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Although transit stop location problem has been extensively studied, the two main categories of modeling methodologies, i.e., discrete models and continuum approximation (CA) ones, seem have little intersection. Both have strengths and weaknesses, respectively. This study intends to integrate them by taking the advantage of CA models' parsimonious property and discrete models' fine consideration of practical conditions. In doing so, we first employ the state-of-the-art CA models to yield the optimal design, which serves as the input to the next discrete model. Then, the stop location problem is formulated into a multivariable nonlinear minimization problem with a given number of stop location variables and location constraint. The interior-point algorithm is presented to find the optimal design that is ready for implementation. In numerical studies, the proposed model is applied to a variety of scenarios with respect to demand levels, spatial heterogeneity, and route length. The results demonstrate the consistent advantage of the proposed model in all scenarios as against its counterparts, i.e., two existing recipes that convert CA model-based solution into real design of stop locations. Lastly, a case study is presented using real data and practical constraints for the adjustment of a bus route in Chengdu (China). System cost saving of 15.79% is observed by before-and-after comparison. [ABSTRACT FROM AUTHOR]

Existing research on platoon dispersion models either describe homogeneous traffic flow feature, or are in lack of analytical solutions. By analyzing the field data, the truncated mixed simplified phase-type distribution is proved to be capable of capturing the characteristics of heterogeneous traffic flow with an excellent fitting result. In light of this, we derive a generic heterogeneous platoon dispersion model with truncated mixed simplified phase-type of speed in the forms of integrable functions. Numerical case studies are conducted to compare the performance of the proposed model and the conventional models (i.e., the Robertson model and truncated mixed Gaussian model). The results show that the proposed model not only better captures the platoon dispersion laws of heterogeneous traffic flow, but also presents higher computational efficiency, which provides practical implications on traffic signal control. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background. Despite afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion or other rare EGFR-mutation patients, the acquired resistance or toxic effects associated with it limited its use clinically. The controlling of acquired resistance or optimization of the afatinib dosage in EGFR/T790M mutation-positive non-small-cell lung cancer (NSCLC) is still an important fundamental problem. Ethacrynic acid (EA) has been proved as a dual inhibitor of GST and WNT, and the α, β-unsaturated-keto structure of it is similar to that of irreversible tyrosine kinase inhibitors (TKIs). However, these beneficial effects of EA combined with afatinib have never been reported in NSCLC. Therefore, the antitumor effects of afatinib combined with EA in EGFR L858R/T790M-mutated NSCLC cells and related mechanisms were analyzed. Our in vitro and in vivo results showed that EA has strong synergistic antitumor effects with afatinib in EGFR L858R/T790M-mutated NSCLC cells, but has no cytotoxic effects in NSCLC cells when used it alone, i.e., the cytotoxic effects of afatinib (IC30) plus EA (IC30) were stronger than the effects of afatinib (IC50) alone. Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy. [ABSTRACT FROM AUTHOR]

Background. Despite afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion or other rare EGFR-mutation patients, the acquired resistance or toxic effects associated with it limited its use clinically. The controlling of acquired resistance or optimization of the afatinib dosage in EGFR/T790M mutation-positive non-small-cell lung cancer (NSCLC) is still an important fundamental problem. Ethacrynic acid (EA) has been proved as a dual inhibitor of GST and WNT, and the α, β-unsaturated-keto structure of it is similar to that of irreversible tyrosine kinase inhibitors (TKIs). However, these beneficial effects of EA combined with afatinib have never been reported in NSCLC. Therefore, the antitumor effects of afatinib combined with EA in EGFR L858R/T790M-mutated NSCLC cells and related mechanisms were analyzed. Our in vitro and in vivo results showed that EA has strong synergistic antitumor effects with afatinib in EGFR L858R/T790M-mutated NSCLC cells, but has no cytotoxic effects in NSCLC cells when used it alone, i.e., the cytotoxic effects of afatinib (IC30) plus EA (IC30) were stronger than the effects of afatinib (IC50) alone. Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy. [ABSTRACT FROM AUTHOR]

Background. Despite afatinib as a new first-line treatment for EGFR L858R and exon 19 deletion or other rare EGFR-mutation patients, the acquired resistance or toxic effects associated with it limited its use clinically. The controlling of acquired resistance or optimization of the afatinib dosage in EGFR/T790M mutation-positive non-small-cell lung cancer (NSCLC) is still an important fundamental problem. Ethacrynic acid (EA) has been proved as a dual inhibitor of GST and WNT, and the α, β-unsaturated-keto structure of it is similar to that of irreversible tyrosine kinase inhibitors (TKIs). However, these beneficial effects of EA combined with afatinib have never been reported in NSCLC. Therefore, the antitumor effects of afatinib combined with EA in EGFR L858R/T790M-mutated NSCLC cells and related mechanisms were analyzed. Our in vitro and in vivo results showed that EA has strong synergistic antitumor effects with afatinib in EGFR L858R/T790M-mutated NSCLC cells, but has no cytotoxic effects in NSCLC cells when used it alone, i.e., the cytotoxic effects of afatinib (IC30) plus EA (IC30) were stronger than the effects of afatinib (IC50) alone. Our functional studies found that the antitumor mechanisms of afatinib when combined with EA mainly occurred by inhibiting WNT/β-catenin pathway activation and suppression of the secretion of anti-inflammatory factors. These results revealed that combination of afatinib with EA derivatives not only provided a new therapeutic approach for EGFR/T790M-mutated NSCLC patients but also offered a new idea for developing new drugs or optimizing the dose of afatinib in clinical use in future antitumor therapy. [ABSTRACT FROM AUTHOR]

Background. Bardet–Biedl syndrome (BBS) is a rare multisystem developmental disorder. In this study, we report the genetic causes and clinical manifestations in two Chinese families with BBS. Materials and Methods. Two families were recruited in this study. Family A was a four-generation family with four affected and 15 unaffected members participating in the study, and family B was a consanguineous family with one affected and three unaffected members participating. Whole exome sequencing was performed in the two families, followed by a multistep bioinformatics analysis. Sanger sequencing was used to verify the variants and to perform a segregation analysis. Comprehensive ocular and systemic examinations were also conducted. Results. Novel compound heterozygous variants c.235T > G (p.T79P) and c.534 + 1G > T were detected in the BBS2 gene in family A, and known homozygous variant c.748G > A (p.G250R) was detected in the MKKS gene in family B. Both families presented with retinitis pigmentosa; however, except for polydactyly, all other systemic manifestations were different. All of the affected family members in family A were overweight with a high body mass index (range from 26.5 to 41.9) and high blood pressure. Family A also presented with a delay in the onset of secondary sex characteristics and genital anomalies, while other systemic abnormalities were absent in family B. Conclusions. This study presents one family with two novel BBS2 variants, expanding the variant spectrum of BBS, and one family with a known homozygous MKKS variant. The different phenotypes seen between the families with BBS2 and MKKS variants will contribute to the literature and our overall understanding of BBS. [ABSTRACT FROM AUTHOR]

Armadillo gene subfamily members (ARMCX1-6) are well-known to regulate protein-protein interaction involved in nuclear transport, cellular connection, and transcription activation. Moreover, ARMCX signals on cell pathways also implicated in carcinogenesis and tumor progression. However, little is known about the associations of the ARMCX subfamily members with gastric carcinoma. This study investigated the prognostic value of ARMCX subfamily mRNA expression levels with the prognosis of gastric carcinoma (GC). We retrieved the data of a total of 351 GC patients from TCGA database. Survival and gene set enrichment analyses were employed to explore the predictive value and underlying mechanism of ARMCX genes in GC. The multivariate survival analysis revealed that individually low expressions of ARMCX1 (adjusted P = 0.006 , HR = 0.620 , CI = 0.440 − 0.874) and ARMCX2 (adjusted P = 0.005 , HR = 0.610 , 95 % CI = 0.432 – 0.861) were related to preferable overall survival (OS). The joint-effects analysis shown that combinations of low level expression of ARMCX1 and ARMCX2 were correlated with favorable OS (adjusted P = 0.003 , HR = 0.563 , 95 % CI = 0.384 – 0.825). ARMCX1 and ARMCX2 were implicated in WNT and NF-kappaB pathways, and biological processes including cell cycle, apoptosis, RNA modification, DNA replication, and damage response. Our results suggest that mRNA expression levels of ARMCX subfamily are potential prognostic markers of GC. [ABSTRACT FROM AUTHOR]

Armadillo gene subfamily members (ARMCX1-6) are well-known to regulate protein-protein interaction involved in nuclear transport, cellular connection, and transcription activation. Moreover, ARMCX signals on cell pathways also implicated in carcinogenesis and tumor progression. However, little is known about the associations of the ARMCX subfamily members with gastric carcinoma. This study investigated the prognostic value of ARMCX subfamily mRNA expression levels with the prognosis of gastric carcinoma (GC). We retrieved the data of a total of 351 GC patients from TCGA database. Survival and gene set enrichment analyses were employed to explore the predictive value and underlying mechanism of ARMCX genes in GC. The multivariate survival analysis revealed that individually low expressions of ARMCX1 (adjusted P = 0.006 , HR = 0.620 , CI = 0.440 − 0.874) and ARMCX2 (adjusted P = 0.005 , HR = 0.610 , 95 % CI = 0.432 – 0.861) were related to preferable overall survival (OS). The joint-effects analysis shown that combinations of low level expression of ARMCX1 and ARMCX2 were correlated with favorable OS (adjusted P = 0.003 , HR = 0.563 , 95 % CI = 0.384 – 0.825). ARMCX1 and ARMCX2 were implicated in WNT and NF-kappaB pathways, and biological processes including cell cycle, apoptosis, RNA modification, DNA replication, and damage response. Our results suggest that mRNA expression levels of ARMCX subfamily are potential prognostic markers of GC. [ABSTRACT FROM AUTHOR]