Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib.

Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled. Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial-mesenchymal transition markers was analyzed by a multiplex-PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression-free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P = .008 and 3.3 vs 2.0 months, P = .004, respectively). Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P < .001 and 8.7 vs 3.8 months, P = .003, respectively). In multivariable analysis, CTC counts remained significantly associated with OS at baseline and day 21 (P = .019 and P = .028). Circulating tumor cell EGFR gene expression was upregulated at day 21 and/or PD in 64% of patients. Patients had significantly increased EGFR expression at PD compared to baseline (P = .041) and at day 21 and/or PD compared to baseline (P = .004). Our findings suggest that CTC count and EGFR expression could be useful markers of regorafenib efficacy and outcomes. Upregulation of CTC EGFR expression might be a molecular escape mechanism under regorafenib therapy

Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stage II/III colon cancer

The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil. In this study 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56% vs 33%, HR: 1.87; p =0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28% vs 40%; HR: 0.66; p =0.07). In left-sided tumors, this association was stronger (HR: 0.29; p =0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stage II and III colon cancer

NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients

Background: Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. Materials and methods: Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. Results: In the exploratory cohort 1 (TRIBE A), patients with CCTTT any> 13repeats (N = 57) showed improved median PFS compared with patients carrying the 26repeats/ 13 repeats (N = 24) had improved PFS results compared with those carrying the 26 repeats/26 repeats vs repeats/<= 2626 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. Conclusion: We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

WCA-Based Low-PSLL and Wide-Nulling Beampattern Synthesis for Radar Applications

There are many unavoidable array errors in practical scenarios, which would drastically increase the sidelobe level (SLL) and distort the performance of radar systems accordingly. In this paper, an effective beampattern synthesis approach is proposed to realize a low peak sidelobe level (PSLL) and wide-nulling in the presence of array errors, thus improving the consequent performance of the radar. In particular, the covariance matrix of the sidelobe region (CMSR) is incorporated into the optimization. Considering the randomness of array errors, the statistical mean method is adopted to obtain a more accurate calculation of the CMSR in the presence of array errors based on a Monte Carlo trial. To efficiently and effectively solve the optimization problem, an advanced metaheuristic algorithm, i.e., the water cycle algorithm (WCA), is adopted when seeking the corresponding optimal weight vectors. Numerical results are provided and discussed to demonstrate the effectiveness of the proposed approach including the results based on a wideband linearly spaced magneto-electric (ME) dipole array

Research on the Complexity of Game Model about Recovery Pricing in Reverse Supply Chain considering Fairness Concerns

A reverse recycling supply chain consisting of two recyclers is established in this paper, which takes into account the fact that the recyclers will consider the issue of fair concern in pricing. The paper discusses the local stability of the Nash equilibrium point in this price game model showing that the fair concern factors will reduce the stable area of the system. The paper also discusses the impacts of the sensitivity of the recovery price and the price cross coefficient on the stable area of the system. Through the method of system simulation and use of some indicators, such as the singular attractor, bifurcation diagram, attraction domain, power spectrum, and maximum Lyapunov exponent, the characteristics of the system at different times will be illustrated

Initial State Estimation for Boost Phase Object Based on 8-State Gravity Turn Model using Pseudo-linear Estimator

For space-based bearing-only observations, the initial state estimation of the boost phase object is the solution to the nonlinear Least squared estimation (LSE) problem. This paper transformed the nonlinear problem into a linear LSE problem using the linearization of the bearing-only measurement and the target trajectory, which facilitated the direct estimation of initial state whilst avoiding to use the Gauss-Newton iteration. In particular, the explicit derivation of the pseudo-linear measurement and its statistical moments are deduced, which helped to determine the applying conditions of the proposed method. The numerical simulations illustrated the advantage of the proposed method with respect to precision and efficiency

QTL Mapping of Somatic Regeneration-Related Traits in Maize

The somatic regeneration of maize depends on its genotypes, so improving its variety with modern biotechnology is severely restricted. Locating the quantitative trait loci (QTLs) associated with somatic regeneration is important for breeding elite inbred lines that undergo genetic transformations. Here, by crossing the high-regeneration inbred line H99 and non-regeneration inbred line Fr993, an F2 population and its F2:3 and F2:4 population families were constructed. Immature embryos from the family populations were subjected to tissue culture in two independent seasons to determine their embryogenic callus induction rates (EIRs), green callus rates (GCRs) and plantlet regeneration rates (PRRs). Genetic linkage maps were constructed for the F2 population to locate somatic regeneration QTLs. The results showed that variation in the EIR, GCR and PRR ranged from 0.00–99.33%, and their broad-sense heritabilities were 0.50, 0.52 and 0.53, respectively. The total genetic distance of the linkage maps constructed by the GenoBaits 10 K chip was 2319.50 cM, and twelve QTLs were associated with somatic regeneration traits, accounting for 3.90–14.06% of the phenotypic variation. Expression analysis revealed six candidate genes screened from the QTLs with distinct responses to induction culture in the parental lines, suggesting that they may impact commitment to somatic cell fate. These results provide a basis for the molecular breeding of maize varieties with high-frequency somatic regeneration

Promotive effect of multi-walled carbon nanotubes on Co3O4 nanosheets and their application in lithium-ion battery

Co3O4/MWCNTs composites have been synthesized by a simple hydrothermal method using a surfactant (CTAB) and a precipitation agent (urea). The samples were characterized by XRD, SEM and BET methods. The electrochemical properties of the samples as anode materials for lithium batteries were studied by EIS and Galvanostatic measurements. The Co3O4/MWCNTs composites displayed higher capacity and better cycle performance in comparison with the Co3O4 nanosheets. The remarkable improvement of electrochemical performance within the hybrid composites is probably related to the addition of MWCNTs that possesses improved properties such as excellent electric conductivity and large surface area, which helps to alleviate the effect of volume change, shorten the distance of lithium ion diffusion, facilitate the transmission of electron and keep the structure stable