Justice and Forced Migration: Beyond the Open Borders Debate

This work is composed of two main parts. Part I is composed of four chapters. Chapter 1 offers a critical overview of the interdisciplinary debate on what counts as forced migration and who is a refugee. It argues that scholars tend to attribute much of the normative salience of concepts such as those of forced migration and refugees to their implications for admission policies in closed borders scenarios. Chapter 2 considers what makes forced migration harmful and distinctively different from voluntary migration. Referring to empirical qualitative works and narratives of forced migrants\u2019 displacement experiences, it illustrates four kinds of harms related to forced displacement: namely, losses of control, the loss of what I call the \u201cHome environment\u201d, losses in social status and material wealth, and a loss of mental wellbeing. Such harms apply also to forced migrants who do not experience restrictions to freedom of movement (e.g., in the case of internal displacement or when borders have been opened). Thus, forced migration remains normatively relevant even when admission is not an issue. Chapter 3 argues that what forced migrants need once displaced depends on the specific harms of displacement. The harms of displacement distinctively undermine the fundamental interests that all human beings share in having place and purpose, which provide the conditions for a dignified, minimally flourishing life. Thus, forced migrants have distinctive claim rights, analogous to human rights, to the fulfilment of the needs that derive from the harms of displacement. Chapter 4 moves to the issue of who is responsible for addressing the specific needs of forced migrants and how. I argue that not only states of origin but also external states and non-state actors often individually or jointly contribute to forced displacement. Agents whose actions caused displacement or contributed to processes and structures causing displacement bear reparative responsibility towards those who have been harmed by displacement. Therefore, meeting the needs of forced migrants is not just a matter of humanitarian obligations, but rather an issue of justice. Finally, I propose three principles that policies should respect to count as reparations for the harms of displacement: namely, the specificity, continuity, and expressivity principles. Based on this theoretical frame, part II explores three case studies. Chapter 5 is devoted to forced displacement in Colombia, which counts the largest number of internally displaced people worldwide. The chapter explores displacement underlying causes, shows how the specific harms suffered by Colombian forced migrants shape their needs and illustrates how current policy approaches fail to adequately recognise and repair those harms. Chapter 6 looks at a form of forced migration taking place across borders in a regional free-movement area, namely intra\u2013European Union trafficking for labour exploitation. Finally, chapter 7 is devoted to forced migration from Syria. The chapter adopts a harms-based approach to responsibility and to needs assessment and it illustrates shortcomings even in the policy of a European state, namely Germany, which has been praised for its generosity and efficiency in providing admission and integration to Syrian forced migrants

Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?

This Special Issue in Biomolecules explores the roles of Transient Receptor Potential channels (TRPs) in cancer. The main goal is to collect articles that describe recent progress in elucidating the mechanisms by which these channels modulate tumor progression

Editorial: Calcium signaling in cancer immunity.

Not availabl

Axitinib induces DNA damage response leading to senescence, mitotic catastrophe, and increased NK cell recognition in human renal carcinoma cells.

Tyrosine kinase inhibitors (TKIs) including axitinib have been introduced in the treatment of renal cell carcinoma (RCC) because of their anti-angiogenic properties. However, no evidence are presently available on a direct cytotoxic anti-tumor activity of axitinib in RCC.Herein we reported by western blot analysis that axitinib treatment induces a DNA damage response (DDR) initially characterized by γ-H2AX phosphorylation and Chk1 kinase activation and at later time points by p21 overexpression in A-498 and Caki-2 RCC cells although with a different potency. Analysis by immunocytochemistry for the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine in cellular DNA and flow cytometry using the redox-sensitive fluorescent dye DCFDA, demonstrated that DDR response is accompanied by the presence of oxidative DNA damage and reactive oxygen species (ROS) generation. This response leads to G2/M cell cycle arrest and induces a senescent-like phenotype accompanied by enlargement of cells and increased senescence-associated β-galactosidase activity, which are abrogated by N-acetyl cysteine (NAC) pre-treatment. In addition, axitinib-treated cells undergo to cell death through mitotic catastrophe characterized by micronucleation and abnormal microtubule assembly as assessed by fluorescence microscopy.On the other hand, axitinib, through the DDR induction, is also able to increase the surface NKG2D ligand expression. Accordingly, drug treatment promotes NK cell recognition and degranulation in A-498 RCC cells in a ROS-dependent manner.Collectively, our results indicate that both cytotoxic and immunomodulatory effects on RCC cells can contribute to axitinib anti-tumor activity

Capsaicin triggers autophagic cell survival which drives epithelial mesenchymal transition and chemoresistance in bladder cancer cells in an Hedgehog-dependent manner

Bladder cancer (BC) is a common urologic tumor characterized by high risk of recurrence and mortality. Capsaicin (CPS), used as an intravesical drug for overactive bladder, was demonstrated to induce cell death in different cancer cells including BC cells.Here we found that treatment of high-grade BC cells with high dose of CPS triggers autophagy. Infact, the CPS treatment alters the redox homeostasis by inducing production of radicals, mitochondrial depolarization, alterations of ADP/ATP ratio and activation of AMPK pathway stimulating the autophagic process in BC cells. The inhibition of autophagy, by using the specific inhibitor bafilomycin A or Beclin 1 knock-down, enhanced the CPS-induced cell death, demonstrating that CPS-induced autophagy acts as a pro-survival process in BC cells. By using PCR arrays and FACS analysis, we found that the CPS-treated BC cells displayed typical mesenchymal features of the epithelial mesenchymal transition (EMT) as elongated shape and over-expression of vimentin, α5 and β1 integrin subunits, integrin-like kinase and the anti-apoptotic Bcl-2 proteins. Moreover, we demonstrated that CPS treatment stimulates upregulation of Dhh/Ptch2/Zeb2 members of the Hedgehog signaling pathway, increases CD24, VEGFA and TIMP1 and decreases CD44 and ALCAM mRNA expression levels. By PTCH2 knock-down we found that the Hedgehog signaling pathway is involved in the CPS-induced autophagy and EMT phenotype.Finally, we also showed that the CPS-resistant EMT-positive BC cells displayed an increased drug-resistance to the cytotoxic effects of mitomycin C, gemcitabine and doxorubicine drugs commonly used in BC therapy

Axitinib induces senescence-associated cell death and necrosis in glioma cell lines: The proteasome inhibitor, bortezomib, potentiates axitinib-induced cytotoxicity in a p21(Waf/Cip1) dependent manner.

Glioblastoma is associated with a poor overall survival despite new treatment advances. Antiangiogenic strategies targeting VEGF based on tyrosine kinase inhibitors (TKIs) are currently undergoing extensive research for the treatment of glioma. Herein we demonstrated that the TKI axitinib induces DNA damage response (DDR) characterized by γ-H2AX phosphorylation and Chk1 kinase activation leading to G2/M cell cycle arrest and mitotic catastrophe in U87, T98 and U251 glioma cell lines. Moreover, we found that p21(Waf1/Cip1) increased levels correlates with induction of ROS and senescence-associated cell death in U87 and T98 cell lines, which are reverted by N-acetyl cysteine pretreatment. Conversely, U251 cell line showed a resistant phenotype in response to axitinib treatment, as evidenced by cell cycle arrest but no sign of cell death. The combinatorial use of axitinib with other therapies, with the aim of inhibiting multiple signaling pathways involved in tumor growth, can increase the efficiency of this TKI. Thus, we addressed the combined effects of axitinib with no toxic doses of the proteasome inhibitor bortezomib on the growth of U87 and T98 axitinib- sensitive and axitinib-resistant U251 cell lines. Compared to single treatments, combined exposure was more effective in inhibiting cell viability of all glioma cell lines, although with different cell death modalities. The regulation of key DDR and cell cycle proteins, including Chk1, γ-H2AX and p21(Waf1/Cip1) was also studied in glioma cell lines. Collectively, these findings provide new perspectives for the use of axitinib in combination with Bortezomib to overcome the therapy resistance in gliomas

What is new about somatosensory evoked potentials as neurological predictors of comatose survivors after cardiac arrest

n/

Cannabidiol stimulates AML-1a-dependent glial differentiation and inhibits glioma stem-like cells proliferation by inducing autophagy in a TRPV2-dependent manner

Glioma stem-like cells (GSCs) correspond to a tumor cell subpopulation, involved in glioblastoma multiforme (GBM) tumor ini- tiation and acquired chemoresistance. Currently, drug-induced differentiation is considered as a promising approach to eradi- cate this tumor-driving cell population. Recently, the effect of cannabinoids (CBs) in promoting glial differentiation and inhibiting gliomagenesis has been evidenced. Herein, we demonstrated that cannabidiol (CBD) by activating transient receptor potential vanilloid-2 (TRPV2) triggers GSCs differentiation activating the autophagic process and inhibits GSCs proliferation and clonogenic capability. Above all, CBD and carmustine (BCNU) in combination overcome the high resistance of GSCs to BCNU treatment, by inducing apoptotic cell death. Acute myeloid leukemia (Aml-1) transcription factors play a pivotal role in GBM proliferation and differentiation and it is known that Aml-1 control the expression of several nociceptive receptors. So, we evaluated the expression levels of Aml-1 spliced variants (Aml-1a, b and c) in GSCs and during their differentiation. We found that Aml-1a is upregulated during GSCs differentiation, and its downregulation restores a stem cell phenotype in differ- entiated GSCs. Since it was demonstrated that CBD induces also TRPV2 expression and that TRPV2 is involved in GSCs differ- entiation, we evaluated if Aml-1a interacted directly with TRPV2 promoters. Herein, we found that Aml-1a binds TRPV2 promoters and that Aml-1a expression is upregulated by CBD treatment, in a TRPV2 and PI3K/AKT dependent manner. Alto- gether, these results support a novel mechanism by which CBD inducing TRPV2-dependent autophagic process stimulates Aml-1a-dependent GSCs differentiation, abrogating the BCNU chemoresistance in GSCs

Nucleophilic ring opening of 1,2-epoxides in aqueous medium

n/