titres of IgG and faecal IgA antibodies in the BI-CfaB plus BI-LTB mixed vaccination group were significantly greater than those in the other two groups, which were immunized with a single vaccine (P<0.05). However, no significant difference was seen between the two groups that received a single immunization. These results suggest that expressing CfaB and LTB in BI provides a probiotic system with immunogenic properties. Furthermore, the expression of LTB in BI preserved its mucosal adjuvant effect. So this study confirms that BI can be used as a novel oral vaccine expression system for a heterologous antigen and BI-LTB can provide mucosal adjuvant properties.

NFBD1/MDC1 is a protein of oncogenic potential in human cervical cancer.

A large nuclear protein of 2089 amino acids, NFBD1/MDC1 has recently been implicated in tumorigenesis and tumor growth. In this study, we investigated its expression in cervical cancers and explored its function using gene knockdown approaches. We report here that NFBD1 expression is substantial increased in 24 of 39 cases (61.5%) of cervical cancer tissues at the mRNA level and in 35 of 60 cases (58.3%) at the protein level compared with the case matched normal tissues. Tumors with higher grade of malignancy tend to have higher levels of NFBD1 expression. By infecting cells with retroviruses expressing NFBD1 shRNA, we successfully knocked down NFBD1 expression in cervical cancer cell lines HeLa, SiHa, and CaSki. NFBD1 knockdown cells display significant growth inhibition, cell cycle arrest, higher apoptotic rate, and enhanced sensitivity to adriamycin. Furthermore, NFBD1 knockdown also inhibits the growth of HeLa cells in nude mice. Western blot analyses further revealed that NFBD1 knockdown induced Bax, Puma, and Noxa while down-regulating Bcl-2; it also up-regulated cytochrome C and activated caspases 3 and 9. Therefore, the function of NFBD1 may be involved in the CDC25C-CyclinB1/CDC2 pathway at the G2/M checkpoint, and the cytochrome C/caspase 3 apoptotic pathway. Since expression of NFBD1 seems to be related to the oncogenic potential of cervical cancer, and suppression of its expression can inhibit cancer cell growth both in vitro and in vivo, NFBD1 may be a potential therapeutic target in human cervical cancer.

Identification of immune-related cells and genes in the breast invasive carcinoma microenvironment.

The clinical prognosis of breast cancer is closely related to its infiltrating immune status. The study sought to explore tumor-infiltrating immune cells (TILs) and immune-associated genes in the tumor microenvironment of breast invasive carcinoma (BRCA). The ESTIMATE algorithm was used to evaluate the microenvironment of breast cancer patients in TCGA database. The tumor's matrix score and immune score were obtained. The median was divided into two sub groups according to the median of the score, and the correlation between the score and prognosis was also discussed. Differentially expressed genes were screened from two subgroups with high and low score of breast cancer, and the differentially expressed genes were analyzed by GO and KEGG enrichment to explore their possible molecular functions, biological processes, cellular components and signal pathways involved in gene enrichment. It was found that there was a significant correlation between immune score and five-year survival rate, and the high score group had a better prognosis. Macrophage M1 and T cell CD8+ cells were positively related to 5-year overall survival in patients with breast invasive carcinoma. However, Macrophage M2 was negatively related to 5-year overall survival. We also observed that the low expression of four genes (CLEC3A, MCTS1, PDP1 and TCP1,) was related to favorable survival outcomes. High expression of FOXP3, CXCL9, CCR5, CXCR3, and CD37 was related to a high overall survival rate in BRCA. We identified a list of immune - related cells and genes that are useful for Prognostic evaluation and individualized treatment of BRCA.

Evaluation of Growth Hormone Therapy in Seven Chinese Children With Familial Short Stature Caused by Novel ACAN Variants.

Objective: ACAN gene variants are an important cause of familial short stature (FSS). Appropriate growth-promoting therapies effectively improve the patient height. Here, we report a therapeutic assessment of cases of seven families of FSS patients with heterozygous ACAN variants. Our findings provide a valuable theoretical basis for the clinical diagnosis and treatment of this disease. Methods: From December 2020 to June 2021, 32 FSS patients were examined in Tianjin Medical University General Hospital (Tianjin, China) by whole-exome sequencing to determine whether ACAN variants were present. Their clinical data were summarized and scrupulously analyzed. Results: We found seven novel heterozygous ACAN variants: c.1051 + 2T > A, c.313T > C (p.S105P), c.2660C > G (p.S887X), c.2153C > A (p. T718K), c.7243delG (p.D2415Tfs*4), c.2911G > T (p.G971X), c.758-7T > C. All seven patients had proportionate short stature and mild skeletal dysplasia. Endocrine examination results were normal. Only one of the patients had an advanced bone age (1.1 years older than chronological age), whereas the other patients had normal bone ages. All of them had a family history of short stature, with or without osteoarthritis or intervertebral disc disease. All seven patients accepted treatment with recombinant human growth hormone (rhGH) and were regularly followed up. One patient did not come at the follow-up visit. The height of the remaining six patients before and after the treatment was -2.89 ± 0.68 SDS, -1.91 ± 0.93 SDS, respectively, with a treatment course of 1.85 ± 1.91 years. A good therapeutic response was observed in all of them. Conclusions: In this study, seven novel heterozygous variants in ACAN were discovered, which expanded the spectrum of the already established ACAN pathogenic variants. In FSS cohort, the proportion of ACAN variants accounted was large. The treatment with rhGH effectively increased the patient height, but further studies with longer follow-up periods and more extensive observations are required to elucidate the long-term effect.

Case report: A Chinese boy with facial dysmorphism, immunodeficiency, livedo, and short stature syndrome.

Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome is a rare autosomal recessive disease. In this study we reported the first Chinese patient with FILS syndrome. The patient had short stature and suffered from recurrent respiratory infections up to the age of 4 years. Other symptoms of the disease included livedo on the inner side of upper limbs and thigh skin, prominent forehead, low anterior and posterior hairline, short and down-slanting palpebral fissure, low-set ears, long nasal tip and columella, and a small mouth with irregular teeth. A whole exome sequencing (WES) was performed and revealed two variants within the polymerase ε (POLE) gene. One of the variants was a splicing variant (c.5811 + 2T > C) derived from the mother, while the other was a nonsense variant (c.2006G > A) derived from the father. These two variants were not reported in previous FILS syndrome cases. Therefore this case provides further insight into the POLE gene variant spectrum that enriches the clinical phenotype.

Influence of Dichloroacetate on Wilms'Tumor in vitro.

OBJECTIVE: To investigate the effect of dichloroacetate (DCA) on Wilms' tumor (WT) G401 cells. METHODS: CCK-8 assay was used to detect the influence of DCA on G401 cells viability and 10 mmol/L DCA was selected for subsequent experiments. The expression of glycolysis-related enzymes, such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), lactic acid dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1), and pyruvate dehydrogenase (PDH), were detected by qRT-PCR and western blot. The extracellular lactic acid and glucose concentrations were measured by the lactic acid assay kit and glucose oxidase method kit respectively. Flow cytometry was used to detect the effect of DCA on G401 cells apoptosis. The invasion and migration ability of G401 cells were detected by Transwell assay and wound-healing assay. RESULTS: The results showed that DCA reduced glycolysis-related enzymes expression, inhibited lactic acid production, and glucose consumption. DCA also suppressed cells growth, induced cells apoptosis and inhibited cells invasion and migration. CONCLUSION: Inhibition of aerobic glycolysis by DCA can reduce the viability of G401 cells, promote cells apoptosis and inhibit cells invasion and migration. Therefore, aerobic glycolysis may be a potential therapeutic target for Wilms' tumor.

Growth Curves of Chinese Children with Androgen Insensitivity Syndrome: A Multicenter Registry Study.

Objective: To provide new information about androgen insensitivity syndrome (AIS), we studied growth patterns in Chinese children with AIS. Subjects: Data are from 118 untreated AIS patients who were admitted to eight pediatric endocrine centers from January 2010 to December 2019. Methods: In this retrospective cohort study, clinical data were collected from a multicenter database. We compared physical assessment data among AIS patients and standard growth charts for Chinese pediatric population. Results: 1. Children with AIS grew slightly less than the mean before 6 months of age, and then, height gradually increased before 12 years of age, from the median to +1 standard deviation (SD), according to the standard reference for Chinese pediatric population. After 12 years of age, height showed differently in profiles: The mean height in AIS patients gradually decreased from the mean to −1 SD, according to the standard for Chinese boys, and increased from the mean to +2 SD, according to the standard for Chinese girls. 2. The weights of children with AIS were greater than the mean standards of Chinese pediatric population from newborn to 11 years of age. From 12−16 years of age, the mean weight of children with AIS showed different profiles, from the mean to −1 SD, according to the standard for Chinese boys and from the mean to +1.5 SD, according to the standard for Chinese girls. 3. Weight standard deviation (WtSDS) and target height (THt) in northern Chinese AIS patients were significantly higher than those from the southern region (p = 0.035, 0.005, respectively). Age in northern Chinese AIS patients was significantly younger than those from the southern region (p = 0.034). No difference was found among birth weight (BW), birth length (BL), height standard deviation (HtSDS) and body mass index (BMI) in AIS patients from different regions (p > 0.05). 4. HtSDS and WtSDS in complete AIS (CAIS) patients were higher than those in partial AIS (PAIS) patients without significant difference (p > 0.05). Conclusions: Growth of children with AIS varied to different degrees. AIS patients seemed not to experience a puberty growth spurt. CAIS and PAIS patients show little difference in their growth. Regional differences have no effect on the height but influence the weight of AIS patients.

Efficacy and safety of a Chinese herbal formula Maxing Ganshi Decoction in children with community-acquired pneumonia: A randomized, double-blind, placebo-controlled, multicenter trial.

Background: As one of the most commonly used Chinese medicine formula in the manage of respiratory diseases, Maxing Ganshi Decoction (MGD) has been demonstrated to improve the clinical symptoms of pneumonia. To evaluate the efficacy and safety of MGD in treating children with community-acquired pneumonia (CAP), we conducted the clinical trial. Methods: A randomized, double-blind, placebo-controlled, multicenter trial was conducted in 3 study sites in Tianjin, China. MDG or placebo were randomly given to patients aged 3-6 years with onset of CAP within 48 h. Changes in disease efficacy during the study period (which was measured as recovery, significant effect, improvement and no effect) was evaluated as the primary outcome. Time from enrollment to fever resolution was assessed as the secondary outcome. The adverse event was analyzed as safety evaluation. Results: A total of 71 patients (36 in MGD and 35 in placebo) were randomized and completed the whole study. The patient demographics and other characteristics at baseline were similar between the 2 groups (p > 0.05). After 10 days of intervention, the proportion of recovered and significant effective patients was increased significantly in the MGD group (34.85% [95% CI, 12.44%-57.26%]; p < 0.05) compared with the control group. Besides, the symptom score of the MGD group was lowered significantly (p < 0.001). The estimated time to fever resolution in the MGD group was also reduced compared with the control group (p < 0.05). During the whole study, no side effects were observed in both MGD and control groups. Conclusion: MGD was effective in improving disease efficacy, clinical symptoms and reducing time to fever resolution in patients with childhood CAP, which suggested that MGD may be used as an alternative therapy in the treatment of childhood CAP. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx?proj=5612, identifier 13003955.

Primary cilia regulate gastric cancer-induced bone loss via cilia/Wnt/ß-catenin signaling pathway.

Cancer-associated bone disease is a frequent occurrence in cancer patients and is associated with pain, bone fragility, loss, and fractures. However, whether primary or non-bone metastatic gastric cancer induces bone loss remains unclear. Here, we collected clinical evidence of bone loss by analyzing serum and X-rays of 25 non-bone metastatic gastric cancer patients. In addition, C57BL mice were injected with the human gastric cancer cell line HGC27 and its effect on bone mass was analyzed by Micro-CT, immunoblotting, and immunohistochemistry. Furthermore, the degree of the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) co-cultured with HGC-27 or SGC-7901 cells was analyzed by colony-formation assay, alizarin red staining, immunofluorescence, qPCR, immunoblotting, and alkaline phosphatase activity assay. These indicated that gastric cancer could damage bone tissue before the occurrence of bone metastases. We also found that cilia formation of MSCs was increased in the presence of HGC27 cells, which was associated with abnormal activation of the Wnt/ß-catenin pathway. Expression of DKK1 inhibited the Wnt/ß-catenin signaling pathway and partially rescued osteogenic differentiation of MSCs. In summary, our results suggest that gastric cancer cells might cause bone damage prior to the occurrence of bone metastasis via cilia-dependent activation of the Wnt/ß-catenin signaling pathway.