Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target

Since reprogramming energy metabolism is considered a new hallmark of cancer, tumor metabolism is again in the spotlight of cancer research. Many studies have been carried out and many possible therapies have been developed in the last years. However, tumor cells are not alone. A series of extracellular components and stromal cells, such as endothelial cells, cancer-associated fibroblasts, tumor-associated macrophages and tumor-infiltrating T cells, surround tumor cells in the so-called tumor microenvironment. Metabolic features of these cells are being studied in deep in order to find relationships between metabolism within the tumor microenvironment and tumor progression. Moreover, it cannot be forgotten that tumor growth is able to modulate host metabolism and homeostasis, so that tumor microenvironment is not the whole story. Importantly, the metabolic switch in cancer is just a consequence of the flexibility and adaptability of metabolism and should not be surprising. Treatments of cancer patients with combined therapies including anti-tumor agents with those targeting stromal cell metabolism, anti-angiogenic drugs and/or immunotherapy are being developed as promising therapeutics.Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. Supported by grants BIO2014-56092-R (MINECO and FEDER), P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Future cities and autonomous vehicles: analysis of the barriers to full adoption

The inevitable upcoming technology of autonomous vehicles (AVs) will affect our cities and several aspects of our lives. The widespread adoption of AVs repose at crossing distinct barriers that prevent their full adoption. This paper presents a critical review of recent debates about AVs and analyse the key barriers to their full adoption. This study has employed a mixed research methodology on a selected database of recently published research works. Thus, the outcomes of this review integrate the barriers into two main categories; (1) User/Government perspectives that include (i) Users' acceptance and behaviour, (ii) Safety, and (iii) Legislation. (2) Information and Communication Technologies (ICT) which include (i) Computer software and hardware, (ii) Communication systems V2X, and (iii) accurate positioning and mapping. Furthermore, a framework of barriers and their relations to AVs system architecture has been suggested to support future research and technology development

Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch

Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min application in patients with neuropathic pain produced effective pain relief for up to 12 weeks. Advantages of the high-concentration capsaicin patch include longer duration of effect, patient compliance, and low risk for systemic effects or drug–drug interactions. The mechanism of action of topical capsaicin has been ascribed to depletion of substance P. However, experimental and clinical studies show that depletion of substance P from nociceptors is only a correlate of capsaicin treatment and has little, if any, causative role in pain relief. Rather, topical capsaicin acts in the skin to attenuate cutaneous hypersensitivity and reduce pain by a process best described as ‘defunctionalization’ of nociceptor fibres. Defunctionalization is due to a number of effects that include temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fibre terminals. Peripheral neuropathic hypersensitivity is mediated by diverse mechanisms, including altered expression of the capsaicin receptor TRPV1 or other key ion channels in affected or intact adjacent peripheral nociceptive nerve fibres, aberrant re-innervation, and collateral sprouting, all of which are defunctionalized by topical capsaicin. Evidence suggests that the utility of topical capsaicin may extend beyond painful peripheral neuropathies

Reactive Oxygen Species Hydrogen Peroxide Mediates Kaposi's Sarcoma-Associated Herpesvirus Reactivation from Latency

Kaposi's sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the host following an acute infection. Reactivation from latency contributes to the development of KSHV-induced malignancies, which include Kaposi's sarcoma (KS), the most common cancer in untreated AIDS patients, primary effusion lymphoma and multicentric Castleman's disease. However, the physiological cues that trigger KSHV reactivation remain unclear. Here, we show that the reactive oxygen species (ROS) hydrogen peroxide (H2O2) induces KSHV reactivation from latency through both autocrine and paracrine signaling. Furthermore, KSHV spontaneous lytic replication, and KSHV reactivation from latency induced by oxidative stress, hypoxia, and proinflammatory and proangiogenic cytokines are mediated by H2O2. Mechanistically, H2O2 induction of KSHV reactivation depends on the activation of mitogen-activated protein kinase ERK1/2, JNK, and p38 pathways. Significantly, H2O2 scavengers N-acetyl-L-cysteine (NAC), catalase and glutathione inhibit KSHV lytic replication in culture. In a mouse model of KSHV-induced lymphoma, NAC effectively inhibits KSHV lytic replication and significantly prolongs the lifespan of the mice. These results directly relate KSHV reactivation to oxidative stress and inflammation, which are physiological hallmarks of KS patients. The discovery of this novel mechanism of KSHV reactivation indicates that antioxidants and anti-inflammation drugs could be promising preventive and therapeutic agents for effectively targeting KSHV replication and KSHV-related malignancies

Emerging Themes and Future Directions of Multi-Sector Nexus Research and Implementation

Water, energy, and food are all essential components of human societies. Collectively, their respective resource systems are interconnected in what is called the “nexus”. There is growing consensus that a holistic understanding of the interdependencies and trade-offs between these sectors and other related systems is critical to solving many of the global challenges they present. While nexus research has grown exponentially since 2011, there is no unified, overarching approach, and the implementation of concepts remains hampered by the lack of clear case studies. Here, we present the results of a collaborative thought exercise involving 75 scientists and summarize them into 10 key recommendations covering: the most critical nexus issues of today, emerging themes, and where future efforts should be directed. We conclude that a nexus community of practice to promote open communication among researchers, to maintain and share standardized datasets, and to develop applied case studies will facilitate transparent comparisons of models and encourage the adoption of nexus approaches in practice

Heat-shock proteins in infection-mediated inflammation-induced tumorigenesis

Inflammation is a necessary albeit insufficient component of tumorigenesis in some cancers. Infectious agents directly implicated in tumorigenesis have been shown to induce inflammation. This process involves both the innate and adaptive components of the immune system which contribute to tumor angiogenesis, tumor tolerance and metastatic properties of neoplasms. Recently, heat-shock proteins have been identified as mediators of this inflammatory process and thus may provide a link between infection-mediated inflammation and subsequent cancer development. In this review, the role of heat-shock proteins in infection-induced inflammation and carcinogenesis will be discussed

Cooperative management and its effects on shade tree diversity, soil properties and ecosystem services of coffee plantations in western El Salvador

We compared how management approaches affected shade tree diversity, soil properties, and provisioning and carbon sequestration ecosystem services in three shade coffee cooperatives. Collectively managed cooperatives utilized less diverse shade, and pruned coffee and shade trees more intensively, than individual farms. Soil properties showed significant differences among the cooperatives, with the following properties contributing to differentiation: N, pH, P, K, and Ca. Higher tree richness was associated with higher soil pH, CEC, Ca, and Mg, and lower K. Higher tree densities were associated with lower N, K, and organic matter. Although we found differences in the incidence of provisioning services (e.g., fruit), all plantations generated products other than coffee. No differences were observed between C-stocks. The history and institutional arrangements of cooperatives can influence management approaches, which affect ecosystem properties and services. Our study corroborates that interdisciplinary investigations are essential to understand the socio-ecological context of tropical shade coffee landscapes

Impact of magnetic field on the stability of the CMS GE1/1 GEM detector operation

The Gas Electron Multiplier (GEM) detectors of the GE1/1 station of the CMS experiment have been operated in the CMS magnetic field for the first time on the 7$^{th}$ of October 2021. During the magnetic field ramps, several discharge phenomena were observed, leading to instability in the GEM High Voltage (HV) power system. In order to reproduce the behavior, it was decided to conduct a dedicated test at the CERN North Area with the Goliath magnet, using four GE1/1 spare chambers. The test consisted in studying the characteristics of discharge events that occurred in different detector configurations and external conditions. Multiple magnetic field ramps were performed in sequence: patterns in the evolution of the discharge rates were observed with these data. The goal of this test is the understanding of the experimental conditions inducing discharges and short circuits in a GEM foil. The results of this test lead to the development of procedure for the optimal operation and performance of GEM detectors in the CMS experiment during the magnet ramps. Another important result is the estimation of the probability of short circuit generation, at 68 % confidence level, p$_{short}$$^{HV}$ $^{OFF}$ = 0.42$^{-0.35+0.94}$% with detector HV OFF and p$_{short}$$^{HV}$ $^{OFF}$ < 0.49% with the HV ON. These numbers are specific for the detectors used during this test, but they provide a first quantitative indication on the phenomenon, and a point of comparison for future studies adopting the same procedure

Triple-GEM discharge probability studies at CHARM: Simulations and experimental results

The CMS muon system in the region with 2.03<|η|<2.82 is characterized by a very harsh radiation environment which can generate hit rates up to 144 kHz/cm$^{2}$ and an integrated charge of 8 C/cm$^{2}$ over ten years of operation. In order to increase the detector performance and acceptance for physics events including muons, a new muon station (ME0) has been proposed for installation in that region. The technology proposed is Triple—Gas Electron Multiplier (Triple-GEM), which has already been qualified for the operation in the CMS muon system. However, an additional set of studies focused on the discharge probability is necessary for the ME0 station, because of the large radiation environment mentioned above. A test was carried out in 2017 at the Cern High energy AcceleRator Mixed (CHARM) facility, with the aim of giving an estimation of the discharge probability of Triple-GEM detectors in a very intense radiation field environment, similar to the one of the CMS muon system. A dedicated standalone Geant4 simulation was performed simultaneously, to evaluate the behavior expected in the detector exposed to the CHARM field. The geometry of the detector has been carefully reproduced, as well as the background field present in the facility. This paper presents the results obtained from the Geant4 simulation, in terms of sensitivity of the detector to the CHARM environment, together with the analysis of the energy deposited in the gaps and of the processes developed inside the detector. The discharge probability test performed at CHARM will be presented, with a complete discussion of the results obtained, which turn out to be consistent with measurements performed by other groups

Detector Control System for the GE1/1 slice test

Gas Electron Multiplier (GEM) technology, in particular triple-GEM, was selected for the upgrade of the CMS endcap muon system following several years of intense effort on R&D. The triple-GEM chambers (GE1/1) are being installed at station 1 during the second long shutdown with the goal of reducing the Level-1 muon trigger rate and improving the tracking performance in the harsh radiation environment foreseen in the future LHC operation [1]. A first installation of a demonstrator system started at the beginning of 2017: 10 triple-GEM detectors were installed in the CMS muon system with the aim of gaining operational experience and demonstrating the integration of the GE1/1 system into the trigger. In this context, a dedicated Detector Control System (DCS) has been developed, to control and monitor the detectors installed and integrating them into the CMS operation. This paper presents the slice test DCS, describing in detail the different parts of the system and their implementation