Considerations for design and evaluation of clinical similarity comparison trial of biosimilars / 中国药学杂志

OBJECTIVE: To discuss the key considerations and evaluation criteria in designing a clinical comparison study to assess the clinical similarity of biosimilars. METHOD: Relevant guidelines and literatures on clinical similarity evaluation were reviewed, the cases were analyzed, discussions were carried out with biotech industry sponsors and clinical and statistical experts, the key considerations and evaluation criteria were proposed for assessing the clinical similarity of biosimilars. RESULTS AND CONCLUSION: The clinical similarity criteria should reflect the characteristics of the biological products. It is critical to select right patient population, clinical endpoints and equivalence/non-inferiority margin for development of different biosimilar products on the basis of fully understanding the quality, efficacy and safety profile of the original biological products. To set up the clinical similarity criterion and selection of the equivalence/non-inferiority margin, the consistency of the therapeutic effect of the reference product and subject variability need to be taken into consideration for robust evaluation of clinical similarity.

Sodium current kinetics of transitional myocytes in Koch triangle of rabbit hearts / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Few studies have explored the inward sodium current (INa) kinetics of transitional cardiomyocytes. This study aimed to explore the kinetics of transitional cardiomyocytes types alpha and beta.</p><p><b>METHODS</b>The whole-cell patch clamp technique was used to study the rapid INa of isolated transitional cardiomyocytes in the Koch triangle of rabbit hearts.</p><p><b>RESULTS</b>Maximal amplitude and density of INa in type alpha and type beta was (-1627 +/- 288) pA (alpha), (-35.17 +/- 6.56) pA/pF (beta) and (-3845 +/- 467) pA (alpha), (-65.64 +/- 10.23) pA/pF (beta) (P < 0.05). Steady state activation curves of INa, fitted to a Boltzmann distribution for both types, were sigmoid in shape. Half activation voltage and slope factors did not significantly differ between types at (-43.46 +/- 0.85) mV (alpha), (-41.39 +/- 0.47) mV (beta) or (9.04 +/- 0.66) mV (alpha), (11.08 +/- 0.89) mV (beta). Steady state inactivation curves of INa, fitted to a Boltzmann distribution in both types were inverse "S" shape. Half inactivation voltage and slope factors were (-109.9 +/- 0.62) mV (alpha), (-107.5 +/- 0.49) mV (beta) and (11.78 +/- 0.36) mV (alpha), (11.57 +/- 0.27) mV(beta), (P > 0.05), but time constants of inactivation were significantly different at (1.10 +/- 0.19) mV (alpha) and (2.37 +/- 0.33) ms (beta), (P < 0.05). Time constants of recovery from inactivation of INa for both types were (122.16 +/- 27.43) mV (alpha) and (103.84 +/- 28.97) ms (beta) (P < 0.05).</p><p><b>CONCLUSIONS</b>Transitional cardiomyocytes in rabbit hearts show a heterogeneous, voltage gated and time dependent fast inward sodium current. Types alpha and beta show the features of INa similar to those in slow- and fast-response myocytes, with probably better automaticity and conductivity, respectively.</p>

Polymorphism of killer cell immunoglobulin-like receptor gene and its correlation with leukemia / 中国实验血液学杂志

The study was purposed to investigate the polymorphism of killer cell immunoglobulin-like receptor (KIR) gene of the patients with leukemia and to explore the correlation between the KIR gene and susceptibility of leukemia. The KIR genotype of 50 patients with leukemia and 60 healthy controls in northern. Hans were analyzed by PCR-SSP. The results indicated that the present known 18 KIR genes were detected and identified. The frequencies of KIR 3DL3, 3DL2 and 2DL4 were 100% in all subjects, with the most frequent genotype KIR 3DP1 (0.86) followed by 2DP1, 2DL3, 3DL1, 2DL1, 3DS1, 2DL5, 2DS4, 2DS2, 1D, 2DS5, 2DL2, 2DS1, 2DS3 and 3DP1v in leukemia successively. Compared with the control, the KIR 3DL1 (0.60) and 2DL1 (0.57) were significantly lower in the leukemia patient group than that in the control group (1.00) (P < 0.01). It is concluded that the polymorphism of KIR gene is associated with susceptibility of leukemia in Hans. There may be a negative correlation between pathogenesis of leukemia and KIR 3DL1, KIR 3DS1, KIR 2DL1, KIR 2DL5 genes.

Morphological and electrophysiological study on the inferior nodal extension and transitional cellular band in the rabbit atrioventricular junctional area / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Advances in catheter ablation procedures for the treatment of supraventricular arrhythmias have created the need to understand better the morphological and electrophysiological characteristics of the inferior nodal extension (INE) and transitional cellular band (TCB) in the atrioventricular (AV) junctional area.</p><p><b>METHODS</b>Firstly, we observed the histological features of 10 rabbit AV junctional areas by serial sections under light microscopy. Then we recorded the action potentials (APs) of transitional cells (TCs) in the INE, TCBs, AV node, and ordinary right atrial myocytes from the AV junctional area of 30 rabbits using standard intracellular microeletrode techniques.</p><p><b>RESULTS</b>Under light microscopy, the INE appeared to be mostly composed of transitional cells linking upward to the AV node. Four smaller TCBs originated in the orifice of the coronary sinus, the region between the septal leaflet of the tricuspid valve and the coronary sinus, the inferior wall of the left atrium, and the superior interatrial septum, respectively, all linking to the INE or the AV node. Compared with ordinary atrial myocytes, the AP of the TCs in both the INE and the TCBs had a spontaneous phase 4 depolarization (not present in ordinary atrial myocytes), with a less negative maximum diastolic potential, a smaller amplitude, a slower maximum velocity of AP upstroke, and a longer action potential duration at 50% repolarization (APD50) and at 30% repolarization (APD30). The AP characteristics of these TCs were similar to those of the AV node, except that the velocities of the phase 4 spontaneous depolarization were slower and their action potential durations at 90% repolarization (APD90) were shorter. Moreover, APD50 and APD30 of the TCs of the TCBs were shorter than in the case of TCs of the AV node.</p><p><b>CONCLUSIONS</b>The TCs of the INE and TCBs are similar to slow response automatic cells. They provide a substrate for slow pathway conduction. In addition, repolarization heterogeneity exists in the AV junctional area.</p>

Prediction of acute GVHD after umbilical cord blood transplantation by HLA three-dimensional structure matching / 中国实验血液学杂志

To explore a method of predicting acute graft versus host disease (aGVHD) after unrelated cord blood transplantation (UCBT), the HLA-A, -B, -DRB1 molecular three-dimensional structures in 25 patients with blood disorder who underwent UCBT and their donors were modeled by using molecular modeling technique. First, full amino acid sequences of each HLA antigen from HLA data banks were loaded down, and then amino acid sequence of extracellular antigen binding region was chosen. Third step, SPDBV software of SWISS-MODEL server was used to modeling the three-dimensional structures of each different allele of HLA-A, -B and -DRB1 between patients and donors and the parameter "root mean square deviation" (RMSD) was used to indicate the structure differences. Last, RMSD of each different HLA allele of each donor-patient pair were added together to get total RMSD. The 25 patients were divided into 3 groups: the first group did not develop aGVHD; the second group developed aGVHD graded I-II and the third group developed aGVHD graded III-IV. The results showed that in the 25 patients divided into three groups, 8 patients in the first group did not develop aGVHD (32%); 13 patients in the second group developed grade I-II of aGVHD (52%) and 4 patients in the third group developed aGVHD III-IV (16%). The total RMSDs of each group were 0.24 +/- 0.15, 0.25 +/- 0.14 and 0.47 +/- 0.22 respectively. The total RMSD of the third group was significantly higher than that of the other two groups. In conclusion, utilization of modeling HLA molecular three-dimension can predict the severe aGVHD after UCBT quickly, simply and accurately. It provides scientific basis in choosing a optimal cord blood donor to avoid severe aGVHD for physicians and the cord blood banks. And it is instructive too to direct the application of immunosuppressive agents after transplantation in clinic.

Distribution features of HLA-DRB1 allele frequencies in normal cord blood donors of 3 438 Shandong Hans / 中国实验血液学杂志

The objective of the study was to research the distribution features of HLA-DRB1 alleles in Shandong Hans' population and explore the possibility of finding the cord blood donor of HLA-DR matched to perform the stem cell transplantation for more patients from larger region of China and even other areas in the world. The subjects of the study were drawn from 3 438 Shandong Hans donors in Shandong Umbilical Cord Blood Bank and were tested by PCR-SSP technique for HLA-DR low resolution typing. The result indicated that the most prevalent five alleles of HLA-DRB1 locus were DRB1 * 15 (0.1817), * 07 (0.1369), * 09 (0.1221), * 04 (0.1084) and * 12 (0.1038). The DR18 has the lowest gene frequency 0.0003, while DRB1 * 10, * 16 and * 01 showed lower gene frequencies (GF), which GF were 0.0151, 0.0262, and 0.0322 respectively. As compared the HLA-DRB1 GF of Shandong Hans with those of other Han Chinese and other ethnic populations, there were unique distributed features of DRB1 alleles among various races populations, and those among the studied population groups from various regions with the same race origin. The difference from various regions in the same race was less than that among different races. In conclusion, a patient of Han Chinese is easier to search a DR-matched cord blood donor in Shandong Umbilical Cord Blood Bank, especially from northern Hans. No DRB1 allele is unique to single racial group and majority of DRB1 low-resolution phenotypes are common to all studied groups. It is reasonable for some patients from other races including Caucasian and Japanese to receive a transplant of cord blood stem cell matched with HLA-DR in Shandong Umbilical Cord Blood Bank.