Middle Pleistocene human femoral diaphyses from Hualongdong, Anhui Province, China.

OBJECTIVES: The paleontological description and comparative analysis using discrete morphology, morphometrics (linear and geometric) and cross-sectional geometry of three femoral diaphyseal sections from the Middle Pleistocene site of Hualongdong, China. MATERIALS AND METHODS: The material consists of the original Hualongdong femoral fossils and available data on femoral diaphyses from Middle and Late Pleistocene archaic humans and Middle and earlier Upper Paleolithic modern humans. The methods include visual observation, diaphyseal diameters, cross-sectional parameters (transverse areas and second moments of area derived from micro-CT scans), and geometric morphometrics using semilandmark data. RESULTS: The Hualong 11 midshaft section is similar to other Middle and Late Pleistocene archaic humans in being transversely broad and lacking a pilaster despite a prominent linea aspera. It clusters principally with archaic human femora in all measured parameters. The Hualong 15 and 16 subtrochanteric pieces are similar to many Middle Pleistocene and early modern human femora in being transversely broad. In particular, Hualong 15 exhibits a prominent lateral (gluteal) buttress, similar to many Upper Paleolithic femora but also the Lazaret and Krapina archaic ones. In addition, Hualong 15 has a small third trochanter, a common Upper Paleolithic but rare earlier feature. DISCUSSION: The Hualong 11 femoral piece reinforces the general Middle Pleistocene pattern, especially for eastern Eurasia from which archaic human femora are rare. The subtrochanteric proportions of Hualong 15 and 16 reinforce the Early Pleistocene and (generally) Middle Pleistocene pattern of bone distributions, but their subperiosteal contours align them (along with those of the Lazaret and Krapina femora) with Upper Paleolithic ones. It is difficult to account for these proportions from the generally broad pelves of Pleistocene archaic humans.

Archaic human remains from Hualongdong, China, and Middle Pleistocene human continuity and variation.

Middle to Late Pleistocene human evolution in East Asia has remained controversial regarding the extent of morphological continuity through archaic humans and to modern humans. Newly found ∼300,000-y-old human remains from Hualongdong (HLD), China, including a largely complete skull (HLD 6), share East Asian Middle Pleistocene (MPl) human traits of a low vault with a frontal keel (but no parietal sagittal keel or angular torus), a low and wide nasal aperture, a pronounced supraorbital torus (especially medially), a nonlevel nasal floor, and small or absent third molars. It lacks a malar incisure but has a large superior medial pterygoid tubercle. HLD 6 also exhibits a relatively flat superior face, a more vertical mandibular symphysis, a pronounced mental trigone, and simple occlusal morphology, foreshadowing modern human morphology. The HLD human fossils thus variably resemble other later MPl East Asian remains, but add to the overall variation in the sample. Their configurations, with those of other Middle and early Late Pleistocene East Asian remains, support archaic human regional continuity and provide a background to the subsequent archaic-to-modern human transition in the region.

The earliest unequivocally modern humans in southern China.

The hominin record from southern Asia for the early Late Pleistocene epoch is scarce. Well-dated and well-preserved fossils older than ∼45,000 years that can be unequivocally attributed to Homo sapiens are lacking. Here we present evidence from the newly excavated Fuyan Cave in Daoxian (southern China). This site has provided 47 human teeth dated to more than 80,000 years old, and with an inferred maximum age of 120,000 years. The morphological and metric assessment of this sample supports its unequivocal assignment to H. sapiens. The Daoxian sample is more derived than any other anatomically modern humans, resembling middle-to-late Late Pleistocene specimens and even contemporary humans. Our study shows that fully modern morphologies were present in southern China 30,000-70,000 years earlier than in the Levant and Europe. Our data fill a chronological and geographical gap that is relevant for understanding when H. sapiens first appeared in southern Asia. The Daoxian teeth also support the hypothesis that during the same period, southern China was inhabited by more derived populations than central and northern China. This evidence is important for the study of dispersal routes of modern humans. Finally, our results are relevant to exploring the reasons for the relatively late entry of H. sapiens into Europe. Some studies have investigated how the competition with H. sapiens may have caused Neanderthals' extinction (see ref. 8 and references therein). Notably, although fully modern humans were already present in southern China at least as early as ∼80,000 years ago, there is no evidence that they entered Europe before ∼45,000 years ago. This could indicate that H. neanderthalensis was indeed an additional ecological barrier for modern humans, who could only enter Europe when the demise of Neanderthals had already started.

Downregulation of VMP1 confers aggressive properties to colorectal cancer.

Vacuole membrane protein 1 (VMP1) was recently found to be involved in the process of tumor metastasis and is also considered to play a vital role in balancing apoptosis and autophagy. In the present study, the expression of VMP1 in colorectal cancer and matched adjacent non­cancerous tissues was evaluated by immunohistochemistry (IHC) for studying the role of VMP1 in the process of colorectal cancer. Kaplan­Meier analysis and the log-rank test were used to calculate the correlation of classic clinicopathological characteristics related to survival and the expression of VMP1. In vitro, a VMP1 stable gene silencing cell model was constructed using a lentiviral vector. The invasive ability and proliferation of colorectal cancer cells were evaluated by Transwell and MTT assays, respectively, and the underlying signaling pathway was explored by western blotting. Additionally, drug susceptibility to cisplatin, oxaliplatin and 5-FU was tested before and after VMP1 knockout. Finally, an animal model was constructed to explore the role of VMP1 in the physiopathologic process of colorectal cancer. Our results indicated that VMP1 showed increased expression in the adjacent non-cancer tissues compared with that in the colorectal cancer tissues. For different stages of colorectal cancer, expression of VMP1 had a negative correlation with the malignancy of the cancer. In clinical research, we also found that the median survival of patients with low VMP1 expression was much shorter than the survival of patients with high expression. In vitro, after infection with the lentivirus, cells with VMP1 knockout gained significant aggressive properties in regards to invasion and proliferation, and the mechanisms may be related to the activation of the PI3K/Akt/ZO-1/E-cadherin pathway. We also found that shVMP1 cells were more sensitive to 5-FU, but not cisplatin and oxaliplatin. Finally, we found a higher number of formed nodules in nude mice after intraperitoneal injection with shVMP1 cells in the in vivo study.

Treatment with telbivudine positively regulates antiviral immune profiles in Chinese patients with chronic hepatitis B.

Chronic infection with hepatitis B virus (HBV) is associated with impairment of T and NK cell immunity. This study was aimed at investigating the impact of treatment with telbivudine (LDT) on T and NK cell immunity in patients with chronic hepatitis B (CHB). A total of 54 CHB patients and 30 healthy controls (HC) were recruited. Individual patients were treated orally with 600 mg LDT daily for 13 months. The serum HBV DNA loads, the levels of the HBV-related biomarkers alanine aminotransferase (ALT) and aspartate transaminase (AST), and the numbers of different subsets of peripheral T and NK cells in subjects were measured before and longitudinally after LDT treatment. Following treatment with LDT, the serum HBV DNA loads and the percentages of HBsAg- or HBeAg-seropositive cases were gradually reduced, accompanied by decreased levels of serum ALT and AST. In comparison with the HC, fewer CD3(-) CD56(+) and CD244(+) NK cells and CD3(+) CD8(+) T cells, lower frequencies of cytokine(+) CD4(+) T cells, and more CD3(+) CD4(+), CD4(+) CD25(+) Foxp3(+), CD4(+) CD25(+) CD127(low), and CD8(+) PD-1(+) T cells were detected in CHB patients. Treatment with LDT increased the numbers of NK and CD8(+) cells and the frequencies of cytokine(+) CD4(+) T cells but reduced the numbers of CD4(+) CD25(+) Foxp3(+), CD4(+) CD25(+) CD127(low), and CD8(+) PD-1(+) T cells in CHB patients. The frequencies of cytokine(+) CD4(+) T cells were negatively associated with the levels of serum HBV DNA, ALT, and AST. Thus, treatment with LDT inhibits HBV replication, modulates T and NK cell immunity, and improves liver function in Chinese patients with CHB.

Dentoalveolar paleopathology of the early modern humans from Zhirendong, South China.

The fragmentary early Late Pleistocene, early modern human remains from Zhirendong, south China, present a suite of dentoalveolar pathologies and anomalies. The lesions include lower molar buccal alveolar resorption (Zhiren 1), massive dental caries in a mandibular molar associated with hypercementosis (Zhiren 2), and bilateral mesial premolar (P3) periapical lesions (granulomata with a probable left abscess) (Zhiren 3). The Zhiren 3 periapical lesions, given their bilaterality and the non-pathological incisor and canine alveoli, suggest dens evaginatus, although absence of the Zhiren 3 dentition prevents full evaluation of this diagnosis. These periodontal abnormalities join a number of similar lesions in Pleistocene humans, of varying severity. The carious lesion is noteworthy, given the rarity of them in the Pleistocene human fossil record. In addition, Zhiren 3 exhibits unilateral P3 rotation and bilateral I1 rotation (winging).

Human remains from Zhirendong, South China, and modern human emergence in East Asia.

The 2007 discovery of fragmentary human remains (two molars and an anterior mandible) at Zhirendong (Zhiren Cave) in South China provides insight in the processes involved in the establishment of modern humans in eastern Eurasia. The human remains are securely dated by U-series on overlying flowstones and a rich associated faunal sample to the initial Late Pleistocene, >100 kya. As such, they are the oldest modern human fossils in East Asia and predate by >60,000 y the oldest previously known modern human remains in the region. The Zhiren 3 mandible in particular presents derived modern human anterior symphyseal morphology, with a projecting tuber symphyseos, distinct mental fossae, modest lateral tubercles, and a vertical symphysis; it is separate from any known late archaic human mandible. However, it also exhibits a lingual symphyseal morphology and corpus robustness that place it close to later Pleistocene archaic humans. The age and morphology of the Zhiren Cave human remains support a modern human emergence scenario for East Asia involving dispersal with assimilation or populational continuity with gene flow. It also places the Late Pleistocene Asian emergence of modern humans in a pre-Upper Paleolithic context and raises issues concerning the long-term Late Pleistocene coexistence of late archaic and early modern humans across Eurasia.

[Avastin combined with cisplan inhibits malignant ascites production in nude mice bearing transplanted ovary carcinoma with high VEGF expression].

OBJECTIVE: To establish a nude mouse model of malignant ascites with human ovarian carcinoma cell line OVCAR3 which highly expresses VEGF and evaluate the therapeutic of Avastin combined with cisplan. METHODS: Forty-eight nude mice with malignant ascites resulting from intraperitoneal transplantation of human ovarian carcinoma cell line OVCAR3 were treated with intraperitoneal injection of Avastin, cisplan, their combination, and PBS, respectively, to observe the effect on ascites development, VEGF content in the ascites, peritoneal permeability, development of new vessels and number of tumor cells in the ascites. RESULTS: Avastin obviously inhibited ascites accumulation and peritoneal capillary permeability, reduced VEGF protein level and microvascular density in the tumor tissues and the number of red cells and tumor cells in the malignant ascites, and prolonged the survival of the mice. The combination of Avastin and cisplan further enhanced the therapeutic efficacy of Avastin. CONCLUSION: The bio-chemotherapeutic strategy with Avastin combined with cisplan can be a promising method for treatment of malignant ascites.