Angiopoietin‐like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on ...sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial‐mesenchymal transition (EMT)‐driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)‐dependent early growth response protein 1 (Egr‐1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. Conclusion: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor−AKT/ERK−Egr‐1−Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637‐1651)
(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a major global health concern. The increasing prevalence of NAFLD has been related to type 2 diabetes mellitus (T2D). However, the ...relationship between short-chain fatty acids (SCFAs) and NAFLD severity is ambiguous in T2D subjects. This study aimed to explore the association of SCFAs with the severity of NAFLD in T2D patients. (2) Methods: We employed echography to examine the severity of hepatic steatosis. The serum levels of nine SCFAs, namely, formate, acetate, propionate, butyrate, isobutyrate, methylbutyrate, valerate, isovalerate, and methylvalerate, were measured using gas chromatography mass spectrometry. (3) Results: A total of 259 T2D patients was enrolled in this cross-sectional study. Of these participants, 117 with moderate to severe NAFLD had lower levels of formate, isobutyrate, and methylbutyrate than the 142 without NAFLD or with mild NAFLD. Lower circulating levels of isobutyrate and methylbutyrate were associated with an increased severity of NAFLD. A relationship between NAFLD severity and circulating isobutyrate and methylbutyrate levels was found independently of a glycated hemoglobin (HbA1C) level of 7.0%. (4) Conclusion: Circulating levels of isobutyrate and methylbutyrate were significantly and negatively correlated with NAFLD severity in the enrolled T2D patients. SCFAs may be related to NAFLD severity in T2D patients.
•Propose robust-optimization-guiding framework for reinforcement learning in scheduling problem.•Construct a mathematical programming for the chemical material production scheduling problem.•Compare ...to typical optimization models and reinforcement learning with respect to deterministic and stochastic cases.•Numerical study conducted to validate the proposed RLeRO framework.•Provide sensitivity analysis, solution quality analysis, computational time and Gantt similarity, compared with other benchmark methods.
This study presents a novel guiding framework embedded with robust optimization (RO) for the training phase of reinforcement learning (RL), specifically tailored for dynamic scheduling of a single-stage multi-product chemical reactor in an uncertain environment. The proposed framework addresses the challenge of local optima in policy gradient methods by integrating optimization methods, enhancing both the objective value and learning stability of the RL. We further enhance the robustness of the proposed model against parameter distortions by incorporating RO as a guiding engine. A numerical study of chemical material production scheduling is conducted to validate the proposed model and the results demonstrate the effectiveness to address demand volatility with several metrics including sensitivity analysis, solution quality analysis, computational time, compared to a typical actor-critic RL.
Insomnia is a worldwide problem with substantial deleterious health effects. Twin studies have shown a heritable basis for various sleep-related traits, including insomnia, but robust genetic risk ...variants have just recently begun to be identified. We conducted genome-wide association studies (GWAS) of soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). GWAS were carried out separately for each ancestral group (EUR, AFR, LAT) using logistic regression for each of the STARRS component studies (including 3,237 cases and 14,414 controls), and then meta-analysis was conducted across studies and ancestral groups. Heritability (SNP-based) for lifetime insomnia disorder was significant (h
= 0.115, p = 1.78 × 10
in EUR). A meta-analysis including three ancestral groups and three study cohorts revealed a genome-wide significant locus on Chr 7 (q11.22) (top SNP rs186736700, OR = 0.607, p = 4.88 × 10
) and a genome-wide significant gene-based association (p = 7.61 × 10
) in EUR for RFX3 on Chr 9. Polygenic risk for sleeplessness/insomnia severity in UK Biobank was significantly positively associated with likelihood of insomnia disorder in STARRS. Genetic contributions to insomnia disorder in STARRS were significantly positively correlated with major depressive disorder (r
= 0.44, se = 0.22, p = 0.047) and type 2 diabetes (r
= 0.43, se = 0.20, p = 0.037), and negatively with morningness chronotype (r
= -0.34, se = 0.17, p = 0.039) and subjective well being (r
= -0.59, se = 0.23, p = 0.009) in external datasets. Insomnia associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease.
Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in ...humans. We conducted genome‐wide association studies (GWASs) of self‐assessed (by questionnaire) and outcome‐based (incident mental disorders from predeployment to postdeployment) resilience among European (EUR) ancestry soldiers in the Army study to assess risk and resilience in servicemembers. Self‐assessed resilience (N = 11,492) was found to have significant common‐variant heritability (h2 = 0.162, se = 0.050, p = 5.37 × 10−4), and to be significantly negatively genetically correlated with neuroticism (rg = −0.388, p = .0092). GWAS results from the EUR soldiers revealed a genome‐wide significant locus on an intergenic region on Chr 4 upstream from doublecortin‐like kinase 2 (DCLK2) (four single nucleotide polymorphisms (SNPs) in LD; top SNP: rs4260523 p = 5.65 × 10−9 is an eQTL in frontal cortex), a member of the doublecortin family of kinases that promote survival and regeneration of injured neurons. A second gene, kelch‐like family member 36 (KLHL36) was detected at gene‐wise genome‐wide significance p = 1.89 × 10−6. A polygenic risk score derived from the self‐assessed resilience GWAS was not significantly associated with outcome‐based resilience. In very preliminary results, genome‐wide significant association with outcome‐based resilience was found for one locus (top SNP: rs12580015 p = 2.37 × 10−8) on Chr 12 downstream from solute carrier family 15 member 5 (SLC15A5) in subjects (N = 581) exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress‐related psychopathology and point to new avenues for therapeutic intervention.
This study showed an interaction between oral bacteria, lifestyle factors and genetic polymorphisms on the risk of oral cancer. The results also provided biological support for the established ...association between poor oral hygiene and oral cancer risk.
Abstract
Poor oral hygiene may lead to overgrowth of pathogenic oral bacteria, which may induce chronic inflammation to promote the oncogenesis of oral squamous cell carcinoma (OSCC). This study investigated the association between oral bacterial profile and OSCC risk in a case-control study of 138 OSCC cases and 151 controls (88 cases and 90 controls for the discovery group and 50 cases and 61 controls for the validation group). Oral bacterial profiles were characterized by targeted sequencing of the 16S rRNA gene. Three species of periodontopathogenic bacteria, Prevotella tannerae, Fusobacterium nucleatum, and Prevotella intermedia, were associated with an increased OSCC risk. This association was modified by the genetic polymorphisms of TLR2 and TLR4. Use of alcohol, betel quids and cigarettes and poor oral hygiene were associated with a higher percentage of oral periodontopathogenic bacteria. The association between alcohol and periodontopathogenic bacteria was modified by the genetic polymorphism of ALDH2, with a stronger positive association observed among the ALDH2-deficient individuals. The percentage of periodontopathogenic bacteria was positively correlated with the level of salivary IL1β, an inflammatory cytokine. Overall, our results showed a positive association between periodontopathogenic bacteria and OSCC risk and this relationship may be influenced by lifestyle and genetic factors. Our results provided further biological support for the established association between poor oral hygiene and OSCC risk. This suggested that improving oral hygiene may reduce OSCC risk and should be part of a public health campaign to prevent the occurrence of OSCC.
Many studies have reported a positive association between lower socioeconomic status (SES) and higher head and neck cancer (HNC) risk. Fewer studies have examined the impact of SES on the association ...between alcohol or cigarette use and HNC risk. The current case‐control study (1104 HNC cases and 1363 controls) investigated the influence of education, a SES indicator, on the association between HNC and the use of alcohol, cigarettes, or betel quids in Taiwan, a country with universal health care. Our results showed a larger increase in HNC risk associated with alcohol among those with lower educational level (odds ratio OR = 2.07; 95% confidence interval CI, 1.53‐2.80) than those with higher educational level (OR = 1.38; 95% CI, 1.04‐1.85) (heterogeneity‐P = .03). Educational level had an influence on the association between alcohol use and HNC risk among those with genetic susceptibility (ALDH2‐deficient) to the carcinogenic effect of alcohol. The association between cigarette or betel quid use and HNC risk was similar between the high and low educational groups. National policies and social interventions have led to the decline in the prevalence of cigarette and betel quid users in Taiwan. In contrast, due to the lack of adequate alcohol control policies, alcohol consumption in Taiwan has continued to rise. A higher impact of alcohol on HNC risk among lower SES individuals even with universal health care could be the result of insufficient alcohol control policies in Taiwan.
The latest video coding standard, high efficiency video coding (HEVC), aims to achieve better coding efficiency than the H.264/AVC standard. To improve the coding performance of HEVC, tools and ...structures are included that also increase the computational complexity of encoding, especially for the mode decisions in the coding unit (CU), which is a structural element in the HEVC. For each CU size, the HEVC encoder performs mode decision and motion estimation using all prediction unit (PU) types and incurs massive computational burdens. In this paper, we investigate the depth correlation between the current and the collocated CU to avoid irrelevant CU procedure and truncate some PU predictions as a result. We also investigate the relationship of the rate-distortion (RD) costs after the Merge/SKIP prediction. By analyzing different CU sizes and quantization parameters, we build a mathematical model to represent the relationship for the RD costs after the Merge/SKIP prediction with an adaptive termination of the CU procedure. In addition, the relationship of the RD costs after the Merge/SKIP prediction and 2N\boldsymbol {\times }2\text{N} mode is also explored. Search range reduction is used to further speed up our algorithm. Experimental results show that our algorithm can reduce the coding time by up to 80%, and provide average coding time savings of 46%, 45%, and 52%, for low delay B, low delay P, and random access configurations, respectively. Moreover, the proposed algorithm is able to maintain coding performance similar to HM 11.0. The proposed scheme outperforms previous work in terms of both the coding speed and the RD performance.
Objectives
To investigate the significant predictors of contralateral upper tract recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.
Methods
Between January 2001 and ...December 2015, 548 patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy in a single institution were included in this retrospective cohort study. Several clinicopathological characteristics and outcomes were explored. The crucial end‐point was the diagnosis of contralateral upper tract recurrence after radical nephroureterectomy.
Results
Of the 548 patients, the median age was 68 years (range 24–93 years), and the median follow‐up time after radical nephroureterectomy was 41 months (range 8–191 months). Contralateral upper tract recurrence occurred in 28 patients (5.1%). The median time period between radical nephroureterectomy and contralateral upper tract recurrence was 15.4 months (range 3.4–52.4 months). In the multivariate analysis, preoperative estimated glomerular filtration rate <30 mL/min/1.73 m2 (hazard ratio 3.08, P = 0.003) and tumor multifocality (hazard ratio 2.16, P = 0.043) were independent risk factors.
Conclusion
Preoperative estimated glomerular filtration rate <30 and tumor multifocality are significant predictors of contralateral upper tract recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.
The capacity expansion problem is solved by accurately measuring the existing demand-supply mismatch and controlling the emissions output, considering multiple objectives, specific constraints, ...resource diversity, and resource allocation. This article proposes a reinforcement learning (RL) framework embedded with data envelopment analysis (DEA) to generate the optimal policy and guide the productivity improvement. The proposed framework uses DEA to evaluate efficiency and effectiveness for reward estimation in RL, and also assesses conditional value-at-risk to characterize the risk-averse capacity decision. Instead of focusing on short-term fluctuations in demand, RL optimizes the expected future reward with sequential capacity decisions over time. An empirical study of U.S. power generation validates the proposed framework and provides the managerial implications to policy makers. The results show that the RL agent can successfully learn the optimal policy through observing the interactions between the agent and the environment, and suggest the capacity adjustment that can improve efficiency by 8.3% and effectiveness by 0.9%. We conclude that RL complements productivity analysis, and emphasizes ex-ante planning over ex-post evaluation.
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