Pharmacological effects of site specific conjugated anti-human epidermal growth factor receptor 2-antibody drug conjugate using unnatural amino acid technology / 北京大学学报(医学版)

OBJECTIVE@#To investigate inhibitory activities of a homogenous anti-human epidermal growth factor receptor 2 (HER2)-antibody drug conjugate (ADC) on the proliferation of nine tumor cell lines with different levels of HER2 expressions, and its activities on the tumor growth of five xenograft mouse models.@*METHODS@#The HER2 expression levels of BT-474, Calu-3, MCF-7, MDA-MB-231, MDA-MB-468, SK-BR-3, SK-OV-3, HCC1954, NCI-N87 tumor cell lines were measured using QIFI KIT. For the in vitro anti-proliferation assay, serial diluted anti-HER2-ADC, ado-trastuzumab emtansine, AS269, pAF-AS269 and paclitaxel were added to the seeded cells, and after 72 or 96 hours of incubation, the cell proliferation was analyzed. For the in vivo activity, 5-6 weeks old mice were inoculated with four HER2 positive tumor cell lines HCC1954, BT-474, SK-OV-3, NCI-N87 or one HER2 negative tumor cell line MDA-MB-468. Different amounts of anti-HER2-ADC, ado-trastuzumab emtansine, trastuzumab, paclitaxel and phosphate buffered saline control were injected after the tumor volume reached a certain size, then the tumor growth inhibition was analyzed.@*RESULTS@#The expression levels of the six high HER2-expression cell lines SK-OV-3, NCI-N87, SK-BR-3, Calu-3, HCC1954, BT-474 were between 430 000 to 800 000 receptors per cell, which were 50 times higher than those of the other three low HER2 expression tumor cell lines MDA-MB-231, MCF-7, MDA-MB-468. Anti-HER2-ADC had inhibition effects on cell lines with high level of HER2 expression in the in vitro anti-proliferation assay. The half maximal inhibitory concentrations of anti-HER2-ADC on SK-OV-3, NCI-N87, SK-BR-3, Calu-3, HCC1954, BT-474 tumor cell lines were 46 pmol/L, 17 pmol/L, 17 pmol/L, 161 pmol/L, 125 pmol/L, 50 pmol/L, respectively. Anti-HER2-ADC had a dose dependent antitumor activity in vivo in all the HER2 positive xenograft mouse models. In NCI-N87 xenograft tumor model, the same dose of anti-HER2-ADC showed better anti-tumor activity compared with trastuzumab and ado-trastuzumab emtansine, and its relative tumor proliferation rates were about 1/30 to 1/20 of the two. In HCC1954 xenograft tumor model, the complete regression of the tumor was observed. As expected, anti-HER2-ADC had no tumor inhibitory effects on MDA-MB-468 xenograft models with low HER2 expression. The antitumor activities of anti-HER2-ADC in HER2 positive xenograft tumor models were the same as or better than the activities of ado-trastuzumab emtansine.@*CONCLUSION@#The homogenous site-specific anti-HER2-ADC obtained using unnatural amino acid technology can inhibit the growth of high HER2-expression tumor cells with high potency both in vivo and in vitro.

Efficacy and safety of domestic leuprorelin in girls with idiopathic central precocious puberty: a multicenter, randomized, parallel, controlled trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>In central precocious puberty (CPP), the pulse secretion and release of gonadotropin-releasing hormone (GnRH) are increased due to early activation of the hypothalamic-pituitary-gonadal axis, resulting in developmental abnormalities with gonadal development and appearance of secondary sexual characteristics. The CPP without organic disease is known as idiopathic CPP (ICPP). The objective of the study was to evaluate the clinical efficacy and safety of domestic leuprorelin (GnRH analog) in girls with ICPP.</p><p><b>METHODS</b>A total of 236 girls with ICPP diagnosed from April 2012 to January 2014 were selected and were randomized into two groups. One hundred fifty-seven girls in the test group were treated with domestic leuprorelin acetate, 79 girls in the control group were treated with imported leuprorelin acetate. They all were treated and observed for 6 months. After 6-month treatment, the percentage of children with peak luteinizing hormone (LH) ≤3.3 U/L, the percentage of children with peak LH/peak follicle stimulating hormone (FSH) ratio <0.6, the improvements of secondary sexual characteristics, gonadal development and sex hormone levels, the change of growth rate of bone age (BA) and growth velocity, and drug adverse effects between two groups were compared.</p><p><b>RESULTS</b>After the treatment, the percentage of children with a suppressed LH response to GnRH, defined as a peak LH ≤3.3 U/L, at 6 months in test and control groups were 96.80% and 96.20%, respectively, and the percentage of children with peak LH/FSH ratio ≤0.6 at 6 months in test and control groups were 93.60% and 93.70%, respectively. The sizes of breast, uterus and ovary of children and the levels of estradiol (E 2 ) were significantly reduced, and the growth rate of BA was also reduced. All the differences between pre- and post-treatment in each group were statistically significant (P < 0. 05), but the differences of the parameters between two groups were not significant (P > 0.05).</p><p><b>CONCLUSIONS</b>Domestic leuprorelin is effective and safe in the treatment of Chinese girls with ICPP. Its effectiveness and safety are comparable with imported leuprorelin.</p>

Four cases of transient neonatal diabetes mellitus / 中华实用儿科临床杂志

Objective To reveal the clinical features of children with transient neonatal diabetes mellitus (TNDM) in order to provide a basis for the TNDM treatment strategy formulation.Methods Four patients diagnosed as TNDM hospitalized in Beijing Children's Hospital Affiliated to Capital Medical University from Dec.2008 to Dec.2010 were chosen as research subjects.Their clinical data were analyzed retrospectively.Results The 4 patients diagnosed as TNDM started insulin therapy.Two cases of the 4 patients transferred from insulin to oral Sulfonylureas for 2-3 weeks after their conditions became steady.One patient was treated with Sulfonylureas successfully and the other one was partially effective with this therapy.After 2 to 3 years follow-up,3 cases remitted in 1 month after birth with no other severe complications,one case lost.Conclusions Infants with TNDM had unique clinical features.The patients develop diabetes in the first few weeks of life but go into remission in a few months.So the follow-up for those TNDM patient is very essential for clinical classification.Oral glibenclamide therapy seems highly effective and safe for some TNDM patients.

Clinical analysis of 18 cases with congenital hyperinsulinism without response to diazoxide / 中华实用儿科临床杂志

Objective To investigate the clinical features of these children with congenital hyperinsulinism (CHI) who had no response to diazoxide and provide a theoretical foundation for the formulation of CHI treatment strategy.Methods Eighteen patients with CHI who had no response to diazoxide hospitalized in Beijing Children's Hospital from 2008 to 2012 were chosen as research subjects.Their clinical data were analyzed retrospectively.Results There were 18 patients with persistent hypoglycemia after using diazoxide,which indicated that they had no response to diazoxide.Twelve patients of them were born as macrosomia and their onset age was less than 6 months.Half of the children(9/18 cases) even had hypoglycemia in neonatal period.All the manifestations were conformed to the clinical characteristics of ATP-sensitive potassium channel CHI.Four children who were unresponsive to diazoxide received octreotide treatment,and it was effective on them.Four patients had a near-total pancreatectomy.After a long-term followup study,their blood sugar maintained a normal level,and they did not appear serious postoperative complications.Conclusions Children with CHI who have no response to diazoxide are characterized by coming earlier and higher birth weight.Octreotide is proposed in case of non-response to diazoxide.When medical treatment is not efficient in prevention of hypoglycemia,a subtotal pancreatectomy has to be considered as a last resort.

Clinical significance of pancreatic beta-cell function in obese children with acanthosis nigricans / 中华儿科杂志

<p><b>OBJECTIVE</b>The strong relation between type 2 diabetes mellitus and obesity with acanthosis nigricans is widely concerned. This study investigated the pancreatic beta-cell function in obese children with acanthosis nigricans, so as to find out the role of insulin secretion and insulin resistance in obese children with acanthosis nigricans.</p><p><b>METHODS</b>Thirty-five obese children with acanthosis nigricans (19 males and 16 females with mean age 12.8 +/- 1.5 years) were enrolled in this study. Thirty-eight obese children (21 boys and 17 girls with mean age 11.9 +/- 2.6 years) and 39 normal children (20 boys and 19 girls with mean age 11.2 +/- 2.2 years) were recruited as obese and normal control groups. The levels of serum fasting insulin, C-peptide, proinsulin and true insulin were measured in all the subjects. The ratios of proinsulin/insulin and proinsulin/C-peptide were calculated. Homeostasis model assessment was applied to assess the status of insulin resistance and basic function of pancreatic beta-cell.</p><p><b>RESULTS</b>The levels of fasting insulin, C-peptide proinsulin, true insulin, the ratios of proinsulin/insulin and proinsulin/C-peptide, insulin resistance index and insulin secretion index of obese children with acanthosis nigricans, obese control children and normal control children were: 18.5 (5.0-60.5) pmol/L, 12.4 (6.1-35.8) pmol/L and 5.1 (2.0-32.8) pmol/L; 3.9 (1.3-14.0) microg/L, 2.4 (1.1-4.0) microg/L and 1.1 (1.0-4.2) microg/L; 28.8 (9.9-64.2) pmol/L, 9.5 (2.2-34.5) pmol/L and 4.2 (2.0-16.0) pmol/L; 33.0 (6.2-66.0) pmol/L, 10.6 (4.8-29.4) pmol/L and 4.5 (1.3-30.1) pmol/L; 1.2 (0.4-8.9), 0.9 (0.2-1.9) and 0.8 (0.4-2.0); 6.9 (2.5-36.6), 4.7 (1.2-12.3) and 3.6 (1.2-9.6); 5.0 (0.8-14.1), 2.6 (1.3-8.1) and 1.2(0.4-6.9); 303.3 (52.2-1,163.8), 213.6 (84.6-572.0) and 51.1 (19.1-561.4). The levels of fasting insulin, C-peptide, proinsulin, true insulin, the ratios of proinsulin/insulin and proinsulin/C-peptide, insulin resistance index and insulin secretion index in obese children with acanthosis nigricans were significantly higher than those in obese children (P < 0.001) and normal children (P < 0.001).</p><p><b>CONCLUSION</b>Obese children with acanthosis nigricans had higher insulin resistance and pancreatic beta-cell dysfunction; acanthosis nigricans may be a skin sign of high risk of type 2 diabetes mellitus.</p>

Significance of measuring serum proinsulin and true insulin in obese children with impaired glucose tolerance / 实用儿科临床杂志

Objective To investigate clinical significance of proinsulin and true insulin in obese children with impaired glucose tolerance (IGT).Methods There were 21 IGT and 52 normal glucose tolerance (NGT) children. Control cases were 40 normal children. The levels of serum fasting proinsulin,true insulin,insulin,c-peptide and glucose were measured in all the subjects.Results 1.Levels of fasting proinsulin,c-peptide, glucose, insulin, true insulin and homeostasis insulin resistance in obese children with IGT showed significant difference compared with NGT (P