Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.     

Semi-annual oscillations in Saturn's low-latitude stratospheric temperatures

Observations of oscillations of temperature and wind in planetary atmospheres provide a means of generalizing models for atmospheric dynamics in a diverse set of planets in the Solar System and elsewhere. An equatorial oscillation similar to one in the Earth's atmosphere has been discovered in Jupiter. Here we report the existence of similar oscillations in Saturn's atmosphere, from an analysis of over two decades of spatially resolved observations of its 7.8-microm methane and 12.2-microm ethane stratospheric emissions, where we compare zonal-mean stratospheric brightness temperatures at planetographic latitudes of 3.6 degrees and 15.5 degrees in both the northern and the southern hemispheres. These results support the interpretation of vertical and meridional variability of temperatures in Saturn's stratosphere as a manifestation of a wave phenomenon similar to that on the Earth and in Jupiter. The period of this oscillation is 14.8 +/- 1.2 terrestrial years, roughly half of Saturn's year, suggesting the influence of seasonal forcing, as is the case with the Earth's semi-annual oscillation.     

Accurate whole human genome sequencing using reversible terminator chemistry

DNA sequence information underpins genetic research, enabling discoveries of important biological or medical benefit. Sequencing projects have traditionally used long (400-800 base pair) reads, but the existence of reference sequences for the human and many other genomes makes it possible to develop new, fast approaches to re-sequencing, whereby shorter reads are compared to a reference to identify intraspecies genetic variation. Here we report an approach that generates several billion bases of accurate nucleotide sequence per experiment at low cost. Single molecules of DNA are attached to a flat surface, amplified in situ and used as templates for synthetic sequencing with fluorescent reversible terminator deoxyribonucleotides. Images of the surface are analysed to generate high-quality sequence. We demonstrate application of this approach to human genome sequencing on flow-sorted X chromosomes and then scale the approach to determine the genome sequence of a male Yoruba from Ibadan, Nigeria. We build an accurate consensus sequence from >30x average depth of paired 35-base reads. We characterize four million single-nucleotide polymorphisms and four hundred thousand structural variants, many of which were previously unknown. Our approach is effective for accurate, rapid and economical whole-genome re-sequencing and many other biomedical applications.     

Cool Indonesian throughflow as a consequence of restricted surface layer flow

Approximately 10 million m3 x s(-1) of water flow from the Pacific Ocean into the Indian Ocean through the Indonesian seas. Within the Makassar Strait, the primary pathway of the flow, the Indonesian throughflow is far cooler than estimated earlier, as pointed out recently on the basis of ocean current and temperature measurements. Here we analyse ocean current and stratification data along with satellite-derived wind measurements, and find that during the boreal winter monsoon, the wind drives buoyant, low-salinity Java Sea surface water into the southern Makassar Strait, creating a northward pressure gradient in the surface layer of the strait. This surface layer 'freshwater plug' inhibits the warm surface water from the Pacific Ocean from flowing southward into the Indian Ocean, leading to a cooler Indian Ocean sea surface, which in turn may weaken the Asian monsoon. The summer wind reversal eliminates the obstructing pressure gradient, by transferring more-saline Banda Sea surface water into the southern Makassar Strait. The coupling of the southeast Asian freshwater budget to the Pacific and Indian Ocean surface temperatures by the proposed mechanism may represent an important negative feedback within the climate system.     

Formation and propagation of matter-wave soliton trains

Attraction between the atoms of a Bose-Einstein condensate renders it unstable to collapse, although a condensate with a limited number of atoms can be stabilized by confinement in an atom trap. However, beyond this number the condensate collapses. Condensates constrained to one-dimensional motion with attractive interactions are predicted to form stable solitons, in which the attractive forces exactly compensate for wave-packet dispersion. Here we report the formation of bright solitons of (7)Li atoms in a quasi-one-dimensional optical trap, by magnetically tuning the interactions in a stable Bose-Einstein condensate from repulsive to attractive. The solitons are set in motion by offsetting the optical potential, and are observed to propagate in the potential for many oscillatory cycles without spreading. We observe a soliton train, containing many solitons; repulsive interactions between neighbouring solitons are inferred from their motion.     

HIV preferentially infects HIV-specific CD4+ T cells

HIV infection is associated with the progressive loss of CD4(+) T cells through their destruction or decreased production. A central, yet unresolved issue of HIV disease is the mechanism for this loss, and in particular whether HIV-specific CD4(+) T cells are preferentially affected. Here we show that HIV-specific memory CD4(+) T cells in infected individuals contain more HIV viral DNA than other memory CD4(+) T cells, at all stages of HIV disease. Additionally, following viral rebound during interruption of antiretroviral therapy, the frequency of HIV viral DNA in the HIV-specific pool of memory CD4(+) T cells increases to a greater extent than in memory CD4(+) T cells of other specificities. These findings show that HIV-specific CD4(+) T cells are preferentially infected by HIV in vivo. This provides a potential mechanism to explain the loss of HIV-specific CD4(+) T-cell responses, and consequently the loss of immunological control of HIV replication. Furthermore, the phenomenon of HIV specifically infecting the very cells that respond to it adds a cautionary note to the practice of structured therapy interruption.     

Land degradation, government subsidy, and smallholders＇ conservation decision： the case of the loess plateau in China

Land degradation is one of the severe environmental problems in China. In order to combat land degradation, a soil conservation program was introduced since 2000 to reduce soil erosion by converting slope-cultivated land into forestry and pasture. This paper represents the first systematic attempt to investigate the impact of the soil conservation program on land degradation in the loess plateau. The results indicate that the soil conservation program to convert slope fields into forest or pasture is an effective way to combat soil erosion. However, a subsidy that is higher than profit of land use activity of slope fields before their conversion into forest and pasture is needed to encourage farmers to join the conservation program. A policy measure to encourage and assist farmers to develop sedentary livestock by using crops produced from fields as well as fodder and forage grass from the converted slope fields might contribute to combat soil erosion. Increase in off-farm job opportunities may encourage households to reduce cultivation in slope fields. That implies a policy measure to encourage rural urbanization might contribute to combat soil erosion.     

Developmental reprogramming after chromosome transfer into mitotic mouse zygotes

Until now, animal cloning and the production of embryonic stem cell lines by somatic cell nuclear transfer have relied on introducing nuclei into meiotic oocytes. In contrast, attempts at somatic cell nuclear transfer into fertilized interphase zygotes have failed. As a result, it has generally been assumed that unfertilized human oocytes will be required for the generation of tailored human embryonic stem cell lines from patients by somatic cell nuclear transfer. Here we report, however, that, unlike interphase zygotes, mouse zygotes temporarily arrested in mitosis can support somatic cell reprogramming, the production of embryonic stem cell lines and the full-term development of cloned animals. Thus, human zygotes and perhaps human embryonic blastomeres may be useful supplements to human oocytes for the creation of patient-derived human embryonic stem cells.     

Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.