Immobilization of W(VI) and/or Cr(VI) in soil treated with montmorillonite modified by a gemini surfactant and tetrachloroferrate (FeCl4-).

The coexistence of highly toxic chromium (Cr) and the emerging contaminant tungsten (W) in the soil adjacent to W mining areas is identified. Immobilization of W and/or Cr is vital for the safe utilization of contaminated soil. In this study, the cationic gemini surfactant (butane-1,4-bis(dodecyl dimethyl ammonium bromide)) and tetrachloroferrate (FeCl4-)-modified montmorillonite (FeOMt) was applied to investigate the retention performance of W and/or Cr in the soil. Regardless of the initially spiked amount of WO42- and/or CrO42-, the W and/or Cr leached in soil solution was rapidly immobilized within 5 min. The immobilization rates of W and/or Cr in the single and binary soil systems were stably maintained against the variations in pH and coexisting anion. FeOMt showed more favorable performance in the retention of W and/or Cr with respect to the precursors (i.e., the original Mt and surfactant-modified Mt) and efficiently inhibited the phytotoxicity and bioaccumulation of W and/or Cr in mung beans. Due to the ion exchange, complexation, reduction, and flocculation, the addition of FeOMt transformed W and/or Cr from exchangeable/carbonate species to reducible/oxidizable fractions, reducing the environmental risk. FeCl4- complex, as a byproduct of the steel pickling process in industry, plays the pivotal role in the efficient retention of W and Cr. Based on the facile synthesis procedure and the efficient performance, the use of FeOMt for the amendment of W- and/or Cr-contaminated soil is feasible and promising.

Gemini surfactant-modified montmorillonite with tetrachloroferrate (FeCl4-) as a counterion simultaneously sequesters nitrate and phosphate from aqueous solution.

Alkyl quaternary ammonium-modified clay minerals, which are common environmentally friendly materials, have been widely studied and applied for the removal of pollutants. However, there are few reports on functionalizing the counterions to expand the application. In this study, the cationic gemini surfactant butane-1,4-bis(dodecyl dimethyl ammonium bromide) (gBDDA) and tetrachloroferrate (FeCl4-) are designed to modify montmorillonite (Mt), and the obtained FeCl4-/Gemini-Mt composite (FeOMt) is used for the removal of nitrate and/or phosphate from aqueous solution. The successful intercalation of gBDDA and favorable loading of FeCl4- into FeOMt are suggested by the characterization results of X-ray diffraction and Raman spectroscopy. Nitrate and/or phosphate are rapidly sequestered, and the respective maximum uptakes of 8.77 (N) and 28.1 (P) mg/g in the binary system are obtained. The phosphate uptake is stably maintained against many coexisting ions, but the nitrate uptake decreases with the increase in ionic strength. FeOMt is reusable and shows comparable uptake for nitrate and phosphate with respect to gBDDA-modified Mt and polymerized ferric chloride. Considering the multi-functionality and facile synthesis, FeOMt shows promising potential in the purification of wastewater contaminated simultaneously by poorly hydrated anions (e.g., ClO4-, TcO4-, etc.) and iron-selective anions (e.g., H2AsO4-, etc.).

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Prevalence and Genetic Diversity of Bacillus cereus Isolated from Raw Milk and Cattle Farm Environments.

Bacillus cereus not only has adverse effects on the nutrition and shelf life of dairy products but also seriously endanger people's health. This study was conducted to reveal the prevalence and genetic diversity of B. cereus strains isolated from raw milk and cattle farm environments. A total 56 of B. cereus strains were detected from 300 environmental samples (soil, water, fodder, air, milk pails, milking machines, cowsheds, bedding, excrement, cow surfaces, udders, overalls, soles, and staff hand samples) and 50 raw milk samples, and divided into 18 sequence types (STs) using multilocus sequence typing method. These STs included ST27, ST61, ST92, ST142, ST168, ST208, ST378, ST427, ST766, ST 857, ST1098, ST1140, ST1194, ST1236, ST1336, ST1339, ST1341, and ST1348, among them, ST857 (7/56, 12.5%) was the dominant ST, and were detected from air, cowsheds, bedding, excrement, and raw milk samples. Our findings could reveal the distribution and genetic diversity of B. cereus strains in raw milk and cattle farm environments, and provide a theoretical basis for controlling the potential harm of this pathogenic bacteria in dairy products.

Occurrence, Genotyping, and Antibiotic Susceptibility of Cronobacter spp. in Drinking Water and Food Samples from Northeast China.

Cronobacter species (formerly Enterobacter sakazakii) are emerging opportunistic bacterial pathogens that can infect both infants and adults. This study was conducted to isolate and genotype diverse Cronobacter species from drinking water, chilled fresh pork, powdered infant formula, instant noodles, cookies, fruits, vegetables, and dishes in Northeast China and to evaluate the antibiotic resistance and susceptibility of the isolates. Thirty-four Cronobacter strains were isolated and identified: 21 C. sakazakii isolates (61.8%), 10 C. malonaticus isolates (29.4%), 2 C. dublinensis isolates (5.9%), and 1 C. turicensis isolate (2.9%). These isolates were further divided into 15 sequence types (STs) by multilocus sequence typing. C. sakazakii ST4 (10 isolates, 29.4%), ST1 (3 isolates, 8.8%), and ST8 (3 isolates, 8.8%) and C. malonaticus ST7 (four isolates, 11.8%) were dominant. Antibiotic susceptibility testing indicated that all 34 Cronobacter isolates were susceptible to ampicillin-sulbactam, cefotaxime, ciprofloxacin, gentamicin, meropenem, tetracycline, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole, 88.2% were susceptible to chloramphenicol, and 67.6% were resistant to cephalothin. The results of this study enhance knowledge about genotyping and antibiotic resistance of these Cronobacter species and could be used to prevent potential hazards caused by these strains in drinking water and various food products.

Prevalence, Molecular Characterization, and Antibiotic Susceptibility of Cronobacter sakazakii Isolates from Powdered Infant Formula Collected from Chinese Retail Markets.

Cronobacter sakazakii is an opportunistic pathogen that causes severe infections in neonates and infants through contaminated powdered infant formula (PIF). Therefore, the aim of this study was a large-scale study on determine the prevalence, molecular characterization and antibiotic susceptibility of C. sakazakii isolates from PIF purchased from Chinese retail markets. Two thousand and twenty PIF samples were collected from different institutions. Fifty-six C. sakazakii strains were isolated, and identified using fusA sequencing analysis, giving a contamination rate of 2.8%. Multilocus sequence typing (MLST) was more discriminatory than other genotyping methods. The C. sakazakii isolates were divided into 14 sequence types (STs) by MLST, compared with only seven clusters by ompA and rpoB sequence analysis, and four C. sakazakii serotypes by PCR-based O-antigen serotyping. C. sakazakii ST4 (19/56, 33.9%), ST1 (12/56, 21.4%), and ST64 (11/56, 16.1%) were the dominant sequence types isolated. C. sakazakii serotype O2 (34/56, 60.7%) was the primary serotype, along with ompA6 and rpoB1 as the main allele profiles, respectively. Antibiotic susceptibility testing indicated that all C. sakazakii isolates were susceptible to ampicillin-sulbactam, cefotaxime, ciprofloxacin, meropenem, tetracycline, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole. The majority of C. sakazakii strains were susceptible to chloramphenicol and gentamicin (87.5 and 92.9%, respectively). In contrast, 55.4% C. sakazakii strains were resistant to cephalothin. In conclusion, this large-scale study revealed the prevalence and characteristics of C. sakazakii from PIF in Chinese retail markets, demonstrating a potential risk for neonates and infants, and provide a guided to effective control the contamination of C. sakazakii in production process.

LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer.

Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms. Here, we further examined the effects of LY3009120, a panRAF and RAF dimer inhibitor, in human models of CRC with various mutational backgrounds. We demonstrate that LY3009120 induced anti-proliferative effects in BRAFmut and KRASmut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRASmut CRC cell lines phenocopied molecular inhibition of RAF isoforms by simultaneous siRNA-mediated knockdown of ARAF, BRAF and CRAF. Additionally, LY3009120 displayed significant activity in in vivo BRAFmut and KRASmut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRASmut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAFmut and KRASmut CRC setting.

Improved potentiometric response of solid-contact lanthanum (III) selective electrode.

For the first time, the analytical application of integrate ionophore-transducer material based on magnetic graphene hybrids and 2,2-dithiodipyridine (DTDP) in solid-contact lanthanum (III) selective electrode is reported. The attachment of Fe3O4 nanoparticles (NPs) to graphene oxide (GO) for magnetic graphene hybrid is achieved by covalent bonding, and the universal problem, Fe3O4 NPs may easily leach out from the graphene during application, is successfully solved by the method above. The proposed electrode exhibits an excellent near-Nernstian response to lanthanum (III) ranging from 1.0×10(-9) to 1.0×10(-3)M with a slope of 17.81 mV/dec. Moreover, the excellent performance on fairly good selectivity, wide applicable pH range (3.0(_)8.0), fast response time (10s) and long life time (2 months) reveal the superiority of the electrode. Most importantly, we have made a great improvement in the detection limit (2.75×10(-10)M), which brings new dawn to the real-time detection of lanthanum (III) using ion selective electrode.

Cloning and functional characterization of the rabbit C-C chemokine receptor 2.

BACKGROUND: CC-family chemokine receptor 2 (CCR2) is implicated in the trafficking of blood-borne monocytes to sites of inflammation and is implicated in the pathogenesis of several inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and atherosclerosis. The major challenge in the development of small molecule chemokine receptor antagonists is the lack of cross-species activity to the receptor in the preclinical species. Rabbit models have been widely used to study the role of various inflammatory molecules in the development of inflammatory processes. Therefore, in this study, we report the cloning and characterization of rabbit CCR2. Data regarding the activity of the CCR2 antagonist will provide valuable tools to perform toxicology and efficacy studies in the rabbit model. RESULTS: Sequence alignment indicated that rabbit CCR2 shares 80 % identity to human CCR2b. Tissue distribution indicated that rabbit CCR2 is abundantly expressed in spleen and lung. Recombinant rabbit CCR2 expressed as stable transfectants in U-937 cells binds radiolabeled 125I-mouse JE (murine MCP-1) with a calculated Kd of 0.1 nM. In competition binding assays, binding of radiolabeled mouse JE to rabbit CCR2 is differentially competed by human MCP-1, -2, -3 and -4, but not by RANTES, MIP-1alpha or MIP-1beta. U-937/rabbit CCR2 stable transfectants undergo chemotaxis in response to both human MCP-1 and mouse JE with potencies comparable to those reported for human CCR2b. Finally, TAK-779, a dual CCR2/CCR5 antagonist effectively inhibits the binding of 125I-mouse JE (IC50 = 2.3 nM) to rabbit CCR2 and effectively blocks CCR2-mediated chemotaxis. CONCLUSION: In this study, we report the cloning of rabbit CCR2 and demonstrate that this receptor is a functional chemotactic receptor for MCP-1.

Regulation of sensitivity to TRAIL by the PTEN tumor suppressor.

The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis preferentially in cancer cells is attractive for its development as a novel cancer therapeutic agent, but many cancer cell lines are resistant to TRAIL. While the molecular basis for TRAIL resistance is not always clear, a number of factors have been proposed to mediate TRAIL resistance, including decoy receptor, c-FLIP, nuclear factor (NF)-kappaB, and activation of antiapoptotic kinase signaling. Many growth factor receptors mediate their survival signals through the pathway involving recruitment and activation of phosphatidylinositol (PI) 3-kinase and the serine?threonine kinase Akt. The PTEN tumor suppressor is a phosphatase that dephosphorylates the phospholipids phosphorylated by PI-3 kinase, thereby opposing the action of PI 3-kinase, and acts as the primary negative regulator of the PI-3 kinase?Akt pathway in the cell. Loss of PTEN function occurs frequently in human tumors and leads to constitutive activation of Akt in cancer cells. Constitutively active Akt protects cells from TRAIL-induced apoptosis in multiple tumor types. Growth factors such as epidermal growth factor or insulin-like growth factor-1 also inhibit TRAIL-induced apoptosis through the Akt pathway. Akt exerts its antiapoptotic function by its ability to phosphorylate many key components of the cellular apoptotic regulatory circuit, such as BAD, MDM2, FOXO Forkhead transcription factors, and PED?PEA-15 as well as by its role in activating NF-kappaB. Because PTEN loss is common in tumors, strategies to inactivate Akt may be necessary to overcome TRAIL resistance and make TRAIL-based therapy more effective.

PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit.

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.

PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway.

The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.

[The analysis of medical-related cost for in-patients with injuries in Ningxia region].

OBJECTIVE: To understand socio-economic losses of inpatients and deaths caused by injuries in 2000 in Ningxia and to estimate their extent of harmfulness. METHODS: Eight of 35 local hospitals totaling 5 876 inpatients were recruited with two-stage sampling in Ningxia in 2000. All medical cost incurred during their hospitalizations for injuries, cardiovascular and cerebrovascular diseases, respiratory disease, cancer and communicable diseases, losses in labor time were analyzed, and years of potential life lost (YPLL), working years of potential lost (WYPLL), valued years of potential life lost (VYPLL) due to these diseases were estimated for the residents in Ningxia with corrected human capital method. RESULTS: The study showed that indirect economic losses due to hospitalization for injuries accounted for 24 million yuan, higher than those for other diseases. YPLL, WYPLL and VYPLL due to injuries were also higher than those in other diseases. CONCLUSIONS: Injury has caused serious threat to their health of the residents in Ningxia and brought heavy burden for the society and economy. It has become an important public health problem and its prevention and control should be strengthened as soon as possible.