In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

We discuss the use of a recent class of sequential Monte Carlo methods for solving inverse problems characterized by a semi-linear structure, i.e. where the data depend linearly on a subset of variables and non-linearly on the remaining ones. In this type of problems, under proper Gaussian assumptions one can marginalize the linear variables. This means that the Monte Carlo procedure needs only to be applied to the non-linear variables, while the linear ones can be treated analytically; as a result, the Monte Carlo variance and/or the computational cost decrease. We use this approach to solve the inverse problem of magnetoencephalography, with a multidipole model for the sources. Here, data depend non-linearly on the number of sources and their locations, and depend linearly on their current vectors. The semi-analytic approach enables us to estimate the number of dipoles and their location from a whole time-series, rather than a single time point, while keeping a low computational cost.

A recent result obtained by means of an in vitro experiment with cancer cultured cells has configured the endoplasmic reticulum as the preferential site for the accumulation of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Such a result is coherent with cell biochemistry and is made more significant by the fact that the reticular accumulation rate of FDG is dependent upon extracellular glucose availability. The objective of the present paper is to confirm in vivo the result obtained in vitro concerning the crucial role played by the endoplasmic reticulum in FDG cancer metabolism. This study utilizes data acquired by means of a Positron Emission Tomography scanner for small animals in the case of CT26 models of cancer tissues. The recorded concentration images are interpreted within the framework of a three-compartment model for FDG kinetics, which explicitly assumes that the endoplasmic reticulum is the dephosphorylation site for FDG in cancer cells. The numerical reduction of the compartmental model is performed by means of a regularized Gauss-Newton algorithm for numerical optimization. This analysis shows that the proposed three-compartment model equals the performance of a standard Sokoloff’s two-compartment system in fitting the data. However, it provides estimates of some of the parameters, such as the phosphorylation rate of FDG, more consistent with prior biochemical information. These results are made more solid from a computational viewpoint by proving the identifiability and by performing a sensitivity analysis of the proposed compartment model.

We consider the problem of reconstructing the cross-power spectrum of an unobservable multivariate stochatic process from indirect measurements of a second multivariate stochastic process, related to the first one through a linear operator. In the two-step approach, one would first compute a regularized reconstruction of the unobservable signal, and then compute an estimate of its cross-power spectrum from the regularized solution. We investigate whether the optimal regularization parameter for reconstruction of the signal also gives the best estimate of the cross-power spectrum. We show that the answer depends on the regularization method, and specifically we prove that, under a white Gaussian assumption: (i) when regularizing with truncated SVD the optimal parameter is the same; (ii) when regularizing with the Tikhonov method, the optimal parameter for the cross-power spectrum is lower than half the optimal parameter for the signal. We also provide evidence that a one-step approach would likely have better mathematical properties of the two-step approach. Our results apply particularly to the brain connectivity estimation from magneto/electro-encephalographic recordings and provide a formal interpretation of recent empirical results.

In this work we use numerical simulation to investigate how the temporal length of the data affects the reliability of the estimates of brain connectivity from EEG time-series. We assume that the neural sources follow a stable MultiVariate AutoRegressive model, and consider three connectivity metrics: imaginary part of coherency (IC), generalized partial directed coherence (gPDC) and frequency-domain granger causality (fGC). In order to assess the statistical significance of the estimated values, we use the surrogate data test by generating phase-randomized and autoregressive surrogate data. We first consider the ideal case where we know the source time courses exactly. Here we show how, expectedly, even exact knowledge of the source time courses is not sufficient to provide reliable estimates of the connectivity when the number of samples gets small; however, while gPDC and fGC tend to provide a larger number of false positives, the IC becomes less sensitive to the presence of connectivity. Then we proceed with more realistic simulations, where the source time courses are estimated using eLORETA, and the EEG signal is affected by biological noise of increasing intensity. Using the ideal case as a reference, we show that the impact of biological noise on IC estimates is qualitatively different from the impact on gPDC and fGC.

This paper studies a system of Ordinary Differential Equations modeling a chemical reaction network and derives from it a simulation tool mimicking Loss of Function and Gain of Function mutations found in cancer cells. More specifically, from a theoretical perspective, our approach focuses on the determination of moiety conservation laws for the system and their relation with the corresponding stoichiometric surfaces. Then we show that Loss of Function mutations can be implemented in the model via modification of the initial conditions in the system, while Gain of Function mutations can be implemented by eliminating specific reactions. Finally, the model is utilized to examine in detail the G1-S phase of a colorectal cancer cell.

Colorectal cancer (CRC) is one of the most deadly and commonly diagnosed tumors worldwide. Several genes are involved in its development and progression. The most frequent mutations concern APC, KRAS, SMAD4, and TP53 genes, suggesting that CRC relies on the concomitant alteration of the related pathways. However, with classic molecular approaches, it is not easy to simultaneously analyze the interconnections between these pathways. To overcome this limitation, recently these pathways have been included in a huge chemical reaction network (CRN) describing how information sensed from the environment by growth factors is processed by healthy colorectal cells. Starting from this CRN, we propose a computational model which simulates the effects induced by single or multiple concurrent mutations on the global signaling network. The model has been tested in three scenarios. First, we have quantified the changes induced on the concentration of the proteins of the network by a mutation in APC, KRAS, SMAD4, or TP53. Second, we have computed the changes in the concentration of p53 induced by up to two concurrent mutations affecting proteins upstreams in the network. Third, we have considered a mutated cell affected by a gain of function of KRAS, and we have simulated the action of Dabrafenib, showing that the proposed model can be used to determine the most effective amount of drug to be delivered to the cell. In general, the proposed approach displays several advantages, in that it allows to quantify the alteration in the concentration of the proteins resulting from a single or multiple given mutations. Moreover, simulations of the global signaling network of CRC may be used to identify new therapeutic targets, or to disclose unexpected interactions between the involved pathways.

Background: Magneto-and Electro-encephalography record the electromagnetic field generated by neural currents with high temporal frequency and good spatial resolution, and are therefore well suited for source localization in the time and in the frequency domain. In particular, localization of the generators of neural oscillations is very important in the study of cognitive processes in the healthy and in the pathological brain. New method: We introduce the use of a Bayesian multi-dipole localization method in the frequency domain. Given the Fourier Transform of the data at one or multiple frequencies and/or trials, the algorithm approximates numerically the posterior distribution with Monte Carlo techniques. Results: We use synthetic data to show that the proposed method behaves well under a wide range of experimental conditions, including low signal-to-noise ratios and correlated sources. We use dipole clusters to mimic the effect of extended sources. In addition, we test the algorithm on real MEG data to confirm its feasibility. Comparison with existing method(s): Throughout the whole study, DICS (Dynamic Imaging of Coherent Sources) is used systematically as a benchmark. The two methods provide similar general pictures; the posterior distributions of the Bayesian approach contain much richer information at the price of a higher computational cost. Conclusions: The Bayesian method described in this paper represents a reliable approach for localization of multiple dipoles in the frequency domain.