Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB

Metastasis is a major factor in the malignancy of cancers, and is often responsible for the failure of cancer treatment. Anoikis (apoptosis resulting from loss of cell-matrix interactions) has been suggested to act as a physiological barrier to metastasis; resistance to anoikis may allow survival of cancer cells during systemic circulation, thereby facilitating secondary tumour formation in distant organs. In an attempt to identify metastasis-associated oncogenes, we designed an unbiased, genome-wide functional screen solely on the basis of anoikis suppression. Here, we report the identification of TrkB, a neurotrophic tyrosine kinase receptor, as a potent and specific suppressor of caspase-associated anoikis of non-malignant epithelial cells. By activating the phosphatidylinositol-3-OH kinase/protein kinase B pathway, TrkB induced the formation of large cellular aggregates that survive and proliferate in suspension. In mice, these cells formed rapidly growing tumours that infiltrated lymphatics and blood vessels to colonize distant organs. Consistent with the ability of TrkB to suppress anoikis, metastases--whether small vessel infiltrates or large tumour nodules--contained very few apoptotic cells. These observations demonstrate the potent oncogenic effects of TrkB and uncover a specific pro-survival function that may contribute to its metastatic capacity, providing a possible explanation for the aggressive nature of human tumours that overexpress TrkB.     

Isolation of human epidermal stem cells by adherence and the reconstruction of skin equivalents

The isolation of human epidermal stem cells is critical for their clinical applications. In the present study, we isolated three populations of epidermal keratinocytes according to their ability to adhere to collagen type IV: i.e., rapidly adhering (RA), slowly adhering (SA), and non-adhering (NA) cells. The aim of this study was to characterize RA cells and to investigate the possibility of using these cells for epidermis reconstruction. To identify RA cells, flow cytometric analysis was performed using anti-₆ integrin and anti-CD71 antibodies. RA cells express high levels of ₆ integrin and low levels of CD71, which are considered as markers of an epidermal stem cell nature. Furthermore, electron microscopy showed that RA cells are small and have a high nuclear to cytoplasmic ratio, whereas SA and NA cells have well-developed cellular organelles and abundant tonofilaments. Western blot analysis showed that RA cells are slow cycling and express p63, a putative epidermal stem cell marker, whereas SA and NA cells express c-Myc, which is known to regulate stem cell fate. To compare epidermal regenerative abilities, skin equivalents (SEs) were made using RA, SA, and NA cells. The epidermis constructed from RA cells was well formed compared to those formed from SA or NA cells. In addition, only SEs with RA cells expressed ₆ integrin and ₁ integrin at the basal layer. These results indicate that RA cells represent epidermal stem cells and are predominately comprised of stem cells. Therefore, the isolation of RA cells using a simple technique offers a potential route to their clinical application, because they are easily isolated and provide a high yield of epidermal stem cells.Received 2 July 2004; received after revision 20 August 2004; accepted 10 September 2004     

VEGF links hippocampal activity with neurogenesis, learning and memory

An enriched environment is associated with hippocampal plasticity, including improved cognitive performance and increased neurogenesis. Here, we show that hippocampal expression of vascular endothelial growth factor (VEGF) is increased by both an enriched environment and performance in a spatial maze. Hippocampal gene transfer of VEGF in adult rats resulted in approximately 2 times more neurogenesis associated with improved cognition. In contrast, overexpression of placental growth factor, which signals through Flt1 but not kinase insert domain protein receptors (KDRs), had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant-negative mutant KDR inhibited basal neurogenesis and impaired learning. Coexpression of mutant KDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data support a model in which VEGF, acting through KDR, mediates the effect of the environment on neurogenesis and cognition.     

MRS study on lentiform nucleus in idiopathic Parkinson‘s disease with unilateral symptoms

OBJECTIVE: To investigate changes in magnetic resonance spectroscopy (MRS) of lentiform nucleus during the early stage of Parkinson's disease. METHODS: Twenty-five patients with idiopathic Parkinson disease with unilateral symptoms (IPDUS) and 25 healthy volunteers were enrolled in this study. MRS of the lentiform nucleus in each patient was taken and then concentrations of N-acetylaspartate (NAA), Creatine (Cr) and Choline (Cho) were calculated. RESULTS: Compared to that in the control, NAA/ (Cho+Cr) was significantly lower in the lentiform nucleus contralateral to symptoms and even that in the ipsilateral side in IPDUS patients (all P<0.05); while there was no difference between the two sides in the healthy volunteer (P>0.05). The ratio of NAA/(Cho+Cr) ipsilateral to the sympatomatic side of the patient was also lower than that of the control (P<0.05). CONCLUSIONS: There might be some changes with MRS on the lentiform nucleus during the early stage of idiopathic Parkinson's disease with unilateral symptom. MRS may be one of the reliable methods for early or even sub-clinical diagnosis.     

Interaction of catechins with aluminum in vitro

Tea is one of the most popular beverages, consumed by over two thirds of the world's population; but the aluminum accumulation property of tea plant is becoming the focus of many researches because of aluminum's known adverse effect on human health. Investigation of the interactions of catechins with Al(3+) showed that during the interaction of catechins with Al(3+), the UV-vis spectrum of catechins was changed. Absorption of EGCG at 274 nm decreased and increased at 322 nm; EC and C's at 278 nm changed little. The ratio of Al(3+) to EGCG was 1:1 in pH 5.0 buffer solution; in pH 6.2 buffer solution, the ratio in the Al-EGCG complex was 1:1. Interestingly, while the ratio reached to over 2, after the complex of Al-EGCG started polymerization, the ratio in the polymer was 2:1. In pH 6.2 buffer solution, the complex behavior of C with Al(3+) was the same as that of EGCG, with a little difference for EC. When the ratio of Al(3+) to EC was <1, the complex in ratio was 1:2, but, the complex polymerized when the ratio of Al(3+) to EC was >1. It was found that the ratio of Al(3+) to EC in the polymer was 1:1. Polymerization of Al-catechin complexes might reduce aluminum absorption in the intestine. Kow value was also employed to study the properties of aluminum species in tea infusion (at gastric and intestine pH condition) and the effect of catechins and tea polyphenols on Kow in buffer solution. Results showed that Kow value rose much higher at the intestine pH than at the gastric pH. Tea polyphenols and catechins could greatly reduce aluminum Kow value in acetic buffer, indicating that these compounds may reduce aluminum absorption during tea intake.     

Microfluidic systems: high radial acceleration in microvortices

Microfluidic systems can conveniently be used for rapid analysis of biological samples. Here we describe a single re-circulating flow, or microvortex, that can generate a maximum fluid rotational velocity of up to 12 m s(-1) and a corresponding radial acceleration in excess of 10(6)g. Such microvortices may be exploited in centrifugal microdevices to investigate the effects of high radial acceleration on biological and chemical processes.     

The recent expansion of Pluto's atmosphere

Stellar occultations--the passing of a relatively nearby body in front of a background star--can be used to probe the atmosphere of the closer body with a spatial resolution of a few kilometres (ref. 1). Such observations can yield the scale height, temperature profile, and other information about the structure of the occulting atmosphere. Occultation data acquired for Pluto's atmosphere in 1988 revealed a nearly isothermal atmosphere above a radius of approximately 1,215 km. Below this level, the data could be interpreted as indicating either an extinction layer or the onset of a large thermal gradient, calling into question the fundamental structure of this atmosphere. Another question is to what extent Pluto's atmosphere might be collapsing as it recedes from the Sun (passing perihelion in 1989 in its 248-year orbital period), owing to the extreme sensitivity of the equilibrium surface pressure to the surface temperature. Here we report observations at a variety of visible and infrared wavelengths of an occultation of a star by Pluto in August 2002. These data reveal evidence for extinction in Pluto's atmosphere and show that it has indeed changed, having expanded rather than collapsed, since 1988.