Small ones to fight a big problem-intervention of cancer metastasis by small molecules

Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in high efficiency in metastasis intervention. In result of this, personalized tailored interventions for restriction and prevention of cancer progression and metastasis will improve patient survival. This review defines crucial biological steps of the metastatic cascade, such as cell dissemination, migration and invasion as well as the action of metastasis suppressors. Targeting these biological steps with tailored therapeutic strategies of intervention or even prevention of metastasis using a wide range of small molecules will be discussed

Neural Network-Based Equations for Predicting PGA and PGV in Texas, Oklahoma, and Kansas

Parts of Texas, Oklahoma, and Kansas have experienced increased rates of seismicity in recent years, providing new datasets of earthquake recordings to develop ground motion prediction models for this particular region of the Central and Eastern North America (CENA). This paper outlines a framework for using Artificial Neural Networks (ANNs) to develop attenuation models from the ground motion recordings in this region. While attenuation models exist for the CENA, concerns over the increased rate of seismicity in this region necessitate investigation of ground motions prediction models particular to these states. To do so, an ANN-based framework is proposed to predict peak ground acceleration (PGA) and peak ground velocity (PGV) given magnitude, earthquake source-to-site distance, and shear wave velocity. In this framework, approximately 4,500 ground motions with magnitude greater than 3.0 recorded in these three states (Texas, Oklahoma, and Kansas) since 2005 are considered. Results from this study suggest that existing ground motion prediction models developed for CENA do not accurately predict the ground motion intensity measures for earthquakes in this region, especially for those with low source-to-site distances or on very soft soil conditions. The proposed ANN models provide much more accurate prediction of the ground motion intensity measures at all distances and magnitudes. The proposed ANN models are also converted to relatively simple mathematical equations so that engineers can easily use them to predict the ground motion intensity measures for future events. Finally, through a sensitivity analysis, the contributions of the predictive parameters to the prediction of the considered intensity measures are investigated.Comment: 5th Geotechnical Earthquake Engineering and Soil Dynamics Conference, Austin, TX, USA, June 10-13. (2018

Circulating intercellular adhesion molecule-1 and E-selectin levels in gastric cancer.

A diversity of adhesive interactions occur between the cancer cell and host extracellular matrix which potentiate neoplastic expansion and metastatic dissemination. In miscellaneous malignant diseases, tumour progression has been observed to be associated with alterations in adhesion molecule expression. Recently, circulating soluble intercellular adhesion molecules have been identified. In this study, serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) were determined in patients with gastric cancer. The study group consisted of 27 patients with previously untreated gastric adenocarcinoma. Four patients had stage II, two patients stage III and 21 patients stage IV disease according to the TNM classification. Nineteen patients had distant metastasis. The sera obtained from 18 healthy volunteers served as controls. Serum sICAM-1 and sE-selectin concentrations were determined by enzyme-linked immunosorbent assay (ELISA). In addition, we also studied other tumour-associated antigens, i.e. CEA and CA 19-9. Serum sICAM-1 levels were significantly increased in patients with gastric cancer (P < 0.0001). However, sE-selectin levels did not differ from the controls. sICAM-1 concentrations were also significantly higher in patients with distant metastasis and peritoneal spread (P = 0.0045 and P = 0.0157 respectively), whereas sE-Selectin levels were elevated only in patients with peritoneal metastasis (P = 0.033). Serum concentrations of sICAM-1 and sE-selectin correlated with CEA levels (P = 0.0013 and P = 0.003 respectively). Elevated levels of sE-selectin were associated with poorer prognosis (P = 0.0099), whereas sICAM-1 had no significant impact on survival. Our results suggest that increased sICAM-1 serum levels may reflect widespread disease and contribute directly to the progression of gastric cancer. Further investigation of the molecular mechanisms of adhesive tumour-host interactions may lead to a better understanding of the natural history of gastric cancer

Near-optimal modified base stock policies for the capacitated inventory problem with stochastic demand and fixed cost

In this study, we investigate a single-item, periodic-review inventory problem where the production capacity is limited and unmet demand is backordered. We assume that customer demand in each period is a stationary, discrete random variable. Linear holding and backorder cost are charged per unit at the end of a period. In addition to the variable cost charged per unit ordered, a positive fixed ordering cost is incurred with each order given. The optimization criterion is the minimization of the expected cost per period over a planning horizon. We investigate the infinite horizon problem by modeling the problem as a discrete-time Markov chain. We propose a heuristic for the problem based on a particular solution of this stationary model, and conduct a computational study on a set of instances, providing insight on the performance of the heuristic. © 2014 World Scientific Publishing Co

On asymptotically AdS-like solutions of three dimensional massive gravity

In this paper we have added Maxwell, Maxwell-Chern-Simons and gravitational Chern-Simons terms to Born-Infeld extended new massive gravity and we have found different types of (non)extremal charged black holes. For each black hole we find mass, angular momentum, entropy and temperature. Since our solutions are asymptotically AdS or warped-AdS, we infer central charges of dual CFTs by using Cardy's formula. Computing conserved charges associated to asymptotic symmetry transformations confirms calculation of central charges. For CFTs dual to asymptotically AdS solutions we find left central charges from Cardy's formula, while conserved charge approach gives both left and right central charges. For CFTs dual to asymptotically warped-AdS solutions, left and right central charges are equal when we have Maxwell-Chern-Simons term but they have different values when gravitational Chern-Simons term is included.Comment: 30 pages, 11 tables. Improved version (two new sections added for asymptotic conserved charges). Accepted in JHE

Durability of geothermal grouting materials considering extreme loads

The concern about the massive use of the non-renewable and very limited fossil fuels together with the well-known effects of the global warming makes it more necessary the efficient use of the current forms of renewable energy generation. Because of the crucial role played by the grouting materials in the Ground Source Heat Pumps (GSHP), a proper selection of these elements should be made based on a deep knowledge of their performance. In this paper, thermal conductivity, mechanical strength and grout-pipe permeability of four different highly workable grouts have been tested before and after they were subjected to wet-dry and freeze-thaw durability treatments. Results obtained demonstrated the harmful effects of using a large amount of mixing water in grouts subjected to those extreme loads. However, the use of these type of grouts with very good workability is still possible in GSHP installations with balanced thermal designs provided that regular operational and environment conditions are considered.The authors wish to express their gratitude to the Ministry of Economy and Competitiveness which funded this study within the Spanish National Plan for Scientific and Technical Research and Innovation (INNPACTO program) through the research project IPT-2011-0877-920000. The authors are also grateful to all the organizations and companies participating in this project: Sacyr Industrial, Universidad Politécnica de Madrid and Cype

Flux vacua in DBI type Einstein-Maxwell theory

We study compactification of extra dimensions in a theory of Dirac-Born-Infeld (DBI) type gravity. We investigate the solution for Minkowski spacetime with an $S^2$ extra space as well as that for de Sitter spacetime ($S^4$) with an $S^2$ extra space. They are derived by the effective potential method in the presence of the magnetic flux on the extra sphere. We also consider the higher dimensional generalization of the solutions. We find that, in a certain model, the radius of the extra space has a minimum value independent of the higher-dimensional Newton constant in weak-field limit.Comment: 13 pages, no figure. A reference added, typos fixe

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF\textit{BRAF}V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4$^{+}$/CD8$^{+}$ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]