PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis.

Inactivating mutations in PTEN are prevalent in melanoma and are thought to support tumor development by hyperactivating the AKT/mTOR pathway. Conversely, activating mutations in AKT are relatively rare in melanoma, and therapies targeting AKT or mTOR have shown disappointing outcomes in preclinical models and clinical trials of melanoma. This has led to the speculation that PTEN suppresses melanoma by opposing AKT-independent pathways, potentially through noncanonical functions beyond its lipid phosphatase activity. In this study, we examined the mechanisms of PTEN-mediated suppression of melanoma formation through the restoration of various PTEN functions in PTEN-deficient cells or mouse models. PTEN lipid phosphatase activity predominantly inhibited melanoma cell proliferation, invasion, and tumor growth, with minimal contribution from its protein phosphatase and scaffold functions. A drug screen underscored the exquisite dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Furthermore, activation of AKT alone was sufficient to counteract several aspects of PTEN-mediated melanoma suppression, particularly invasion and the growth of allograft tumors. Phosphoproteomics analysis of the lipid phosphatase activity of PTEN validated its potent inhibition of AKT and many of its known targets, while also identifying the AP-1 transcription factor FRA1 as a downstream effector. The restoration of PTEN dampened FRA1 translation by inhibiting AKT/mTOR signaling, and FRA1 overexpression negated aspects of PTEN-mediated melanoma suppression akin to AKT. This study supports AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis. SIGNIFICANCE: PTEN suppresses melanoma predominantly through its lipid phosphatase function, which when lost, elevates FRA1 levels through AKT/mTOR signaling to promote several aspects of melanomagenesis.

Integrated proteomics identifies PARP inhibitor-induced prosurvival signaling changes as potential vulnerabilities in ovarian cancer.

BRCA1/2-deficient ovarian carcinoma (OC) has been shown to be particularly sensitive to poly (ADP-ribose) polymerase inhibitors (PARPis). Furthermore, BRCA1/2 mutation status is currently used as a predictive biomarker for PARPi therapy. Despite providing a major clinical benefit to the majority of patients, a significant proportion of BRCA1/2-deficient OC tumors do not respond to PARPis for reasons that are incompletely understood. Using an integrated chemical, phospho- and ADP-ribosylation proteomics approach, we sought here to develop additional mechanism-based biomarker candidates for PARPi therapy in OC and identify new targets for combination therapy to overcome primary resistance. Using chemical proteomics with PARPi baits in a BRCA1-isogenic OC cell line pair, as well as patient-derived BRCA1-proficient and BRCA1-deficient tumor samples, and subsequent validation by coimmunoprecipitation, we showed differential PARP1 and PARP2 protein complex composition in PARPi-sensitive, BRCA1-deficient UWB1.289 (UWB) cells compared to PARPi-insensitive, BRCA1-reconstituted UWB1.289+BRCA1 (UWB+B) cells. In addition, global phosphoproteomics and ADP-ribosylation proteomics furthermore revealed that the PARPi rucaparib induced the cell cycle pathway and nonhomologous end joining (NHEJ) pathway in UWB cells but downregulated ErbB signaling in UWB+B cells. In addition, we observed AKT PARylation and prosurvival AKT-mTOR signaling in UWB+B cells after PARPi treatment. Consistently, we found the synergy of PARPis with DNAPK or AKT inhibitors was more pronounced in UWB+B cells, highlighting these pathways as actionable vulnerabilities. In conclusion, we demonstrate the combination of chemical proteomics, phosphoproteomics, and ADP-ribosylation proteomics can identify differential PARP1/2 complexes and diverse, but actionable, drug compensatory signaling in OC.

Optic-fiber vibration sensor based on a reflected 81° tilted fiber grating integrated with a symmetrical flexible hinge.

An optic-fiber vibration sensor based on the reflected 81° tilted fiber grating (81° TFG) integrated with a symmetrical flexible hinge is proposed and experimentally demonstrated in this paper. The vibration sensor is composed of a symmetrical flexible hinge and a reflected 81° TFG, the ends of which are simply fixed on the upper surface of the mass. The theoretical model of the proposed vibration sensor is analyzed, by which the important parameters related to the resonant frequency of the sensor are simulated and discussed; then, the vibration sensing experiments are conducted. Experiment results show that TE/TM mode of the 81° TFG can provide the maximal acceleration sensitivity of 338.28 and 299.94 mV/g at 400 Hz in the flat area of the amplitude-frequency response (50-400 Hz), which is increased by 9.95 and 11.5 times as compared with the optical fiber cantilever beam structure, respectively. Further, the signal-to-noise ratio in the flat area (50-400 Hz) is about ∼66.275dB under the acceleration of 2 g, which is increased by ∼20dB. Furthermore, it can be used for detecting mechanical vibration of medium-high frequency ranging from 50 to 3500 Hz. The proposed 81° TFG vibration sensor has the characteristics of small volume, simple package, high acceleration sensitivity, and wide vibration signal response range, which will ensure it has broad application prospects in the field of mechanical vibration.

Estimating the remaining atmospheric environmental capacity using a single-box model in a high pollution risk suburb of Chengdu, China.

The atmospheric pollution has been the public attention in recent years. In order to better coordinate economic development and atmospheric environmental management, China introduced the concept of atmospheric environmental capacity (AEC). The remaining atmospheric environmental capacity (RAEC) calculated by existing atmospheric pollution sources and AEC is an important basis for regional development and environmental protection. The RAEC of the high-pollution risk suburb of Chengdu in 2015 was estimated by the single-box model and analyzed on multiple time scales. The results show that the RAEC of SO2 and NO2 in this region is 3299 t/a and 2849 t/a, respectively under the annual time scale. However, in the daily time scale, the RAEC of NO2 is negative for 3 days, that is, there are 3 days with serious air pollution. Therefore, it is not appropriate to plan the industrial area only by relying on annual RAEC. Especially, RAEC displays inter-seasonal and monthly variability. On the one hand, in plain areas with low wind speed and little change in wind direction, achieving the prediction of atmospheric mixing layer height could give early warning of atmospheric pollution events. On the other hand, different management measures are taken on different time scales. On a long timescale, the regional energy structure should be optimized. On seasonal and monthly time scales, the production plans should be adapted to RAEC. On the daily time scale, it mainly deals with the serious atmospheric pollution accident timely.

Mechanism-based structure-activity relationship (SAR) analysis of aromatic amines and nitroaromatics carcinogenicity via statistical analyses based on CPDB.

Cancer is a leading cause of human mortality around the globe. In this study, mechanism-based SAR (Structure-Activity Relationship) was employed to investigate the carcinogenicity of aromatic amines and nitroaromatics based on CPDB. Principal component analysis and cluster analysis were used to construct the SAR model. Principle component analysis generated three principal components from 12 mechanism-based descriptors. The extracted principal components were later used for cluster analysis, which divided the selected 55 chemicals into six clusters. The three principal components were proposed to describe the "transport", "reactivity" and "electrophilicity" properties of the chemicals. Cluster analysis indicated that the relevant "transport" properties positively correlated with the carcinogenic potential and were contributing factors in determining the carcinogenicity of the studied chemicals. The mechanism-based SAR analysis suggested the electron donating groups, electron withdrawing groups and planarity are significant factors in determining the carcinogenic potency for studied aromatic compounds. The present study may provide insights into the relationship between the three proposed properties and the carcinogenesis of aromatic amines and nitroaromatics.

[Flux Characteristics of CO2, CH4, and N2 O and their Influencing Factors in Different Types of Ditches on the Chengdu Plain].

In order to study the flux characteristics of CH4, CO2 and N2O in different ditches and their influencing factors, three types of ditches (an agricultural ditch, agricultural-living compound ditch, and living ditch) were monitored once a month from March 2014 to February 2015 using static floating chambers in the Chengdu Plain. The results showed that:① Affected by human activities, CO2, CH4, and N2O fluxes were high in ditches and ranged from -2.26-1504.40 mg·(m2·h)-1, 0.69-40.00 mg·(m2·h)-1, and -2.27-70.35 µg·(m2·h)-1,respectively. All are higher in summer compared to autumn and spring, and are lowest in winter. ② The flux of CO2 in agricultural-living compound ditches was significantly higher than that in agricultural ditches and living ditches (P<0.05), and the fluxes of CH4 and N2O in living ditches were significantly higher than those in agricultural ditches and agricultural-living compound ditches (P<0.05). ③ Water temperature and rainfall were the main environmental factors affecting CO2, CH4, and N2O fluxes, and DO (dissolved oxygen) and TN (total nitrogen) were the main environmental factors affecting CO2 and N2O fluxes. NH4+-N (ammonium nitrogen) and DO were the main water quality parameters affecting the CH4 flux.

Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress.

Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells.

[An automatic extraction algorithm for individual tree crown projection area and volume based on 3D point cloud data].

Tree crown projection area and crown volume are the important parameters for the estimation of biomass, tridimensional green biomass and other forestry science applications. Using conventional measurements of tree crown projection area and crown volume will produce a large area of errors in the view of practical situations referring to complicated tree crown structures or different morphological characteristics. However, it is difficult to measure and validate their accuracy through conventional measurement methods. In view of practical problems which include complicated tree crown structure, different morphological characteristics, so as to implement the objective that tree crown projection and crown volume can be extracted by computer program automatically. This paper proposes an automatic untouched measurement based on terrestrial three-dimensional laser scanner named FARO Photon120 using plane scattered data point convex hull algorithm and slice segmentation and accumulation algorithm to calculate the tree crown projection area. It is exploited on VC+6.0 and Matlab7.0. The experiments are exploited on 22 common tree species of Beijing, China. The results show that the correlation coefficient of the crown projection between Av calculated by new method and conventional method A4 reaches 0.964 (p<0.01); and the correlation coefficient of tree crown volume between V(VC) derived from new method and V(C) by the formula of a regular body is 0.960 (p<0.001). The results also show that the average of V(C) is smaller than that of V(VC) at the rate of 8.03%, and the average of A4 is larger than that of A(V) at the rate of 25.5%. Assumed Av and V(VC) as ture values, the deviations of the new method could be attributed to irregularity of the crowns' silhouettes. Different morphological characteristics of tree crown led to measurement error in forest simple plot survey. Based on the results, the paper proposes that: (1) the use of eight-point or sixteen-point projection with fixed angles to estimate crown projections, and (2) different regular volume formula to simulate crown volume according to the tree crown shapes. Based on the high-resolution 3D LIDAR point cloud data of individual tree, tree crown structure was reconstructed at a high rate of speed with high accuracy, and crown projection and volume of individual tree were extracted by this automatical untouched method, which can provide a reference for tree crown structure studies and be worth to popularize in the field of precision forestry.

[Nitrogen non-point source pollution identification based on ArcSWAT in Changle River].

The ArcSWAT (Soil and Water Assessment Tool) model was adopted for Non-point source (NPS) nitrogen pollution modeling and nitrogen source apportionment for the Changle River watershed, a typical agricultural watershed in Southeast China. Water quality and hydrological parameters were monitored, and the watershed natural conditions (including soil, climate, land use, etc) and pollution sources information were also investigated and collected for SWAT database. The ArcSWAT model was established in the Changle River after the calibrating and validating procedures of the model parameters. Based on the validated SWAT model, the contributions of different nitrogen sources to river TN loading were quantified, and spatial-temporal distributions of NPS nitrogen export to rivers were addressed. The results showed that in the Changle River watershed, Nitrogen fertilizer, nitrogen air deposition and nitrogen soil pool were the prominent pollution sources, which contributed 35%, 32% and 25% to the river TN loading, respectively. There were spatial-temporal variations in the critical sources for NPS TN export to the river. Natural sources, such as soil nitrogen pool and atmospheric nitrogen deposition, should be targeted as the critical sources for river TN pollution during the rainy seasons. Chemical nitrogen fertilizer application should be targeted as the critical sources for river TN pollution during the crop growing season. Chemical nitrogen fertilizer application, soil nitrogen pool and atmospheric nitrogen deposition were the main sources for TN exported from the garden plot, forest and residential land, respectively. However, they were the main sources for TN exported both from the upland and paddy field. These results revealed that NPS pollution controlling rules should focus on the spatio-temporal distribution of NPS pollution sources.