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Supplementary figure S1 describes the molecular mechanisms of resistance across vemurafenib-resistant cell line models. Supplementary figure S2 serves as a repeat of figure 3a describing development of in vivo model of resistance, and demonstrates the effect of vemurafenib withdrawl on the resistant tumors. Supplementary figure S3 describes the effect of vemurafenib treatment on MAPK pathway inhibition in A375-RV2 cells. Supplementary figure S4 shows that selective cyclin D1 knockdown or CDK4/6 inhibition induces apoptosis in A375-R1 and M14-R vemurafenib-resistant melanoma cells.

Supplementary Figure S1. Validation of BRAF deletion in BxPC-3 cells by Sanger's sequencing method. Supplementary Figure S2. BRAF deletion (deltaBRAF), but not WT BRAF, is able to transform cells. Supplementary Figure S3. Validation of in situ PLA in HeLa and HEK293 cells. Supplementary Figure S4. Phospho-CRAF and MAPK activation in selected tumor cells with BRAF alteration or KRAS mutation. Supplementary Figure S5. Phospho-MEK and ERK inhibition by dabrafenib in tumor cells harboring BRAF deletion. Supplementary Figure S6. In vitro effects of MAPK inhibitors on tumor cells harboring BRAF deletions. Supplementary Table S1. Novel somatic BRAF in-frame deletions from cancer cell lines and patient samples. Supplementary Figure S7. LY3009120, but not vemurafenib, exhibited significant tumor growth inhibition and regression in lung and pancreatic tumor xenograft models harboring the BRAF deletions without significant body weight loss. Supplementary Table S2. IC50 of LY3009120 and vemurafenib against tumor cells with atypical BRAF mutations.

Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models.Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial.Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547–60. ©2017 AACR.

S1 and S2

Supplementary Table S1 and S2

Desertification land in Gonghe Basin of Tibetan Plateau, China accounts for 91.9% of the total land area. Vegetation restoration and reconstruction with desert shrubs in degraded ecosystem are effective ways to prevent and control desertification. However, the evaluation studies of fine root dynamic characteristics of desert shrubs and their contribution to carbon sequestration of plantation are limited. To gain a better understanding of vegetation restoration, the vertical distribution of fine root biomass, fine root decomposition, fine root turnover was investigated, as well as their coupling effect on carbon sequestration of plantation in three desert vegetation. The results estimated that the total decomposition time of fine roots of Salix cheilophila (S. cheilophila), Salix psammophila (S. psammophila), and Salix microstachya (S. microstachya) are 39.00, 27.99 and 35.95 years. Biomass carbon density for three Salix plantations ranged from 1.42 to 2.39 t/hm2, which showed that three Salix plantations in alpine sandy land are an important carbon pool. In addition, fine root biomass carbon density for the three shrub plantations varied significantly. Fine root biomass carbon density for S. psammophila reached the largest among the three plantations, which was 1.48 t/hm2, accounting for the ratio of 62% of the plantation total biomass carbon density. The results indicated that the root system of S. psammophila, especially the fine roots, was very developed, which was conducive to soil water transportation and carbon sequestration. Therefore, S. psammophila might be a better species for carbon sequestration of plantation in alpine sandy areas. The carbon input from the fine roots of the three shrub plantations through decomposition and turnover into the plantations accounts for 11.5% to 15.5% of total carbon sequestration of plantations. Therefore, the fine roots dynamics must be considered for long‐term carbon pool estimations in three Salix plantations, otherwise the total carbon sequestration of plantations would be underestimated.

Although KRAS has long been considered undruggable, direct KRAS

Accurate assessment of soil organic carbon (SOC) and total nitrogen (TN) stocks and analyzing the main influencing factors after revegetation for restoration of sandy soils in alpine regions are important for formulating sustainable management measures and understanding the role of revegetation in mitigating climate change. This study compared SOC and TN stocks and their vertical distributions among 6-, 11-, 17- and 31-year-old Caragana intermedia plantations and shifting sand dunes. The results showed that SOC and TN stocks significantly increased as plantation age increased, with the 31-year-old stands having the highest SOC stocks (26.73 Mg ha−1) and TN stocks (2.64 Mg ha−1), which were 97.4% and 149.56% higher, respectively, than those of the shifting sand dunes. Compared to the total soil depth, SOC and TN stocks at all stand ages were higher in surface soil (0–20 cm). SOC stocks in the surface soil of the 6-, 11-, 17- and 31-year-old stands were 38.03%, 71.32%, 103.67% and 253.30% higher, respectively, than those in the surface soil of the shifting sand dunes, and TN stocks in the surface soil were 17.03%, 117.96%, 148.93% and 232.06% higher, respectively, than those in the surface soil of the shifting sand dunes. The percentage of the SOC and TN stock in the 0–20 cm soil depth increased significantly as plantation age increased, with the 31-year-old plantation reaching 43.66% and 33.39%, respectively. Redundancy analysis and correlation analysis showed that at 0–20 cm soil depth, above-ground biomass was the main influencing factor for SOC and TN stocks. At 20–80 cm soil depth, fine root biomass and medium root biomass were the main influencing factors for SOC stocks, and medium root biomass was the main influencing factor for TN stocks.

Precipitation, throughfall, stemflow, and soil water content were measured, whereas interception, transpiration, evaporation, deep percolation, and soil water recharge were estimated in three plots, including oak (Lithocarpus glaber), Chinese fir (Cunninghamia lanceolata) forestlands, and maize (Zea mays) farmland in the Three Gorges Reservoir in China. A physical process-based model (CoupModel) was set up with climatic measurements as input and was calibrated with throughfall and vertical frequency domain reflectometry measurements from January 2018 to December 2019. Simulated values of soil moisture were fairly consistent with measured ones, with a determination coefficient (R2) of 0.73–0.91. Evapotranspiration was the main output of water balance, with a percentage of up to 61%, and such output was ranked as follows: oak forest (720 mm/y) &gt, Chinese fir forest (700 mm/y) &gt, maize farmland (600 mm/y). Afforestation influenced water balance, and water recharge was generally less significant in oak forestland than in Chinese fir forestland. Annual simulated deep percolation decreased by 60 mm for oak and 47 mm for Chinese fir compared with that for farmland (452 mm/y) and even more significantly in wet years. This decrease was mainly attributed to increased interception (122–159 mm/y) and transpiration (49–84 mm/y) after afforestation. Simulations indicated that vegetation species significantly influenced the magnitude of water balance components, calling for further attention to the selection of regrown tree species in the planning for afforestation projects, particularly for such projects that aim to improve the quantity of water infiltrating groundwater. Soil and water conservation measures should also be applied scientifically when converting farmland to forest in this area, particularly in the oak forest stand.

Preferential flow paths have been widely characterized by many visualization methods. However, the differences in preferential flow paths under various land uses and their relationships to hydraulic properties remain uncertain. The objectives of this study are to (1) characterize preferential flow paths under various land uses (forest and orchard) by combining drainage and dye-staining methods and to (2) build a connection between preferential flow paths and hydraulic-related parameters and extract the proportion of preferential flow paths from the compounding effects of matrix flow and preferential flow. The dye-staining experiments were conducted in five sandy soils and one sandy clay loam in situ, including four soils from forest and two soils from orchards. A total of 47 soil cores, 4 cm in height and 9 cm in diameter, were collected in each layer of the dye-stained soils for drainage experiments in the laboratory. Dye coverage and hydraulically equivalent macropore parameters (macroporosity, pore size distribution, and number of macropores) and their relationships were analyzed. The results show that the volume of preferential flow is partly affected by the total macropore volume. The effect of macropores on preferential flow varies by macropore size distribution. Dye coverage exhibited a significant (P &lt, 0.01) correlation with macroporosity (correlation coefficient 0.83). Based on the value of macroporosity or steady effluent rates, the part of the dye coverage that was due to preferential flow on the surface dye-stained soil (resulting from both matrix and preferential flow) could be identified in this study. Compared with orchards, forestland has more preferential flow paths in both surface soil and subsoil. Further studies are needed to quantify the 3-D preferential flow paths and build a connection between preferential flow paths and hydraulic properties.

Desertification land in Gonghe Basin of Tibetan Plateau, China accounts for 91.9% of the total land area. Vegetation restoration and reconstruction with desert shrubs in degraded ecosystem are effective ways to prevent and control desertification. However, the evaluation studies of fine root dynamic characteristics of desert shrubs and their contribution to carbon sequestration of plantation are limited. To gain a better understanding of vegetation restoration, the vertical distribution of fine root biomass, fine root decomposition, fine root turnover was investigated, as well as their coupling effect on carbon sequestration of plantation in three desert vegetation. The results estimated that the total decomposition time of fine roots of Salix cheilophila (S. cheilophila), Salix psammophila (S. psammophila), and Salix microstachya (S. microstachya) are 39.00, 27.99 and 35.95 years. Biomass carbon density for three Salix plantations ranged from 1.42 to 2.39 t/hm2, which showed that three Salix plantations in alpine sandy land are an important carbon pool. In addition, fine root biomass carbon density for the three shrub plantations varied significantly. Fine root biomass carbon density for S. psammophila reached the largest among the three plantations, which was 1.48 t/hm2, accounting for the ratio of 62% of the plantation total biomass carbon density. The results indicated that the root system of S. psammophila, especially the fine roots, was very developed, which was conducive to soil water transportation and carbon sequestration. Therefore, S. psammophila might be a better species for carbon sequestration of plantation in alpine sandy areas. The carbon input from the fine roots of the three shrub plantations through decomposition and turnover into the plantations accounts for 11.5% to 15.5% of total carbon sequestration of plantations. Therefore, the fine roots dynamics must be considered for long‐term carbon pool estimations in three Salix plantations, otherwise the total carbon sequestration of plantations would be underestimated., The total decomposition time of fine roots of Salix cheilophila, Salix psammophila, and Salix microstachya were significantly larger than that of other regions in desert ecosystem. The increase of N concentration in fine roots of Salix would promote the increase of net primary productivity. The contribution of fine roots to carbon storage of plantation could reach 16% through input soil carbon by dynamic activities such as turnover and decomposition.

KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G0/G1 arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.

Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models. Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial. Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition. Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547–60. ©2017 AACR.

Fracture identification and characterization is an important part of fractured reservoir research. To realize the automatic extraction of digital geological outcrop fractures, a fracture extraction method based on multi-scale Beamlet transform is designed. Firstly, the image is enhanced by the adaptive enhancement algorithm to eliminate the influence of noise and uneven illumination. Then the fracture binary image obtained by the Otsu threshold method is used to extract the fracture by Beamlet transform. Finally, discrete line segment connection algorithm is designed to complete the fracture connection. Experiments show that, compared with Canny edge detection algorithm and Hough transform algorithm, the proposed method has better anti-noise ability, and the extracted fracture linear features are more accurate and complete. By adopting adaptive enhancement processing and discrete line segment connection algorithm, the problems of uneven illumination and disconnection of line segments are reduced, and the advantages of Beamlet algorithm in linear feature extraction are fully utilized. Through the analysis of the application of this method on digital outcrop of the Member-2 of Sinian Dengying Formation in Ebian Xianfeng area, it is shown that this method has a good practical application potential in large-scale fracture extraction and complements the study of microscopic fracture identification. It has a good application prospect for improving the interpretation efficiency of digital geological outcrop fractures and has reference value for other linear feature extraction applications.

KRAS-G12C is an important oncogenic mutation in patients with NSCLC, CRC, and other cancer types. Currently, there are no FDA-approved KRAS-G12C inhibitors, and those in clinical development have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers. This modest activity may be potentially due in part to incomplete target occupancy and trapping of mutant KRAS in the inactive GDP-bound state. Achieving maximal clinical benefit in patients harboring a KRAS-G12C mutation, may require a potent inhibitor capable of achieving near complete target engagement. Here, we report the identification of LY3537982, a novel, highly selective and potent inhibitor of the KRAS-G12C protein, discovered using structure-based design. In kinetic studies, LY3537982 showed a high Kinact/Ki value (248,016 M-1 s-1), compared to AMG510 (7,220 M-1 s-1) and MRTX849 (35,000 M-1 s-1). LY3537982 inhibited KRAS-GTP loading with an IC50 value of 3.35 nM in the KRAS-G12C mutant H358 lung cancer cell line, while AMG510 and MRTX849 had IC50 values of 47.9 nM and 89.9 nM, respectively. LY3537982 also inhibited phospho-ERK in H358 cells with an IC50 value of 0.65 nM, while the IC50 values of AMG510 and MRTX849 were 13.5 nM and 14 nM, respectively. In a panel of cancer cell lines with KRAS-G12C or non-G12C mutations, LY3537982 selectively inhibited the growth of KRAS-G12C mutant tumor cells and not KRAS wild-type or non-G12C mutant cells. Sensitivity to LY3537982 varied among the KRAS-G12C mutant cells tested, suggesting that not all cell lines maintain the same dependence on KRAS-G12C. Similarly, in multiple xenograft or patient-derived xenograft (PDX) models harboring a KRAS-G12C mutation, LY3537982 exhibited a range of anti-tumor activity from complete regression to significant tumor growth inhibition, at 3 to 30 mg/kg QD or BID. Mechanism-based combinational screens have also identified certain targeted therapies that can synergize with LY3537982 to achieve better anti-tumor activity in vitro and in vivo, including abemaciclib, the selective AurA inhibitor LY3295668, and cetuximab. Together these data suggest that in certain biologic contexts, broader and more durable anti-tumor activity could be achieved with combination regimens. A first-in-human Phase 1 clinical trial is planned for 2021. Citation Format: Sheng-Bin Peng, Chong Si, Youyan Zhang, Robert D. Van Horn, Xi Lin, Xueqian Gong, Lysiane Huber, Gregory Donoho, Carmen Curtis, John M. Strelow, Wayne P. Bocchinfuso, Deqi Guo, Serge L. Boulet, David Barda, Danalyn Manglicmot, Melbert-Brian D. Saflor, Jing Wang, Junpeng Xiao, Michael J. Chalmers, Lee Burns, Ryan J. Linder, Bradley L. Ackermann, Paul D. Cornwell, Lian Zhou, Denis McCann, James Henry. Preclinical characterization of LY3537982, a novel, highly selective and potent KRAS-G12C inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1259.

// Eliza Vakana 1, * , Susan Pratt 1, * , Wayne Blosser 1 , Michele Dowless 1 , Nicholas Simpson 2 , Xiu-Juan Yuan 3 , Susan Jaken 3 , Jason Manro 4 , Jennifer Stephens 1 , Youyan Zhang 1 , Lysiane Huber 1 , Sheng-Bin Peng 1 , Louis F. Stancato 1 1 Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 2 Discovery Research, Advanced Testing Laboratory, Cincinnati, OH 45242, USA 3 Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 4 Discovery Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA * These authors contributed equally to this work Correspondence to: Louis F. Stancato, email: stancato_louis@lilly.com Keywords: RAS, RAF, signaling pathways, colorectal cancer, xenograft models Received: September 28, 2016 Accepted: December 13, 2016 Published: December 16, 2016 ABSTRACT 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 BRAF mut melanoma, they have limited efficacy in BRAF mut CRC patients. In a RAS mut 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 BRAF mut and KRAS mut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRAS mut 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 BRAF mut and KRAS mut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRAS mut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAF mut and KRAS mut CRC setting.

We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490–deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer–dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive. Significance: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. Cancer Discov; 6(3); 300–15. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 217

In this paper we propose a novel multiple relay selection scheme based on the log-likelihood ratio (LLR). In this scheme, the joint design of precoding matrices at both the source and relay nodes in a multiple relay system based on perfect channel information is considered, which is based on the maximum signal-to-noise ratio. Using eigen-decomposition of matrices and monotonicity of functions, the joint design problem is transformed into two kinds of independent sub-problems and a fast algorithm is proposed. Compared with the traditional scheme based on signal-to-noise ratio (SNR), the proposed scheme is better in the symbol error rate (SER) performance. Simulation results show that the scheme based on LLR is superior to SNR in the SER performance. Meanwhile the multi-relay system with the proposed scheme can improve the SER performance effectively compared with only space-time coding or only precoding system.

Shale oil and gas resources are abundant all over the world. TOC (Total Organic Carbon) content is an important index of shale evaluation. TOC content in organic shale is usually obtained through the shale physics experiment. In this paper we discussed a new method of TOC content prediction in organic shale using laser intensity of terrestrial laser scanning. Firstly, we studied on the correlation relationship between TOC content and laser intensity. Then we built the exponential relationship model between TOC content and laser intensity using exponential fitted methods to predict TOC content. Chang7 shale of Yanchang Formation is one of high-quality source rocks in Erdos Basin, China. So, Chang7 shale was used for testing the TOC content prediction method in shale in this paper. Experiments showed that laser intensity can efficiently predict TOC content in shale. This method can be used to directly predict TOC content in field outcrops of organic shale.

SummaryLY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.

This paper uses high-precision remote sensing and laser scanning to study petroleum geological analysis methods. The research area is Karamay Formation in Junggar Basin, China. Firstly, the outcrop lithologies are identified according to our clastic rock lithology identification pattern based on laser intensity, and the regional lithologies are identified based on high-precision remote sensing images. Furthermore, we analyze the horizontal and vertical distribution characteristics of the sandbodies. At last, we analyze the area sandbody connectivity and sandbody structure characteristics. These data can provide basic information for the analysis of underground reservoirs in Karamay Formation.

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.

This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC50 = 23 and 22 nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.

Quaternary biogenic gas fields in the Sanhu area of the Qaidam Basin are characterized by gentle structures, shallow burial, weak compaction, high porosity and great bulk thickness, which determine their unique geophysical anomalies, such as the locally low gravity, micro-magnetic high frequency anomaly, seismic event push-down and attribute anomaly. An integrated geophysical processing and interpretation scheme is put forward for shallow biogenic gas prediction in this area. Amplitude preservation is performed for 1:100000 gravity data and the processing results are correlated with known gas distributions and aeromagnetic results, remote sensing and seismic hydrocarbon detection. This study shows that the residual gravity low anomaly has a good correlation with the gas field and, as an important feature of the biogenic gas field, the amplitude of residual gravity low anomaly is directly proportional to the measure of gas reservoir. Based on the residual gravity low anomaly and other exploration data, the distribution of gas reservoirs in the Sanhu area is characterized by vertical overlapping, lateral zoning and local enrichment. Residual gravity anomaly, in combination with regional geologic data, reveals three favorable zones, one fairly favorable zone (low gas production zone), five possibly favorable zones and four favorable targets. Key words: Qaidam Basin, Sanhu area, Quaternary, biogenic gas, gravity, magnetic, seismic, geophysical integration, exploration direction

Preferential flow is important in solute transport in the soil, and it indirectly affects the quality of the groundwater. The objectives of the present study were to investigate the distribution characteristics of preferential flow paths under different land-use types (forestland, shrubland, and farmland) and to determine the factors that affect the formation of these paths. Dye tracer experiments were conducted at six sites covering the three land-use types. The relationship of the preferential flow paths to the properties of the soil, root length per soil volume, root holes, and root surface area was analyzed using a partial correlation method. The results show dye coverage of greater than 50% at a soil depth of 0 to 10 cm and dye coverage of less than 30% below a depth of 20 cm in all of the land-use types. The vertical distribution differed widely in the various land-use types. Shrubland and farmland had more preferential flow paths in the topsoil compared with forestland, in contrast to the conditions in the deeper soil layers. The soil chemical properties and the saturated hydraulic conductivity in the preferential flow paths were quite different from those in the soil matrix. The soil organic matter content was approximately 5% to 20% higher in the preferential flow paths than in the soil matrix. The average value of the saturated hydraulic conductivity was 41.3 mm min in the preferential flow paths compared with 21.4 mm min in the soil matrix. The percentage of preferential flow paths in the soil was significantly affected by roots with a diameter of less than 5 mm, root holes, and the root surface area. These findings suggest that land use is significant in the distribution of preferential flow paths, and root characteristics are important in the formation of preferential flow paths.

WCDMA is one of the key technologies of third-generation mobile communication. In this paper we study a new antenna diversity technology for WCDMA systems. The antenna diversity is based on log-likelihood ratio (LLR) which is better than that based on signal-to-noise ratio (SNR) in bit error rate performance. So the average bit-error rate (BER) performance of MQAM WCDMA systems combined with space-time block coding (STBC), 2D-RAKE receiver and the new LLR technology on correlated Nakagami fading channels has been investigated. The expressions of generalized selective combining (GSC) schemes based on Symbol-LLR (SLLR) and Bit-LLR (BLLR) are derived. Furthermore, the resolve expression of BER for a 16QAM WCDMA system with BLLR scheme in receive correlated Nakagami fading channel is presented. The simulation results show that the BLLR scheme is optimum since it minimizes the BER of WCDMA systems. With the increase of the multipath components, the performance of system is improved significantly. Moreover, the system which possesses the smaller rate of average path decay factor exhibits the higher diversity order.

Preferential flow is a runoff mechanism intermediate between matrix flow and surface flow, transmitting water at high velocity through the subsurface zone. To assess the effect of preferential flow on soil-water flow and surface runoff in a forested watershed, precipitation and volumes of preferential flow, matrix flow and surface runoff were measured over a period of four years in a forested watershed in the Three Gorges area of southern China. Results show that preferential-flow hydrographs have gentler rises and steeper recessions than those for matrix flow and surface runoff. Preferential flow as a percentage of soil-water flow ranged from 2.40% to 8.72% and the maximum preferential-flow velocity exceeded as much as 5600 times that of matrix flow. This shows that preferential flow plays an important role in the movement of soil water. Preferential flow has a significant effect on peak surface runoff by increasing the surface runoff rate and accelerating the appearance of peak surface runoff. Preferential flow can also prolong the duration of surface runoff. Surface runoff was observed to be positively correlated with preferential flow. The greater the sum of rainfall amount and antecedent precipitation is, the greater the effect of preferential flow on surface runoff is.

For seismic exploration, it is the basis for better data acquisition to select better line layout in line with morphosequent and geologic conditions, provided that the objective of underground exploration is met. To ensure that the seismic line layout in areas with high-steep mountains and low signal-noise ratio is helpful for the seismic execution, launching, and receiving, a line assessment and semiautomatic optimization method was defined on the basis of remote sensing information through exploitation, study, and practices in complex-surface seismic area. The method is used to evaluate the applicability and launching and receiving conditions at line positions with such information as digital elevation model (DEM), slope, relative humidity, surface roughness, and lithology, so as to select the better layout from optional seismic lines generated from the original seismic layout. The application in the Qiulitage exploration area in the west of Tarim Basin proved that the method can improve the seismic data acquisition conditions and applicability of lines, promoting the data quality and cutting down the exploration cost. Key words: remote sensing information, seismic line, line layout, seismic acquisition, Qiulitage

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the most recently identified member of the proprotein convertase family. Genetic and cell biology studies have suggested a critical role of PCSK9 in regulating low-density lipoprotein receptor (LDLR) protein levels and thus modulating plasma LDL cholesterol. Recent data on the molecular basis for PCSK9 action support the model in which PCSK9 is self-cleaved, secreted, and tightly bound to the EGF-A repeat of LDLR extracellular domain. PCSK9 binding to LDLR is essential for the ensuing receptor-mediated endocytosis and is speculated to lock LDLR in a specific conformation that favors degradation in lysosomal compartment instead of recycling back to plasma membrane. We report here a novel human PCSK9 splicing variant, which we named PCSK9sv. PCSK9sv had an in-frame deletion of the eighth exon of 58 amino acids and was expressed in multiple tissues, including liver, small intestine, prostate, uterus, brain, and adipose tissue. Unlike wild-type PCSK9, which is secreted, PCSK9sv expressed in human embryonic kidney HEK293 cells failed to process the prosegment intracellularly and thus was not secreted into the medium. Examination of potential functions revealed that PCSK9sv did not change the LDLR protein levels. Two mutations that have been reported in humans with the associated changes in plasma LDL cholesterol were within exon 8, and thus the expression and function of the two mutants were studied. Both N425S and A443T mutants were processed normally, secreted, and reduced LDLR levels. However, the physiological function of this novel splicing variant of PCSK9 has yet to be determined.

In order to study the factors affecting preferential flow, a 2.9 m-long, 2.6 m-deep soil profile was dug in the Quxi watershed, Yangtze River. To analyze the influence of rainfall on preferential flow, the preferential flow process was observed when the rainfalls were recorded. Soil physical and infiltration characteristics were also measured to study their effect on preferential flow. The results showed that the rainfall amount that could cause preferential flow was over 26 mm. There are four types of rainfall in the Three Gorges area, namely gradually dropping rain, even rain, sudden rain and peak rain. Preferential flow process was found to be relevant to the rainfall process. It was determined that with different rainfall types, preferential flow appeared at different times, occurring first in peak rain, followed by sudden rain, gradually dropping rain, and then even rain. Preferential flow would appear when the rainfall intensity was over 0.075 mm/min. In the studied area, the coarse soil particles increased with the soil depth, and for the deeper soil layer, the coarse particles promote the formation of preferential flow. Preferential flow accelerates the steady infiltration rate in the 83–110 cm soil horizon, and the quickly moving water in this horizon also enhanced the further formation and development of preferential flow.

Sphingomyelin plays a very important role both in cell membrane formation that may well have an impact on the development of diseases like atherosclerosis and diabetes. However, the molecular mechanism that governs intracellular and plasma membrane SM levels is largely unknown. Recently, two isoforms of sphingomyelin synthase (SMS1 and SMS2), the last enzyme for SM de novo synthesis, have been cloned. We have hypothesized that SMS1 and SMS2 are the two most likely candidates responsible for the SM levels in the cells and on the plasma membrane. To test this hypothesis, cultured cells were treated with tricyclodecan-9-yl-xanthogenate (D609), an inhibitor of SMS, or with SMS1 and SMS2 siRNAs. Cells were then pulsed with [14C]- l -serine (a precursor of all sphingolipids). SMS activity and [14C]-SM in the cells were monitored. We found that SMS activity was significantly decreased in cells after D609 or SMS siRNA treatment, compared with controls. SMS inhibition by D609 or SMS siRNAs significantly decreased intracellular [14C]-SM levels. We measured cellular lipid levels, including SM, ceramide, phosphatidylcholine, and diacylglycerol and found that SMS1 and SMS2 siRNA treatment caused a significant decrease of SM levels (20% and 11%, respectively), compared to control siRNA treatment; SMS1 but not SMS2 siRNA treatment caused a significant increase of ceramide levels (10%). There was a decreasing tendency for diacylglycerol levels after both SMS1 and SMS2 siRNA treatment, however, it was not statistical significant. As shown by lipid rafts isolation and lipid determination, SMS1 and SMS2 siRNA treatment led to a decrease of SM content in detergent-resistant lipid rafts on the cell membrane. Furthermore, SMS1 and SMS2 siRNA-treated cells had a stronger resistance than did control siRNA-treated cells to lysenin (a protein that causes cell lysis due to its affinity for plasma membrane SM). These results indicate that both SMS1 and SMS2 contribute to SM de novo synthesis and control SM levels in the cells and on the cell membrane including plasma membrane, implying an important relationship between SMS activity and cell functions.

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.