Tyrosine kinase inhibitors reprogramming immunity in renal cell carcinoma: rethinking cancer immunotherapy

Review article[Abstract] The immune system regulates angiogenesis in cancer by way of both pro- and antiangiogenic activities. A bidirectional link between angiogenesis and the immune system has been clearly demonstrated. Most antiangiogenic molecules do not inhibit only VEGF signaling pathways but also other pathways which may affect immune system. Understanding of the role of these pathways in the regulation of immunosuppressive mechanisms by way of specific inhibitors is growing. Renal cell carcinoma (RCC) is an immunogenic tumor in which angiogenesis and immunosuppression work hand in hand, and its growth is associated with impaired antitumor immunity. Given the antitumor activity of selected TKIs in metastatic RCC (mRCC), it seems relevant to assess their effect on the immune system. The confirmation that TKIs improve cell cytokine response in mRCC provides a basis for the rational combination and sequential treatment of TKIs and immunotherapy

Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death

Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion, or cell death. However, calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA, MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by calreticulin membrane translocation, as determined by functional knockdown of calreticulin, PERK, or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy

Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment

Tasquinimod (a quinoline-3-carboxyamide) is a small molecule immunotherapy with demonstrated effects on the tumor microenvironment (TME) involving immunomodulation, anti-angiogenesis and inhibition of metastasis. A target molecule of tasquinimod is the inflammatory protein S100A9 which has been shown to affect the accumulation and function of suppressive myeloid cell subsets in tumors. Given the major impact of myeloid cells to the tumor microenvironment, manipulation of this cell compartment is a desirable goal in cancer therapeutics

Company Evaluation & Succession Planning of a family business

Linea Alessandro is a boutique in the center of Lenzburg, specialized in exclusive Italian fashion brands. Currently, the company counts its 37th year of business and enjoys great trust and loyalty from their clients. In regard to the age of the founders, who are approaching retirement, the question surges what strategic options are available in order to extract an economically attractive succession or exit solution. Since both sons are not planning to enter into the succession of the company, the founders are forced to find family-extern solutions for the succession of Linea Alessandro

Su una estensione del principio di Lagrange d'Alembert per un fluido viscoso relativistico

In this paper we show that it is possible to estabilish an autonomous formulation of the Lagrange-d’Alembert principle for a relativistic viscous fiuid in absence of mass forces. Rather it will be possible to obtain the indefinite equations starting from it

On Thermodynamical Kluitenberg Theory in General Relativity

In this paper, we introduce Kluitenberg’s formulation of non-equilibrium thermodynamics with internal variables in the context of a Riemannian space, as required by Einstein’s general relativity. Using the formulation of the second law of thermodynamics in general coordinates with a pseudo-Euclidean metric, we derive a Levi-Civita-like energy tensor and propose a generalization of the second law within a Riemannian space, in agreement with Tolman’s approach. In addition, we determine the expression for the entropy density in a general Riemannian space and identify the new variables upon which it depends. This allows us to deduce, within this framework, the equilibrium inelastic and viscous stress tensors as well as the entropy production. These expressions are consistent with the principle of general covariance and Einstein’s equivalence principle

Relativistic phenomenological equations and transformation laws of relative coefficients

The aim of this paper is to derive the phenomenological equations in the context of special relativistic non-equilibrium thermodynamics with internal variables. In particular, after introducing some results developed in our previous paper, by means of classical non-equilibrium thermodynamic procedure and under suitable assumptions on the entropy density production, the phenomenological equations and transformation laws of phenomenological coefficients are derived. Finally, some symmetries of aforementioned coefficients are obtained