Mutations of the BRAF gene in human cancer

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma

Comparison of Mortality Outcomes in Acute Myocardial Infarction Patients With or Without Standard Modifiable Cardiovascular Risk Factors

Background: Acute myocardial infarction (AMI) cases have decreased in part due to the advent of targeted therapies for standard modifiable cardiovascular disease risk factors (SMuRF). Recent studies have reported that ST-elevation myocardial infarction (STEMI) patients without SMuRF (termed “SMuRF-less”) may be increasing in prevalence and have worse outcomes than “SMuRF-positive” patients. As these studies have been limited to STEMI and comprised mainly Caucasian cohorts, we investigated the changes in the prevalence and mortality of both SMuRF-less STEMI and non-STEMI (NSTEMI) patients in a multiethnic Asian population. Methods: We evaluated 23,922 STEMI and 62,631 NSTEMI patients from a national multiethnic registry. Short-term cardiovascular and all-cause mortalities in SMuRF-less patients were compared to SMuRF-positive patients. Results: The proportions of SMuRF-less STEMI but not of NSTEMI have increased over the years. In hospitals, all-cause and cardiovascular mortality and 1-year cardiovascular mortality were significantly higher in SMuRF-less STEMI after adjustment for age, creatinine, and hemoglobin. However, this difference did not remain after adjusting for anterior infarction, cardiopulmonary resuscitation (CPR), and Killip class. There were no differences in mortality in SMuRF-less NSTEMI. In contrast to Chinese and Malay patients, SMuRF-less patients of South Asian descent had a two-fold higher risk of in-hospital all-cause mortality even after adjusting for features of increased disease severity. Conclusion: SMuRF-less patients had an increased risk of mortality with STEMI, suggesting that there may be unidentified nonstandard risk factors predisposing SMuRF-less patients to a worse prognosis. This group of patients may benefit from more intensive secondary prevention strategies to improve clinical outcomes

Neutralization and cation dissolution characteristics of bauxite refining residue

The neutralization reaction of red mud with various concentrations of HCI acid and the dissolution of cations were studied in order to evaluate the mechanism of Na release from red mud. The changes in the mineralogy of the desilication products (DSP) was simultaneously followed by XRD and SEM. From the neutralization curve, four buffer regions were identified: pH 10.0-8.3 resulting from the neutralization of carbonate and free hydroxyl; pH 7.8-6.2 due to the dissolution of carbonates of Ca and Mg and accompanied by the release of Na from the desilication products; pH 35-3.2 resulting from the dissolution of the aluminum hydroxide precipitated from the decomposition of DSP taking place between pH about 7.0 and 5.4; and pH 0.8-0.4 resulting from a further dissolution of aluminum and iron oxide. The mineralogical study of the DSP particles of red mud revealed it to be a zeolitic mineral akin to natrodavyne consisting of crystalline rods and blobs forming a spherical ball-like network. The rods curved and wrapped on top of each other in a meridian orientation producing what appears to be poles from which rods radiated. The X-ray diffraction analysis only showed the major peaks of natrodavyne at pH 6.2. Scanning electron micrographs on the DSP particles at pH 6.2 showed no observable change in the external morphology of DSP with reduction in pH. In addition, the maximum release of Na was achieved at pH 5.4, thus Al and Si must have been released at a pH higher than 5.4 but immediately re-precipitated and therefore not observed in solution. It can be concluded that Na in the DSP particles were released at pH 7.0- 5.4 by acid hydrolysis. Hence, neutralization of red mud to a pH above 5.4 would produce a maximum release of Na without the possibility of excess dissolution of Al, although in practice we would not necessarily reduce the pH to as low as 5.4

Effectiveness of acidic industrial wastes for reclaiming fine bauxite refining residue (red mud)

Land disposal of bauxite refining residues produced by the aluminum industry has resulted in areas devoid of plants because of the high salinity and alkalinity of the residues. In addition, the fine fraction (red mud) of these residues is prone to wind and water erosion, which can pollute the surrounding soils and surface waters. A glasshouse pot-leaching study was performed to evaluate the effectiveness of waste gypsum (CaSO4) and copperas (FeSO4) as ameliorants for the red mud fraction. Red mud was amended with the wastes at rates of 0, 2, 5, and 8% (w/w), and leached with 1200 ml (126 min rainfall) of deionized water before conducting a seedling emergence test using Agropyron elongatum. Leachate and soil analyses indicated that gypsum and copperas amendments were able to reduce the pH, electrical conductivity (EC) and Na content of red mud significantly. Copperas was more effective in reducing soil Na contents and maintaining a lower soil EC. On the other hand, gypsum-amended red mud maintained a lower pH and a higher Ca content because of the low solubility of gypsum. Both amendments also resulted in significant reductions in soluble Al content and exchangeable sodium percentage (ESP). The reduced pH, ESP and Al content were correlated to the improved seedling emergence of Agropyron at application rates of >2%. The results demonstrate that both gypsum and copperas are effective ameliorants for red mud. However, gypsum appears to provide a more persistent pH buffering capacity and lower ESP for red mud

Use of waste gypsum in the revegetation on red mud deposits: A greenhouse study

The disposal of fine bauxite refining residue (red mud) has occupied huge areas of land which remain derelict and subject to wind and water erosion. The major constraints in rehabilitation are the high alkalinity, salinity and sodicity of red mud. This paper describes a greenhouse study to evaluate the use of waste gypsum as ameliorants for red mud. Red mud was amended with gypsum at 0, 2, 5 and 8% (w/w) and its effect on the growth of two grass species, Agropyron elongatum (Tall wheat grass) and Cynodon dactylon (Bermuda grass), was evaluated. Gypsum amendment significantly reduced the pH, electrical conductivity (EC), and Na and Al content of red mud and provided a continuous supply of Ca2+, which resulted in a lower soil exchangeable sodium percentage (ESP). The improved soil conditions at ≥ 5% gypsum amendment significantly increased seedling emergence and dry weight yields. The enhanced plant growth and seedling emergence show significant negative correlations with pH, Al and ESP of soil. Tissue analyses indicated that the availability of P, K, Mg and Ca also increased for ≥ 5% gypsum amended red mud, while Na and Fe were less available. Results from the present study indicated that waste gypsum is an effective ameliorant for red mud revegetation and no topsoil amendment is required

Sewage sludge as organic ameliorant for revegetation of fine bauxite refining residue

The rise in aluminium demand in the world has significantly increased the generation of bauxite residue which occupies huge areas of land worldwide. Direct revegetation of residue storage areas has been unsuccessful because of the high alkalinity and salinity, and poor nutrient contents of the fine residue (red mud). This paper describes glasshouse and field experiments evaluating the potential use of sewage sludge as an organic ameliorant for gypsum amended red mud. The growth of Agropyron elongatum in red mud receiving gypsum (0 and 38.5 t ha-1) and sewage sludge (0, 38.5 and 77 t ha-1) amendment was assessed in a glasshouse study. Leachate and soil analyses revealed that gypsum was effective in reducing the pH, EC and ESP of red mud, while sewage sludge gave additional reductions in EC, Na and ESP. No evidence of any significant increases in heavy metal contents were observed in the leachates following sewage sludge amendment. However, soil Al contents were more available in red mud receiving only sewage sludge treatment. Sewage sludge amendment significantly increased dry weight yield and provided sufficient nutrients for plant growth except K which was marginal. No heavy metal accumulation was observed in Agropyron. Following that, a field experiment was performed having red mud amended with sewage sludge (38.5, 77 and 154 t ha-1) and gypsum (38.5 and 77 t ha-1) to evaluate their effects on soil physical properties of red mud. Sewage sludge significantly reduced soil bulk density (25%) and particle density (9%) and increased the total porosity of red mud (8%). Hydraulic conductivity also increased from 1.5 to 23 x 10-5 m s-1. Plant cover percentage and dry weight yield of Agropyron increased with an increase in gypsum and sewage sludge amendment. The results confirm that sewage sludge is effective in improving both soil structure and nutrient status of gypsum amended red mud. The use of sewage sludge for red mud revegetation provides not just an option for sludge disposal, but also a cost effective revegetation strategy for bauxite refining industry

Effects of gypsum and sewage sludge amendment on physical properties of fine bauxite refining residue

Fine bauxite refining residue (red mud) was amended with gypsum and sewage sludge to evaluate their effects on soil physical properties in a field experiment. Sewage sludge amendment significantly reduced soil bulk density (25%) and particle density (9%), and increased the total porosity of red mud (8%). Both sewage sludge and gypsum contributed to the increases in hydraulic conductivity after one growing season. Enhanced plant growth was due to improved soil structure and hydraulic conductivity. An application of 77 t/ha gypsum and 144 t/ha sewage sludge exerted the maximum effect on soil physical properties of red mud and should ensure the initial establishment of plants

Cation exchange behavior of bauxite refining residues from Western Australia

Over 60 million tonnes per year of bauxite refining residue (red mud) is produced worldwide. Its high Na concentration inhibits plant growth and hence reclamation. The cation-exchange capacity (CEC) of red mud and the cation exchange equilibria between Na+ and several other cations were measured to elucidate the mechanism of Na release from red mud. The CECs obtained by using K+ and NH4/+ were significantly higher than those obtained using Ca2+ and Ba2+. This unusual cation exchange phenomenon can be attributed to the presence of zeolitic minerals in red mud. Cation exchange equilibria show that Na+ originally present hi red mud was preferentially adsorbed by the mud over other cations. At high cation fractions in red mud (>0.1), the mud selectively sorbed monovalent over divalent cations, with the following order of selectivity: K+ > Li+ > NH4/+ > Ba2+ ≥ Ca2+ > Mg2+. The exchange of Na+ has been found to have significant negative correlations with the radius of hydration and Debye-Huckel parameter. Divalent cations have little ability to exchange Na+ from zeolitic exchange sites. Incremental extraction of Na+ in red mud shows that K+ and NH4/+ displaced 99 (63%) and 57 (44%) cmol(c) kg-1 red mud whereas Ca2+ and Mg2+ could only displace 33 and 29 cmol(c) kg-1 red mud, respectively, out of a total of 99 cmol(c) Na kg-1 red mud. In a reverse process 95% of K+ adsorbed on red mud was readily replaced by Na+. The experimental evidence suggests that the release of Na+ from red mud is due to cation exchange. Over 60 million tonnes per year of bauxite refining residue (red mud) is produced worldwide. Its high Na concentration inhibits plant growth and hence reclamation. The cation-exchange capacity (CEC) of red mud and the cation exchange equilibria between Na+ and several other cations were measured to elucidate the mechanism of Na release from red mud. The CECs obtained by using K+ and NH4+ were significantly higher than those obtained using Ca2+ and Ba2+. This unusual cation exchange phenomenon can be attributed to the presence of zeolitic minerals in red mud. Cation exchange equilibria show that Na+ originally present in red mud was preferentially adsorbed by the mud over other cations. At high cation fractions in red mud (>0.1), the mud selectively sorbed monovalent over divalent cations, with the following order of selectivity: K+>Li+>NH 4+>Ba2+≥Ca2+>Mg2+. The exchange of Na+ has been found to have significant negative correlations with the radius of hydration and Debye-Huckel parameter. Divalent cations have little ability to exchange Na+ from zeolitic exchange sites. Incremental extraction of Na+ in red mud shows that K+ and NH4+ displaced 99 (63%) and 57 (44%) cmolc kg-1 red mud whereas Ca2+ and Mg2+ could only displace 33 and 29 cmolc kg-1 red mud, respectively, out of a total of 99 cmolc Na kg-1 red mud. In a reverse process 95% of K+ adsorbed on red mud was readily replaced by Na+. The experimental evidence suggests that the release of Na+ from red mud is due to cation exchange