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In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown.

Supplementary Figure S1. AUY922 does not significantly affect viability of normal colon epithelial cells; Supplementary Figure S2. Sensitivity of colon cancer cells to AUY922 is not associated with the expression levels of HSP90; Supplementary Figure S3. The general caspase inhibitor z-VAD-fmk efficiently inhibits AUY922-mediated inhibition of mutant KRAS colon cancer cell survival; Supplementary Figure S4. AUY922 kills colon cancer cells by induction of apoptosis; Supplementary Figure S5. AUY922 triggers reduction in the mitochondrial membrane potential, release of mitochondrial apoptogenic proteins in sensitive but not resistant colon cells; Supplementary Figure S6. Inhibition of Bim does not alter sensitivity of Caco-2 cells to AUY922; Supplementary Figure S7. Knockdown of PUMA or p53 does not inhibit cell death induced by AUY922; Supplementary Figure S8. Upregulation of Bim by AUY922 in mutant KRAS colon cancer cells is due to a transcriptional increase; Supplementary Figure S9. Knockdown of CHOP inhibits cell death induced by AUY922; Supplementary Figure S10. BGP-15 and 4-PBA attenuate XBP-1 splicing induced by AUY922; Supplementary Figure S11. Overexpression of GRP78 reduces AUY922-induced upregulation of CHOP and Bim; Supplementary Figure S12. A schematic model comparing different responses of mutant and wild-type KRAS colon cancer cells to AUY922; Supplementary Figure S13. AUY922 does not cause any significant change in the expression of STK33 in mutant KRAS colon cancer cells; Supplementary Table 1. List of Antibodies; Supplementary Table 2. List of reagents; Supplementary Table 3. siRNAs

Figure S1 shows the turnover rates of MTH1 mRNA remained similar between melanoma cells with relatively high (Mel-FH) and low (IgR3) expression of the transcript. Figure S2 shows silencing or overexpression of Skp2 did not alter the expression levels of the MTH1 transcript in melanoma cells. Figure S3 shows silencing of MTH1 did not impinge on the expression Skp2. Figure S4 shows Skp2-NES retains the ability to bind to MTH1. Figure S5 shows Skp2 silencing inhibits melanoma cell proliferation but does trigger apoptosis. Figure S6 shows the oxidative stress inducer elesclomol increases ROS levels. Figure S7 shows BRAF mutant melanoma cells selected for resistance to vemurafenib are more susceptible to killing by knockdown of Skp2 or MTH1.

Table S1 shows the list of antibodies. Table S2 shows the list of reagents. Table S3 shows shRNA sequences. Table S4 shows the list of primers. Table S5 shows the list of proteins identified by mass spectrometry.

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res; 77(22); 6226–39. ©2017 AACR.

Previous studies have only focused on the bioaccessibility of single pesticide/metal without considering the potential impact of post-uptake interactions on bioaccessibility of pesticides/metals in the human digestive system. Hence, the influences of chromium (Cr) speciation on neonicotinoids bioaccessibility were investigated and the potential health risk based on the oral bioaccessibility was evaluated. Bioaccessibility of four neonicotinoids in apple and pear was measured using three common in vitro methods (SBRC, PBET, and IVG). Bioaccessibility of neonicotinoids in apple and pear varied between in vitro methods, which may reflect the difference of determination parameters (i.e., pH values, incubation time, and constituents). The neonicotinoids bioaccessibility was remarkably reduced by 17.21–81.21% and 11.61–73.70% with the addition of Cr(III) and Cr(VI), respectively. Risk assessment based on the hazard quotient (HQ) with bioaccessibility revealed that exposure to pesticide residues in the tested fruits were all below levels that might pose a health risk. These findings are of theoretical value for the safety evaluation of pesticide residues on food.

As the impact of emerging pollutants (EPs) on human health and ecosystems becomes significant, attention is being drawn to the treatment of EPs. Unlike conventional pollutants (e.g., chemical oxygen demand, biochemical oxygen demand, SO2, NO x , etc.), EPs have relatively short history of use and production, or have their hazards be identified only recently, and thus are largely beyond the scope of current laws or regulations on environmental pollutants. Synthetic chemicals and unintentionally released chemical substances constitute an important source of EPs. EPs have diverse chemical structures and can take varied forms, including molecules, polymers, and aggregates. EPs can be released into the environment via multiple routes during the life cycle of products that contain corresponding chemicals. In the environment, EPs can be persistent or pseudo-persistent due to continuous release and resistance to degradation. EPs can exert a variety of hazardous effects, including endocrine disruption, carcinogenicity, mutagenicity, etc. In addition, the chronical effects tend to be insidious. All these features have complicated the treatment and control of EPs, resulting in high cost for restoring the contaminated environment. Hence, it is recognized that the key to the treatment of EPs is to prevent potential pollution of the corresponding chemicals. In order to address the issues of EPs, environmental systems engineering (ESE) thinking is required. Environmental issues such as ecological damage and environmental pollution can be regarded as human activity-induced devastation to the structure and function of the Earth surface system, which involves two EPs or chemicals-related processes: (1) The sources, flows and sinks of EPs or chemicals in the human society and natural environmental system, which are informative for controlling policies and strategies to intervene; (2) the effects of EPs or chemicals on the human society system, ecosystem and inorganic environmental system, which provide the basis for setting “objective functions and constraint conditions” for sustainable development of the system. Briefly, ESE for the treatment of EPs and the risk management of chemicals, aims to realize the simulation of systems evolution under various treatment scenarios, by modeling and analyzing the above EPs and chemicals-involved processes in the human society and the natural environmental system. With the constraints on the sustainability of human society, the objective functions, i.e., the economic and social benefits of chemicals and related products, are maximized. Then, the best strategies and practice for the treatment of EPs could be reasonably selected. Several ESE technologies are discussed, among which material flow analysis and life cycle assessment could track the sources, flows, and sinks of chemicals in the human society-economy system, and further quantify their impacts on the environment. Computational toxicology could, via in silico simulations, predict the distribution and fate of EPs, estimate the exposure of human and ecological species to the EPs, and evaluate the adverse effects of EPs on human and ecological species under certain exposure levels. Green chemistry, namely “benign by design”, on the other hand, aims to diminish the use of hazardous feedstocks and the release of waste, and eventually design and produce chemicals with low or zero hazards. All these ESE technologies combined with the relatively conventional process control and terminal treatment technologies, are promising for supporting the risk prevention and control of chemicals, as well as the effective treatment of EPs.

Background It has been widely accepted that there is a significant difference in peripheral blood oxygen between arteries and veins. Therefore, arterial blood has been collected for blood gas analysis, and venous blood, because it is convenient to collect, has been used for most laboratory examinations. However, venous blood is always difficult to collect in rabbits; in contrast, arterial blood is easier to obtain, and research on whether arterial blood can be used instead of venous blood for routine biochemical parameter examination is rare. Therefore, the present study was designed to explore whether arterial blood can be used as a substitute for venous blood for routine biochemistry parameter examination in rabbits. Results Three venous blood samples with gross hemolysis were excluded. Venous and arterial blood samples were obtained from forty-two rabbits. Arterial blood samples correlate well with venous blood in alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), total protein (TP), globulin (GLB), serum total cholesterol (TC), serum triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), urea (Ur) and creatinine (Cr) levels by Deming regression analysis with slopes ranging from 0.893 to 1.176 and intercepts ranging from − 4.886 to 5.835. Bland-Altman analysis showed that the two sample parameters had 93%-98% of the points within the 95% consistency limits. There were significant differences between venous blood and arterial blood in ALP, TP, TC, TG, HDL, LDL and Cr, while AST, ALT, GGT, GLB and Ur showed no significant differences. Conclusions Arterial blood can be a substitute for venous blood in routine biochemistry parameter examinations in rabbits, especially in situations where venous blood is difficult to collect.

Jiayu Wang,1,2 Yang Li,3 Cuijuan Zheng,2 Yan Sun,1 Jianping Yang1 1Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huaian 223300, Jiangsu, People’s Republic of China; 3Jiangsu College of Nursing, Huaian 223300, Jiangsu, People’s Republic of ChinaCorrespondence: Jianping Yang Email szyangjp@suda.edu.cnBackground: Previous GWAS studies have shown that there is a relationship between M3 muscarinic acetylcholine receptor (CHRM3) rs2165870 polymorphism and postoperative nausea and vomiting (PONV) incidence. However, no Chinese studies have addressed this issue.Methods: To explore the relationship between CHRM3 rs2165870 polymorphism and PONV incidence in a Chinese Han population, we enrolled 512 patients receiving elective surgery in this study. CHRM3 rs2165870 polymorphism was genotyped using PCR-RFLP method.Results: We found that AA genotype or A allele of CHRM3 rs2165870 polymorphism elevated the risk of PONV (AA versus GG; OR, 2.88; 95% CI, 1.51– 5.47; P = 0.001; A versus G; OR, 1.39; 95% CI, 1.07– 1.81; P = 0.013). In addition, CHRM3 rs2165870 polymorphism was related to the risk of PONV among the males, smokers, and those individuals with Apfel Score 3– 4 or ASA classification 2– 3. Last, we assessed the effects of CHRM3 rs2165870 polymorphism on the treatment efficacy of ondansetron for PONV. Data uncovered that 103 of 209 patients (49.3%) showed response to ondansetron treatment for PONV. The PONV incidence was significantly higher in AA genotype carriers compared with GG genotype carriers during the first 2 h after surgery, but not from 2 to 24 h after surgery.Conclusion: To sum up, this study reveals that CHRM3 rs2165870 polymorphism is related to the incidence of PONV and treatment effects of ondansetron for preventing PONV in this Chinese Han population.Keywords: postoperative nausea and vomiting, CHRM3, single nucleotide polymorphism, ondansetron

Artificial intelligence (AI) is playing an increasingly important role in medicine, especially in the field of medical imaging. It can be used to diagnose diseases and predict certain statuses and possible events that may happen. Recently, more and more studies have confirmed the value of AI based on ultrasound in the evaluation of diffuse liver diseases and focal liver lesions. It can assess the severity of liver fibrosis and nonalcoholic fatty liver, differentially diagnose benign and malignant liver lesions, distinguish primary from secondary liver cancers, predict the curative effect of liver cancer treatment and recurrence after treatment, and predict microvascular invasion in hepatocellular carcinoma. The findings from these studies have great clinical application potential in the near future. The purpose of this review is to comprehensively introduce the current status and future perspectives of AI in liver ultrasound.

Several studies have indicated possible associations between age and the prognosis of breast cancer (BC), but limited data are available from hospital-based multicenter studies in China. This study aimed to explore the associations between age at initial diagnosis of BC and the risk of recurrence or metastasis among Chinese women with newly diagnosed advanced breast cancer (ABC) and provide treatment decision support for BC patients of different ages to medical workers.The medical records of patients newly diagnosed with ABC were obtained from 21 hospitals in seven geographic regions in China from 2012 to 2014. Patients' general information, clinicopathological features at first diagnosis, treatment information, and prognosis were retrospectively collected based on the self-designed case report form (CRF). Cox proportional hazards regression models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for the associations between age groups and the risk of recurrence and metastasis.A total of 1,852 cases were included in the final analysis. Age at initial diagnosis was shown to be significantly related to hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtypes, and the number of lymph node metastasis (all P0.05). Patients aged35 years were more likely to have bone metastasis (45.6%). Patients aged ≥65 years had a lower percentage of receiving surgery (87.1%), adjuvant chemotherapy (61.3%), adjuvant radiotherapy (35.5%), and adjuvant endocrine therapy (30.6%) than the other groups (all P0.05). Compared with patients aged35 years, the risk of recurrence or metastasis in those aged 55-64 years was significantly higher (HRAge at initial diagnosis is related to the clinicopathological characteristics and treatment pattern. Although the risk of site-specific metastasis varies by age, age is not an independent factor influencing the risk of total recurrence and metastasis. In accordance with current clinical practice guidelines for BC, however, precise treatment shall be chosen personally for patients whose ages at initial diagnosis are different.

Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.

Some synthetic polymers can block cell death when applied following an injury that would otherwise kill the cell. This cellular rescue occurs through interactions of the polymers with cell membranes. However, general principles for designing synthetic polymers to ensure strong, but nondisruptive, cell membrane targeting are not fully elucidated. Here, we tailored biomimetic phosphorylcholine-containing block copolymers to interact with cell membranes and determined their efficacy in blocking neuronal death following oxygen-glucose deprivation. By adjusting the hydrophilicity and membrane affinity of poly(2-methacryloyloxyethyl phosphorylcholine) (polyMPC)-based triblock copolymers, the surface active regime in which the copolymers function effectively as membrane-targeting cellular rescue agents was determined. We identified nonintrusive interactions between the polymer and the cell membrane that alter the collective dynamics of the membrane by inducing rigidification without disrupting lipid packing or membrane thickness. In general, our results open new avenues for biological applications of polyMPC-based polymers and provide an approach to designing membrane-targeting agents to block cell death after injury.

This paper investigates the failure mode and root cause of drive shaft failure in a vehicle through examination of the macroscopic and microscopic morphologies of the fracture surface, the chemical composition, metallographic analysis, and mechanical properties of the material, and theoretical finite element calculations of the drive shaft. The results show that fatigue was the dominant mechanism of drive shaft failure due to obvious benchmarks on the fracture surfaces. Fatigue cracks initiated from the root fillet region of the spline gear. The absence of material defects in this region indicates that the main cause of fatigue cracks is attributable to a high stress concentration owing to the small geometrical dimensions of the root fillet. Meanwhile, the poor quality of the root fillet due to relatively high manufacturing tolerances also produces a higher stress concentration, and thus accelerates crack initiation and propagation. Furthermore, all the fatigue fractures occur on the right splines owing to higher stress amplitudes at this location. Improper stiffness matching between the left and right smooth shafts, which results in a larger torque transmitted to the right spline, is the root cause of the drive shaft failure. These results indicate that re-evaluating drive shaft design to ensure an equal stiffness between the two smooth shaft sections is recommended for a longer service life.

Background: the wear of tibial insert is still one of primary factors leading to failure of total knee arthroplasty (TKA). Dodecyl gallate (DG) has shown improvements in the oxidation stability of highly cross-linked polyethylene (HXLPE). This study aimed to assess the application of HXLPE supplemented with DG (HXLPE-DG) on the tibial insert in TKA concerning the wear resistance and the potential impact on implant fixation, Methods: tibial inserts made of HXLPE-DG were subjected to a 3 million loading-cycle wear test following ISO 14243-1:2009. The loss of mass and wear rate of the tibial inserts were calculated. The quantity, size,- and shape of wear particles were recorded, Results: the test specimens lost an average mass of 16.00 mg ± 0.94 mg, and were on an average wear rate of 3.92 mg/million cycles ± 0.19 mg/million cycles. The content of wear particles in the calf serum medium was 3.94 × 108 particles/mL ± 3.93 × 107 particles/mL, 96.66% ± 0.77% of the particles had an equivalent circular diameter less than 0.5 μm. The aspect ratio of wear particles was 1.40 (min: 1.01, max: 6.42). Conclusions: HXLPE-DG displayed advantages over the commonly used materials for tibial inserts and presented the potential of application in TKA.

ObjectiveThe purpose of this study was to improve the differentiation between malignant and benign thyroid nodules using deep learning (DL) in category 4 and 5 based on the Thyroid Imaging Reporting and Data System (TI-RADS, TR) from the American College of Radiology (ACR).Design and MethodsFrom June 2, 2017 to April 23, 2019, 2082 thyroid ultrasound images from 1396 consecutive patients with confirmed pathology were retrospectively collected, of which 1289 nodules were category 4 (TR4) and 793 nodules were category 5 (TR5). Ninety percent of the B-mode ultrasound images were applied for training and validation, and the residual 10% and an independent external dataset for testing purpose by three different deep learning algorithms.ResultsIn the independent test set, the DL algorithm of best performance got an AUC of 0.904, 0.845, 0.829 in TR4, TR5, and TR4&5, respectively. The sensitivity and specificity of the optimal model was 0.829, 0.831 on TR4, 0.846, 0.778 on TR5, 0.790, 0.779 on TR4&5, versus the radiologists of 0.686 (P=0.108), 0.766 (P=0.101), 0.677 (P=0.211), 0.750 (P=0.128), and 0.680 (P=0.023), 0.761 (P=0.530), respectively.ConclusionsThe study demonstrated that DL could improve the differentiation of malignant from benign thyroid nodules and had significant potential for clinical application on TR4 and TR5.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a pivotal enzyme in tocopherol and plastoquinone synthesis and a potential target for novel herbicides. Thirty-five pyridine derivatives were selected to establish a Topomer comparative molecular field analysis (Topomer CoMFA) model to obtain correlation information between HPPD inhibitory activity and the molecular structure. A credible and predictive Topomer CoMFA model was established by “split in two R-groups” cutting methods and fragment combinations (q2 = 0.703, r2 = 0.957, ONC = 6). The established model was used to screen out more active compounds and was optimized through the auto in silico ligand directing evolution (AILDE) platform to obtain potential HPPD inhibitors. Twenty-two new compounds with theoretically good HPPD inhibition were obtained by combining the high-activity contribution substituents in the existing molecules with the R-group search via Topomer search. Molecular docking results revealed that most of the 22 fresh compounds could form stable π-π interactions. The absorption, distribution, metabolism, excretion and toxicity (ADMET) prediction and drug-like properties made 9 compounds potential HPPD inhibitors. Molecular dynamics simulation indicated that Compounds Y12 and Y14 showed good root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values and stability. According to the AILDE online verification, 5 new compounds with potential HPPD inhibition were discovered as HPPD inhibitor candidates. This study provides beneficial insights for subsequent HPPD inhibitor design.

Prostate cancer (PCa) is a reproductive system cancer in elderly men. We investigated the effects of betel nut arecoline on the growth of normal and cancerous prostate cells. Normal RWPE-1 prostate epithelial cells, androgen-independent PC-3 PCa cells, and androgen-dependent LNCaP PCa cells were used. Arecoline inhibited their growth in dose- and time-dependent manners. Arecoline caused RWPE-1 and PC-3 cell cycle arrest in the G2/M phase and LNCaP cell arrest in the G0/G1 phase. In RWPE-1 cells, arecoline increased the expression of cyclin-dependent kinase (CDK)-1, p21, and cyclins B1 and D3, decreased the expression of CDK2, and had no effects on CDK4 and cyclin D1 expression. In PC-3 cells, arecoline decreased CDK1, CDK2, CDK4, p21, p27, and cyclin D1 and D3 protein expression and increased cyclin B1 protein expression. In LNCaP cells, arecoline decreased CDK2, CDK4, and cyclin D1 expression, increased p21, p27, and cyclin D3 expression, had no effects on CDK1 and cyclin B1 expression. The antioxidant N-acetylcysteine blocked the arecoline-induced increase in reactive oxygen species production, decreased cell viability, altered the cell cycle, and changed the cell cycle regulatory protein levels. Thus, arecoline oxidant exerts differential effects on the cell cycle through modulations of regulatory proteins.

Background Subintimal plaque modification (SPM) is often performed to restore antegrade flow and facilitate subsequent lesion recanalization. This study aimed to compare the safety and efficacy of modified SPM with traditional SPM. Methods A total of 1454 consecutive patients who failed a chronic total occlusion percutaneous coronary intervention (CTO PCI) attempt and underwent SPM from January 2015 to December 2019 at our hospital were reviewed retrospectively. Fifty-four patients who underwent SPM finally were included in this study. We analyzed the outcomes of all the patients, and the primary endpoint was recanalization rate, which was defined as Thrombolysis in Myocardial Infarction (TIMI) grades 2-3 flow on angiography 30 to 90 days post-procedure. Results The baseline characteristics were similar between the two groups. In the follow-up, the recanalization rate was noticeably higher in the modified SPM group compared with the traditional SPM group (90.9% vs. 62.5%, P < 0.05). The proposed strategy in the modified group was more aggressive, including a larger balloon size (1.83 ± 0.30 vs. 2.48 ± 0.26 mm, P < 0.05) and longer subintimal angioplasty (0.59 ± 0.16 vs. 0.92 ± 0.12 mm, P < 0.05). Also, the common use of a Stingray balloon and guide catheter extension resulted in improvement of patients in the modified SMP group (12.5% vs. 100%, P < 0.05). Conclusion Modified SPM, which is associated with a high likelihood of successful recanalization, is an effective and safe CTO PCI bail out strategy.

Artificial intelligence (AI) is gaining extensive attention for its excellent performance in image-recognition tasks and increasingly applied in breast ultrasound. AI can conduct a quantitative assessment by recognizing imaging information automatically and make more accurate and reproductive imaging diagnosis. Breast cancer is the most commonly diagnosed cancer in women, severely threatening women's health, the early screening of which is closely related to the prognosis of patients. Therefore, utilization of AI in breast cancer screening and detection is of great significance, which can not only save time for radiologists, but also make up for experience and skill deficiency on some beginners. This article illustrates the basic technical knowledge regarding AI in breast ultrasound, including early machine learning algorithms and deep learning algorithms, and their application in the differential diagnosis of benign and malignant masses. At last, we talk about the future perspectives of AI in breast ultrasound.

Artificial intelligence (AI), particularly deep learning algorithms, is gaining extensive attention for its excellent performance in image-recognition tasks. They can automatically make a quantitative assessment of complex medical image characteristics and achieve an increased accuracy for diagnosis with higher efficiency. AI is widely used and getting increasingly popular in the medical imaging of the liver, including radiology, ultrasound, and nuclear medicine. AI can assist physicians to make more accurate and reproductive imaging diagnosis and also reduce the physicians' workload. This article illustrates basic technical knowledge about AI, including traditional machine learning and deep learning algorithms, especially convolutional neural networks, and their clinical application in the medical imaging of liver diseases, such as detecting and evaluating focal liver lesions, facilitating treatment, and predicting liver treatment response. We conclude that machine-assisted medical services will be a promising solution for future liver medical care. Lastly, we discuss the challenges and future directions of clinical application of deep learning techniques.

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. Cancer Res; 77(22); 6226–39. ©2017 AACR.

The effect of MTH1 inhibition on cancer cell survival has been elusive. Here we report that although silencing of MTH1 does not affect survival of melanoma cells, TH588, one of the first-in-class MTH1 inhibitors, kills melanoma cells through apoptosis independently of its inhibitory effect on MTH1. Induction of apoptosis by TH588 was not alleviated by MTH1 overexpression or introduction of the bacterial homolog of MTH1 that has 8-oxodGTPase activity but cannot be inhibited by TH588, indicating that MTH1 inhibition is not the cause of TH588-induced killing of melanoma cells. Although knockdown of MTH1 did not impinge on the viability of melanoma cells, it rendered melanoma cells sensitive to apoptosis induced by the oxidative stress inducer elesclomol. Of note, treatment with elesclomol also enhanced TH588-induced apoptosis, whereas a reactive oxygen species scavenger or an antioxidant attenuated the apoptosis triggered by TH588. Indeed, the sensitivity of melanoma cells to TH588 was correlated with endogenous levels of reactive oxygen species. Collectively, these results indicate that the cytotoxicity of TH588 toward melanoma cells is not associated with its inhibitory effect on MTH1, although it is mediated by cellular production of ROS.

// Chun Yan Wang 1, 2 , Su Tang Guo 1, 2 , Jia Yu Wang 1 , Xu Guang Yan 1 , Margaret Farrelly 1 , Yuan Yuan Zhang 3 , Fen Liu 1 , Hamed Yari 1 , Ting La 1 , Fu Xi Lei 1 , Lei Jin 3 , Xu Dong Zhang 1 , Chen Chen Jiang 3 1 School of Biomedical Sciences and Pharmacy, The University of Newcastle, NSW, Australia 2 Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, Shanxi, China 3 School of Medicine and Public Health, The University of Newcastle, NSW, Australia Correspondence to: Chen Chen Jiang, email: Chenchen.Jiang@newcastle.edu.au Xu Dong Zhang, email: Xu.Zhang@newcastle.edu.au Keywords: colon cancer, mutant BRAF, heat shock protein 90, AUY922, CDC37 Received: May 20, 2016 Accepted: June 29, 2016 Published: July 06, 2016 ABSTRACT Oncogenic mutations of BRAF occur in approximately 10% of colon cancers and are associated with their resistance to clinically available therapeutic drugs and poor prognosis of the patients. Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt. Although AUY922 triggered rapid reduction in ERK and Akt activation in both wild-type and mutant BRAF colon cancer cells, activation of ERK and Akt rebounded shortly in the latter leading to resistance of the cells to AUY922-induced apoptosis. Reactivation of ERK was associated with the persistent expression of mutant BRAF, which, despite being a client of HSP90, was only partially degraded by AUY922, whereas reactivation of Akt was related to the activity of the HSP90 co-chaperone, cell division cycle 37 (CDC37), in that knockdown of CDC37 inhibited Akt reactivation in mutant colon cancer cells treated with AUY922. In support, as a HSP90 client protein, Akt was only diminished by AUY922 in wild-type but not mutant BRAF colon cancer cells. Collectively, these results reveal that reactivation of ERK and Akt associated respectively with the activity of mutant BRAF and CDC37 renders mutant BRAF colon cancer cells resistant to AUY922, with implications of co-targeting mutant BRAF and/or CDC37 and HSP90 in the treatment of mutant BRAF colon cancers.

Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy. Mol Cancer Ther; 15(3); 448–59. ©2016 AACR.

Prostatic enlargement might affect up to 30% of men and can cause signs and symptoms in the lower urinary tract in the elderly. Imbalanced estrogen and androgen secretions are important in prostatic physiopathology. Phthalates-environmental endocrine disruptors-affect androgen secretion and disrupt sexual organs, including testes and the prostate, but the underlying mechanisms are unclear. Using European Association of Urology (EAU) guidelines, we recruited from urology clinics in southern Taiwan 207 elderly men diagnosed with benign prostatic hyperplasia (BPH) and prostatic enlargement between 2015 and 2017. We took blood and urine samples from all patients on the same day. We used multivariate linear regression, associations, and potential interactions after we had measured and analyzed oxidative stress (OS) markers, steroidal hormones, and 11 urinary phthalate metabolites, and then we adjusted for confounders. Di(2-ethylhexyl) phthalate (DEHP) metabolite levels, particularly urinary mono-(2-ethylhexyl) phthalate, were positively associated with androgen, estrogen, hormone ratios, inducible nitric oxide synthetase (iNOS), 8-hydroxy-2′-deoxyguanosine (8-OHdG), prostate specific antigen (PSA), and prostate volume (PV) (p

The actin crosslinking protein α-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor-interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-κB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage-independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-κB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1-NF-κB, with potential implications for targeting ACTN4 in the treatment of melanoma.