Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

SummaryCancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1+ CD11b+ cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1+ CD11b+ cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development—a finding that was dependent on CD8+ T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment

Evaluation of lymph node numbers for adequate staging of Stage II and III colon cancer

<p>Abstract</p> <p>Background</p> <p>Although evaluation of at least 12 lymph nodes (LNs) is recommended as the minimum number of nodes required for accurate staging of colon cancer patients, there is disagreement on what constitutes an adequate identification of such LNs.</p> <p>Methods</p> <p>To evaluate the minimum number of LNs for adequate staging of Stage II and III colon cancer, 490 patients were categorized into groups based on 1-6, 7-11, 12-19, and ≥ 20 LNs collected.</p> <p>Results</p> <p>For patients with Stage II or III disease, examination of 12 LNs was not significantly associated with recurrence or mortality. For Stage II (HR = 0.33; 95% CI, 0.12-0.91), but not for Stage III patients (HR = 1.59; 95% CI, 0.54-4.64), examination of ≥20 LNs was associated with a reduced risk of recurrence within 2 years. However, examination of ≥20 LNs had a 55% (Stage II, HR = 0.45; 95% CI, 0.23-0.87) and a 31% (Stage III, HR = 0.69; 95% CI, 0.38-1.26) decreased risk of mortality, respectively. For each six additional LNs examined from Stage III patients, there was a 19% increased probability of finding a positive LN (parameter estimate = 0.18510, p < 0.0001). For Stage II and III colon cancers, there was improved survival and a decreased risk of recurrence with an increased number of LNs examined, regardless of the cutoff-points. Examination of ≥7 or ≥12 LNs had similar outcomes, but there were significant outcome benefits at the ≥20 cutoff-point only for Stage II patients. For Stage III patients, examination of 6 additional LNs detected one additional positive LN.</p> <p>Conclusions</p> <p>Thus, the 12 LN cut-off point cannot be supported as requisite in determining adequate staging of colon cancer based on current data. However, a minimum of 6 LNs should be examined for adequate staging of Stage II and III colon cancer patients.</p

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis.

Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii) HLI-induced angiogenesis is improved in Il12rb2-/- mice, in ApoE-/-/Il12rb2-/- mice compared to WT and ApoE-/- controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase

Constraining least-square estimates with controlled dynamics enables robust parameter estimation in chaotic models.

A: Squared-difference between 10D Lorenz96 model trajectory x and measured data y, for various values of forcing parameter F, assuming that model was integrated forward from the true initial point. Only states x1, x4, x7, x10 were measured. The global minimum of C(F) (dotted line; F=8), resides in an extremely narrow basin of attraction within a highly nonconvex cost surface. B: Same as A, but for controlled dynamics (u = 4 and u = 15 for middle and right plots, respectively). Higher controls provide a far smoother cost function around the global minimum. C: 2D projection of the high-dimensional DSPE cost surface, along F in one dimension and the line Ul(tn)≡u, ∀l, n in the other. Here, xd(tn) were fixed at the values generated by integrating the model forward from its true initial state for the given F. D: Estimated trajectories of x8, using uncontrolled least squares (top; green) and DSPE (bottom; red). Black line: true trajectory. Shaded regions: SD of estimate across 100 random initializations of the optimization. E: Histogram of parameter estimates across 100 initializations of the optimization, for least squares (green) and DSPE (red).</p

The Dynamics of Nonlinear Inference

The determination of the hidden states of coupled nonlinear systems is frustrated by the presence of high-dimensionality, chaos, and sparse observability. This problem resides naturally in a Bayesian context: an underlying physical process produces a data stream, which -- though noisy and incomplete -- can in principle be inverted to express the likelihood of the underlying process itself. A large class of well-developed methods treat this problem in a sequential predict-and-correct manner that alternates information from the presumed dynamical model with information from the data. One might instead formulate this problem in a temporally global, non-sequential manner, which suggests new avenues of approach within an optimization context, but also poses new challenges in numerical implementation. The variational annealing (VA) technique is proposed to address these problems by leveraging an inherent separability between the convex and nonconvex contributions of the resulting functional forms. VA is shown to reliably track unobservable states in sparsely observed chaotic systems, as well as in minimally-observed biophysical neural models. Second, this problem can be formally cast in continuous time as a Wiener path integral, which then suggests classical solutions derived from Hamilton's principle. These solutions come with their own difficulties in that they comprise an unstable boundary-value problem. Accordingly, a further technique called Hamiltonian variational annealing is proposed, which again exploits an existing separability of convexity and nonlinearity, this time in a an enlarged manifold constrained by underlying symmetries. A running theme in this thesis is that the optimal estimate of a nonlinear system is itself a dynamical system that lives in an unstable, symplectic manifold. When this system is recast in a variational context, instability is manifested as nonconvexity, the central idea being that when this nonconvexity is incorporated in a systematic and gradual way, the classical solutions can be tracked reliably