Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.

Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity

Differential interferometric phases at high spectral resolution as a sensitive physical diagnostic of circumstellar disks

Context. The circumstellar disks ejected by many rapidly rotating B stars (so-called Be stars) offer the rare opportunity of studying the structure and dynamics of gaseous disks at high spectral as well as angular resolution. Aims. This paper explores a newly identified effect in spectro-interferometric phase that can be used for probing the inner regions of gaseous edge-on disks on a scale of a few stellar radii. Methods. The origin of this effect (dubbed central quasi-emission phase signature, CQE-PS) lies in the velocity-dependent line absorption of photospheric radiation by the circumstellar disk. At high spectral and marginal interferometric resolution, photocenter displacements between star and isovelocity regions in the Keplerian disk reveal themselves through small interferometric phase shifts. To investigate the diagnostic potential of this effect, a series of models are presented, based on detailed radiative transfer calculations in a viscous decretion disk. Results. Amplitude and detailed shape of the CQE-PS depend sensitively on disk density and size and on the radial distribution of the material with characteristic shapes in differential phase diagrams. In addition, useful lower limits to the angular size of the central stars can be derived even when the system is almost unresolved. Conclusions. The full power of this diagnostic tool can be expected if it can be applied to observations over a full life-cycle of a disk from first ejection through final dispersal, over a full cycle of disk oscillations, or over a full orbital period in a binary system

Fine-Tuning Tumor Endothelial Cells to Selectively Kill Cancer.

Tumor endothelial cells regulate several aspects of tumor biology, from delivering oxygen and nutrients to shaping the immune response against a tumor and providing a barrier against tumor cell dissemination. Accordingly, targeting tumor endothelial cells represents an important modality in cancer therapy. Whereas initial anti-angiogenic treatments focused mainly on blocking the formation of new blood vessels in cancer, emerging strategies are specifically influencing certain aspects of tumor endothelial cells. For instance, efforts are generated to normalize tumor blood vessels in order to improve tumor perfusion and ameliorate the outcome of chemo-, radio-, and immunotherapy. In addition, treatment options that enhance the properties of tumor blood vessels that support a host's anti-tumor immune response are being explored. Hence, upcoming anti-angiogenic strategies will shape some specific aspects of the tumor blood vessels that are no longer limited to abrogating angiogenesis. In this review, we enumerate approaches that target tumor endothelial cells to provide anti-cancer benefits and discuss their therapeutic potential

Local Granger causality

Granger causality (GC) is a statistical notion of causal influence based on prediction via linear vector autoregression. For Gaussian variables it is equivalent to transfer entropy, an information-theoretic measure of time-directed information transfer between jointly dependent processes. We exploit such equivalence and calculate exactly the local Granger causality, i.e., the profile of the information transferred from the driver to the target process at each discrete time point; in this frame, GC is the average of its local version. We show that the variability of the local GC around its mean relates to the interplay between driver and innovation (autoregressive noise) processes, and it may reveal transient instances of information transfer not detectable from its average values. Our approach offers a robust and computationally fast method to follow the information transfer along the time history of linear stochastic processes, as well as of nonlinear complex systems studied in the Gaussian approximation

Synergistic information transfer in the global system of financial markets

Uncovering dynamic information flow between stock market indices has been the topic of several studies which exploited the notion of transfer entropy or Granger causality, its linear version. The output of the transfer entropy approach is a directed weighted graph measuring the information about the future state of each target provided by the knowledge of the state of each driving stock market index. In order to go beyond the pairwise description of the information flow, thus looking at higher order informational circuits, here we apply the partial information decomposition to triplets consisting of a pair of driving markets (belonging to America or Europe) and a target market in Asia. Our analysis, on daily data recorded during the years 2000 to 2019, allows the identification of the synergistic information that a pair of drivers carry about the target. By studying the influence of the closing returns of drivers on the subsequent overnight changes of target indexes, we find that (i) Korea, Tokyo, Hong Kong, and Singapore are, in order, the most influenced Asian markets; (ii) US indices SP500 and Russell are the strongest drivers with respect to the bivariate Granger causality; and (iii) concerning higher order effects, pairs of European and American stock market indices play a major role as the most synergetic three-variables circuits. Our results show that the Synergy, a proxy of higher order predictive information flow rooted in information theory, provides details that are complementary to those obtained from bivariate and global Granger causality, and can thus be used to get a better characterization of the global financial system

Visual acuity outcome of stable proliferative diabetic retinopathy following initial complete panretinal photocoagulation

BACKGROUND: Recent clinical trials on proliferative diabetic retinopathy (PDR) show that presenting visual acuity can be stabilised with panretinal photocoagulation (PRP) within 2 years despite the need for supplementary PRP or anti-vascular endothelial growth factor therapy for concomitant diabetic macular oedema (DMO). It is unclear whether similar results can be obtained in daily clinical practice. Here, we query the probability of vision loss in patients with treatment-naïve PDR who have attained stability after PRP and its predictors. METHODS: Retrospective cohort study at a tertiary eye centre between 01 January 2015 and 31 December 2019, wherein 2336 eyes met study criteria with first record of stable PRP-treated PDR in at least one eye. Kaplan-Meier and Cox proportional hazards modelling were used to report the probability of vision loss of at least five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. RESULTS: The probability of losing at least five ETDRS letters was 50% at 3.32 (95% CI, 2.94 to 3.78) years after achieving first stability post PRP in treatment-naïve PDR. The mean decrease at this event was 14.2 (SD 13.0) ETDRS letters irrespective of the presence of DMO. The strongest risk factor for vision loss was a history of DMO at baseline (HR 1.62 (95% CI, 1.34 to 1.95), p<0.001). DISCUSSION: One in two patients with stable treated PDR lose a line of vision by 3.5 years. This resulted in 15% of patients losing their eligibility to drive. Notably, 13% of the cohort died during the follow-up period

Comparison of different methods for SNP detection in grapevine

Single nucleotide polymorphisms (SNPs) are the most abundant of all markers, both in animal and plant genomes. In crops and tree species considerable investment has been recently made on this genomic technology. While large-scale characterisation of SNPs by high-throughput techniques is possible, such highthroughput platforms are not available to all plant breeding laboratories. This report compares alternative multi-purpose and affordable methods for SNP assay in grapevine (Vitis spp.). In particular, the efficiency, sensitivity and reliability of single-strand conformation polymorphism (SSCP) on both non-denaturant gels and fluorescence-based capillary electrophoresis are compared with minisequencing (single nucleotide extension reaction). The results indicate that when multiplexing in combination with minisequencing is a mid-throughput, reliable and flexible technique for the detection of SNPs and can therefore be used effectively to improve marker assisted breeding in grapevine.

Rebound pathway overactivation by cancer cells following discontinuation of PI3K or mTOR inhibition promotes cancer cell growth.

Whilst effects of anti-cancer drugs have been thoroughly explored, little is known about the repercussion of drug cessation. However, this has important clinical relevance since several clinical protocols such as intermittent drug scheduling lead to frequent drug discontinuation. In this study, we have thus investigated the consequences of withdrawal of agents that target the PI3K/AKT/mTOR signaling pathway in cancer cells. We report that washout of kinase inhibitors of mTOR or PI3K inhibitors led to a rapid and sustainable overactivation of AKT. Consequently, proliferation of tumor cells was significantly higher following drug washout in cancer cells that were pre-treated with mTOR or PI3K inhibitors compared to untreated cells. This effect was prevented by the addition of an AKT inhibitor following drug washout. Rebound AKT overactivation induced by mTOR or PI3K inhibitors discontinuation was mediated by IGF-1R, as demonstrated by its prevention in the presence of an IGF-1R inhibitor and by increased IGF-1R phosphorylation in treated cells versus control cells. Taken together, our results show that discontinuation of PI3K or mTOR inhibitors results in AKT overactivation that promotes tumor growth. They further highlight the benefit of adding an AKT inhibitor following cessation of PI3K or mTOR inhibitors

Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies.

Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments