Overcoming TGFβ-mediated immune evasion in cancer

This Review discusses the context-dependent functions of transforming growth factor-beta (TGF beta) with regard to the composition and behaviour of different cell populations in the tumour immune microenvironment, as well as emerging data that demonstrate that TGF beta inhibition can restore cancer immunity. Transforming growth factor-beta (TGF beta) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGF beta exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGF beta controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGF beta exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGF beta to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGF beta-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGF beta pathway, many of which are currently in clinical evaluation

In vitro self-organized mouse small intestinal epithelial monolayer protocol

Developing protocols to obtain intestinal epithelial monolayers that recapitulate in vivo physiology to overcome the limitations of the organoids’ closed geometry has become of great interest during the last few years. Most of the developed culture models showed physiological-relevant cell composition but did not prove self-renewing capacities. Here, we show a simple method to obtain mouse small intestine-derived epithelial monolayers organized into proliferative crypt-like domains, containing stem cells, and differentiated villus-like regions, closely resembling the in vivo cell composition and distribution. In addition, we adapted our model to a tissue culture format compatible with functional studies and prove close to physiological barrier properties of our in vitro epithelial monolayers. Thus, we have set-up a protocol to generate physiologically relevant intestinal epithelial monolayers to be employed in assays where independent access to both luminal and basolateral compartments is needed, such as drug absorption, intracellular trafficking and microbiome-epithelium interaction assays

Targeting the Microenvironment in Advanced Colorectal Cancer

Colorectal cancer (CRC) diagnosis often occurs at late stages when tumor cells have already disseminated. Current therapies are poorly effective for metastatic disease, the main cause of death in CRC. Despite mounting evidence implicating the tumor microenvironment in CRC progression and metastasis, clinical practice remains predominantly focused on targeting the epithelial compartment. Because CRCs remain largely refractory to current therapies, we must devise alternative strategies. Transforming growth factor (TGF)-β has emerged as a key architect of the microenvironment in poor-prognosis cancers. Disseminated tumor cells show a strong dependency on a TGF-β-activated stroma during the establishment and subsequent expansion of metastasis. We review and discuss the development of integrated approaches focused on targeting the ecosystem of poor-prognosis CRCs

Identification of N-terminal protein acetylation and arginine methylation of the voltage-gated sodium channel in end-stage heart failure human heart

The α subunit of the cardiac voltage-gated sodium channel, Naᵥ1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of Naᵥ1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-translational modification of any Naᵥ1.5 arginine or lysine residue. Unexpectedly, we found that the N terminus of Naᵥ1.5 was: 1) devoid of the initiation methionine, and 2) acetylated at the resulting initial alanine residue. This is the first evidence for N-terminal acetylation in any member of the voltage-gated ion channel superfamily. Our results open the door to explore Naᵥ1.5 N-terminal acetylation and arginine methylation levels as drivers or markers of end-stage heart failure

Acoustic emission across the magnetostructural transition of the giant magnetocaloric Gd5Si2Ge2 compound

We report on the existence of acoustic emission during the paramagnetic-monoclinic to ferromagnetic-orthorhombic magnetostructural phase transition in the giant magnetocaloric Gd5Si2Ge2 compound. The transition kinetics have been analyzed from the detected acoustic signals. It is shown that this transition proceeds by avalanches between metastable states.Comment: 5 pages, 4 figure

Dynamic flight plan design for UAS remote sensing applications

The development of Flight Control Systems (FCS) coupled with the availability of other Commercial Off-The Shelf (COTS) components is enabling the introduction of Unmanned Aircraft Systems (UAS) into the civil market. UAS have great potential to be used in a wide variety of civil applications such as environmental applications, emergency situations, surveillance tasks and more. In general, they are specially well suited for the so-called D-cube operations (Dirty, Dull or Dangerous). Current technology greatly facilitates the construction of UAS. Sophisticated flight con- trol systems also make them accessible to end users with little aeronautical expertise. How- ever, we believe that for its successful introduction into the civil market, progress needs to be made to deliver systems able to perform a wide variety of missions with minimal reconfiguration and with reduced operational costs. Most current flight plan specification mechanisms consist in a simple list of waypoints, an approach that has important limitations. This paper proposes a new specification mech- anism with semantically richer constructs that will enable the end user to specify more complex flight plans. The proposed formalism provides means for specifying iterative be- havior, conditional branching and other constructs to dynamically adapt the flight path to mission circumstances. Collaborating with the FCS, a new module on-board the UAS will be in charge of executing these plans. This research also studies how the proposed flight plan structure can be tailored to the specific needs of remote sensing. For these type of applications well structured and efficient area and perimeter scanning is mandatory. In this paper we introduce several strategies focused to optimize the scanning process for tactical or mini UAS. The paper also presents a prototype implementation of this module and the results obtained in simulations.Postprint (published version