Therapeutic Targets and Tumor Microenvironment in Colorectal Cancer

Colorectal cancer (CRC) is a genetically, anatomically, and transcriptionally heterogeneous disease. The prognosis for a CRC patient depends on the stage of the tumor at diagnosis and widely differs accordingly. The tumor microenvironment (TME) in CRC is an important factor affecting targeted cancer therapy. The TME has a dynamic composition including various cell types, such as cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, as well as extracellular factors that surround cancer cells and have functional and structural roles under physiological and pathological conditions. Moreover, the TME can limit the efficacy of therapeutic agents through high interstitial pressure, fibrosis, and the degradation of the therapeutic agents by enzymatic activity. For this reason, the TME is a fertile ground for the discovery of new drugs. The aim of this narrative review is to present current knowledge and future perspectives regarding the TME composition based on strategies for patients with CRC

Mesoscopic Casimir forces from effects of discrete particle number in the quantum vacuum

Traditionally it is assumed that the Casimir vacuum pressure does not depend on the ultraviolet cut-off. There are, however, some arguments that the effect actually depends on the regularization procedure and thus on the trans-Planckian physics. We provide the condensed matter example where the Casimir forces do explicitly depend on the microscopic (correspondingly trans-Planckian) physics due to the mesoscopic finite-N effects, where N is the number of bare particles in condensed matter (or correspondingly the number of the elements comprising the quantum vacuum). The finite-N effects lead to mesoscopic fluctuations of the vacuum pressure. The amplitude of the mesoscopic flustuations of the Casimir force in a system with linear dimension L is larger by the factor N^{1/3}\sim L/a than the traditional value of the Casimir force given by effective theory, where a is the interatomic distance which plays the role of the Planck length.Comment: LaTeX file, 13 pages, no figures, submitted to JETP Letter

Convergence and optimality of a new iterative price-based scheme for distributed coordination of flexible loads in the electricity market

This paper proposes a novel distributed control strategy for large-scale deployment of flexible demand. The devices are modelled as competing players that respond to iterative broadcasts of price signals, scheduling their power consumption to operate at minimum cost. By describing their power update at each price broadcast through a multi-valued discrete-time dynamical system and by applying Lyapunov techniques, it is shown that the proposed control strategy always converges to a stable final configuration, characterized as a Wardrop (or aggregative) equilibrium. It is also proved that such equilibrium is socially efficient and optimizes some global performance index of the system (e.g. minimizes total generation costs). These results are achieved under very general assumptions on the electricity price and for any penetration level of flexible demand. Practical implementation of the proposed scheme is discussed and tested in simulation on a future scenario of the UK-grid with large numbers of flexible loads

Distributed Control of Micro-Storage Devices With Mean Field Games

This paper proposes a fully distributed control strategy for the management of micro-storage devices that perform energy arbitrage. For large storage populations, the problem can be approximated as a differential game with infinite players (mean field game). Through the resolution of coupled partial differential equations (PDEs), it is possible to determine, as a fixed point, the optimal feedback strategy for each player and the resulting price of energy if that strategy is applied. Once this price is calculated, it can be communicated to the devices, which are able to independently determine their optimal charge profile. Simulation results are provided, calculating the fixed point through numerical integration of the PDEs. The original model is then extended in order to consider additional elements, such as multiple population of devices and demand uncertainty

Frequency support by scheduling of variable-speed wind turbines

© IFAC.This paper characterizes optimal control policies for wind farms operated as frequency response services in case of a fault of conventional generators. The frequency support is provided through temporary over-production: when frequency drops, the turbines move from the steady-state operating point and extra power is produced by slowing down the turbines and releasing part of their kinetic energy. The control task is formulated and solved as an optimal containment problem: the time during which an extra quantity of power can be produced, within the set speed constraints for each turbine, is maximized. The solutions are calculated and compared for different assumptions on the electric torque of the turbines

A 22-Week-Old Fetus with Nager Syndrome and Congenital Diaphragmatic Hernia due to a Novel SF3B4 Mutation.

Nager syndrome, or acrofacial dysostosis type 1 (AFD1), is a rare multiple malformation syndrome characterized by hypoplasia of first and second branchial arches derivatives and appendicular anomalies with variable involvement of the radial/axial ray. In 2012, AFD1 has been associated with dominant mutations in SF3B4. We report a 22-week-old fetus with AFD1 associated with diaphragmatic hernia due to a previously unreported SF3B4 mutation (c.35-2A>G). Defective diaphragmatic development is a rare manifestation in AFD1 as it is described in only 2 previous cases, with molecular confirmation in 1 of them. Our molecular finding adds a novel pathogenic splicing variant to the SF3B4 mutational spectrum and contributes to defining its prenatal/fetal phenotype

GALNT2 as a novel modulator of adipogenesis and adipocyte insulin signaling

Background/objectives: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes. Methods: Stable over-expressing GALNT2 and GFP preadipocytes (T 0 ) were generated. Adipogenesis was induced with (R+) or without (R−) rosiglitazone and investigated after 15 days (T 15 ). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot. Results: Lipid accumulation, triglycerides and LD measures progressively increased from T 0 to T 15 R- and furthermore to T 15 R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T 15 R+GFP, T 15 R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes. Conclusions: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae

Investigating the social efficiency of merchant transmission planning through a non-cooperative game-theoretic framework

Merchant transmission planning is considered as a further step towards the full liberalization of the electricity industry. However, previous modeling approaches do not comprehensively explore its social efficiency as they cannot effectively deal with a large number of merchant companies. This paper addresses this fundamental challenge by adopting a novel non-cooperative game-theoretic approach. Specifically, the number of merchant companies is assumed sufficiently large to be approximated as a continuum. This allows the derivation of mathematical conditions for the existence of a Nash Equilibrium solution of the merchant planning game. By analytically and numerically comparing this solution against the one obtained through the traditional centralized planning approach, the paper demonstrates that merchant planning can maximize social welfare only when the following conditions are satisfied: a) fixed investment costs are neglected and b) the network is radial and does not include any loops. Given that these conditions do not generally hold in reality, these findings suggest that even a fully competitive merchant transmission planning framework, involving the participation of a very large number of competing merchant companies, is not generally capable of maximizing social welfare