CS1003, a novel human and mouse cross-reactive PD-1 monoclonal antibody for cancer therapy.

The programmed cell death protein 1 (PD-1) is an immune-checkpoint that negatively regulates the immune system and a key mechanism that tumors utilize to escape from immune surveillance. PD-1 antibodies can block the interaction of PD-1 with its ligands (PD-L1 and PD-L2), restore T cells activation, and elicit antitumor activity. In this paper, we reported a novel PD-1 monoclonal antibody (mAb) CS1003, which is a humanized IgG4 PD-1 mAb generated by conventional hybridoma technology, and currently being developed in multiple clinical trials as monotherapy or in combination with other anticancer agents. We showed that CS1003 bound to recombinant human, cynomolgus monkey, and mouse PD-1 with EC50 values of 0.1757, 0.2459, and 0.3664 nM, respectively. CS1003 blocked PD-1 interaction with its ligands, dose-dependently enhanced T cell proliferation and secretion of cytokines (IL-2 and IFN-γ) to the levels comparable to the reference antibody pembrolizumab. Intraperitoneal administration of CS1003 (0.1, 0.5, 2.5 mg/kg, once every 3 days) dose-dependently suppressed the growth of MC38-hPD-L1 colon cancer in hPD-1 knock-in mice. Pharmacokinetics (PK) study revealed a linear PK profile within the dose range of 2-18 mg/kg following single intravenous administration in cynomolgus monkey. These data provide a comprehensive preclinical characterization of CS1003 that supports its clinical development for cancer immunotherapy.

Diversity and phylogeography of Northeast Asian brown frogs allied to Rana dybowskii (Anura, Ranidae).

We investigated the species diversity and phylogeography of the Northeast Asian brown frogs allied to Rana dybowskii (the R. dybowskii species complex: R. dybowskii, R. pirica, and R. uenoi) using four mitochondrial and three nuclear loci. Phylogenetic analyses confirmed the existence of three distinct species in this complex; using extensive molecular data, we confirm the validity of Rana uenoi recognized as a distinct species, and infer R. dybowskii and R. pirica to be sister species. Also, we included populations from previously unsampled regions in Northeast China, and identified them to be R. dybowskii. While many species in Northeast Asia diverged due to Pleistocene glaciation, divergence-dating analyses inferred older, Miocene speciation in the R. dybowskii species complex. Ancestral area reconstruction identified the orogenic movement of the Changbai Mountain Range and the opening of the Sea of Japan/East Sea being major events influencing allopatric speciation.

Influence of geology and human activity on the genetic structure and demography of the Oriental fire-bellied toad (Bombina orientalis).

The Oriental fire-bellied toad (Bombina orientalis) is a commonly used study organism, but knowledge of its evolutionary history is incomplete. We analyze sequence data from four genetic markers (mtDNA genes encoding cytochrome c oxidase subunit I, cytochrome b, and 12S-16S rRNA; nuDNA gene encoding recombination activating gene 2) from 188 individuals across its range in Northeast Asia to elucidate phylogeographic patterns and to identify the historic events that shaped its evolutionary history. Although morphologically similar across its range, B. orientalis exhibits phylogeographic structure, which we infer was shaped by geologic, climatic, and anthropogenic events. Phylogenetic and divergence-dating analyses recover four genetically distinct groups of B. orientalis: Lineage 1-Shandong Province and Beijing (China); Lineage 2-Bukhan Mountain (Korea); Lineage 3-Russia, Northeast China, and northern South Korea; and Lineage 4-South Korea. Lineage 2 was previously unknown. Additionally, we discover an area of secondary contact on the Korean Peninsula, and infer a single dispersal event as the origin of the insular Jeju population. Skyline plots estimate different population histories for the four lineages: Lineages 1 and 2 experienced population decreases, Lineage 3 remained stable, while Lineage 4 experienced a sharp increase during the Holocene. The timing of the population expansion of Lineage 4 coincides with the advent of rice cultivation, which may have facilitated the increase in population size by providing additional breeding habitat.

[The comparative study on maturation of metacarpal bone in puberty children during their growth spurt period between urban and rural areas].

OBJECTIVES: To study maturation of the metacarpal bone in puberty children during their growth spurt period and its difference between urban and rural areas. METHODS: Totally, 560 pupils/students were selected from primary and secondary schools in urban and rural areas each, with 35 children in each gender and age group, ranging 12 - 15 years of age for boys and 10 - 13 for girls. An X-ray film of left hand-wrist site was taken for each of them. Length and width of the metacarpal bone were measured and the metacarpal index was calculated. RESULTS: Increment of length of the metacarpal bone was great in puberty children both in urban and rural areas, (6.26 - 9.31) mm in boys and (5.28 - 9.12) mm in girls. Mean length of the metacarpal bone was longer in children of urban areas than that of rural ones, regardless of their age and gender. There was significant difference in mean length of the metacarpal bone between boys aged 14 - 15 years and girls aged 12. Mean width of the metacarpal bone in most children was wider in rural areas than that in urban ones. Mean metacarpal index in children was higher in urban areas than that in rural ones, with very statistical significance, except for girls of 13 year age group. The peak age of metacarpal maturation was 1 year earlier in urban areas than in rural ones. CONCLUSIONS: Maturation of the metacarpal bone was rapid during puberty growth spurt period, with relatively significant difference in urban and rural ares.