Detection of circulating immunosuppressive cytokines in malignant pleural mesothelioma patients for prognostic stratification.

BACKGROUND: No data on circulating biomarkers for the prognostic stratification of Malignant Pleural Mesothelioma (MPM) patients are available. We prospectively explored the prognostic role of circulating monocyte and cytokine levels and their dynamic change during chemotherapy. PATIENTS AND METHODS: MPM patients receiving a first line treatment based on a platinum compound plus pemetrexed were eligible. Blood samples were collected at the baseline and at the end of induction chemotherapy. CCL-2, IL-10 and TGF-ß levels in plasma were quantified by Enzyme-Linked Immunosorbent Assay (ELISA); white blood cells, monocytes and platelets were evaluated by blood count test. RESULTS: Thirty-one patients were included in the study. Median overall survival (OS) was 12.13 months versus 9.6 months in patients with lower and higher monocytes count, respectively (p value = 0.02). We further stratified patients according to a combined score based on the association of IL-10, TGF-ß levels and monocytes count. High combined score was associated with shorter OS and PFS in univariate and multivariate analysis. Chemotherapy induced an increase in monocytes, IL-10, but not TGF-ß levels. CONCLUSION: The prognostic value of circulating levels of multiple immunosuppressive cytokines and inflammatory cells should be confirmed in a wider validation set of MPM patients.

Functional properties and sequence variation of HTLV-1 p13.

Human T cell leukemia virus type-1 (HTLV-1) was the first retrovirus found to cause cancer in humans, but the mechanisms that drive the development of leukemia and other diseases associated with HTLV-1 infection remain to be fully understood. This review describes the functional properties of p13, an 87-amino acid protein coded by HTLV-1 open reading frame II (orf-II). p13 is mainly localized in the inner membrane of the mitochondria, where it induces potassium (K+) influx and reactive oxygen species (ROS) production, which can trigger either proliferation or apoptosis, depending on the ROS setpoint of the cell. Recent evidence indicates that p13 may influence the cell's innate immune response to viral infection and the infected cell phenotype. Association of the HTLV-1 transcriptional activator, Tax, with p13 increases p13's stability, leads to its partial co-localization with Tax in nuclear speckles, and reduces the ability of Tax to interact with the transcription cofactor CBP/p300. Comparison of p13 sequences isolated from HTLV-1-infected individuals revealed a small number of amino acid variations in the domains controlling the subcellular localization of the protein. Disruptive mutations of p13 were found in samples obtained from asymptomatic patients with low proviral load. p13 sequences of HTLV-1 subtype C isolates from indigenous Australian patients showed a high degree of identity among each other, with all samples containing a pattern of 5 amino acids that distinguished them from other subtypes. Further characterization of p13's functional properties and sequence variants may lead to a deeper understanding of the impact of p13 as a contributor to the clinical manifestations of HTLV-1 infection.

The COQ2 genotype predicts the severity of coenzyme Q10 deficiency.

COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q10 (CoQ) biosynthesis. Its mutations represent a frequent cause of primary CoQ deficiency and have been associated with the widest clinical spectrum, ranging from fatal neonatal multisystemic disease to late-onset encephalopathy. However, the reasons of this variability are still unknown.We have characterized the structure of human COQ2, defined its subcellular localization and developed a yeast model to validate all the mutant alleles reported so far.Our findings show that the main functional transcript of COQ2 is shorter than what was previously reported and that its protein product localizes to mitochondria with the C-terminus facing the intermembrane space. Complementation experiments in yeast showed that the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients.We defined the structure of COQ2 with relevant implications for mutation screening in patients and demonstrated that, contrary to other COQ gene defects such as ADCK3, there is a correlation between COQ2 genotype and patient's phenotype.

Expression of Alternatively Spliced Human T-Cell Leukemia Virus Type 1 mRNAs Is Influenced by Mitosis and by a Novel cis-Acting Regulatory Sequence.

UNLABELLED: Human T-cell leukemia virus type 1 (HTLV-1) expression depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of viral expression. In the present study, we investigated the Rex dependence of the complete set of alternatively spliced HTLV-1 mRNAs. Analyses of cells transfected with Rex-wild-type and Rex-knockout HTLV-1 molecular clones using splice site-specific quantitative reverse transcription (qRT)-PCR revealed that mRNAs encoding the p30Tof, p13, and p12/8 proteins were Rex dependent, while the p21rex mRNA was Rex independent. These findings provide a rational explanation for the intermediate-late temporal pattern of expression of the p30tof, p13, and p12/8 mRNAs described in previous studies. All the Rex-dependent mRNAs contained a 75-nucleotide intronic region that increased the nuclear retention and degradation of a reporter mRNA in the absence of other viral sequences. Selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) analysis revealed that this sequence formed a stable hairpin structure. Cell cycle synchronization experiments indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. These findings indicate a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system. IMPORTANCE: HTLV-1 is a complex retrovirus that causes two distinct pathologies termed adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-1-associated myelopathy in about 5% of infected individuals. Expression of the virus depends on the concerted action of Tax, which drives transcription of the viral genome, and Rex, which favors expression of incompletely spliced mRNAs and determines a 2-phase temporal pattern of virus expression. The findings reported in this study revealed a novel cis-acting regulatory element and indicated that mitosis partially bypasses the requirement for Rex to export Rex-dependent HTLV-1 transcripts. Our results add a layer of complexity to the mechanisms controlling the expression of alternatively spliced HTLV-1 mRNAs and suggest a link between the cycling properties of the host cell and the temporal pattern of viral expression/latency that might influence the ability of the virus to spread and evade the immune system.

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy.

Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virus-encoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

Oncolytic activity of avian influenza virus in human pancreatic ductal adenocarcinoma cell lines.

UNLABELLED: Pancreatic ductal adenocarcinoma (PDA) is the most lethal form of human cancer, with dismal survival rates due to late-stage diagnoses and a lack of efficacious therapies. Building on the observation that avian influenza A viruses (IAVs) have a tropism for the pancreas in vivo, the present study was aimed at testing the efficacy of IAVs as oncolytic agents for killing human PDA cell lines. Receptor characterization confirmed that human PDA cell lines express the alpha-2,3- and the alpha-2,6-linked glycan receptor for avian and human IAVs, respectively. PDA cell lines were sensitive to infection by human and avian IAV isolates, which is consistent with this finding. Growth kinetic experiments showed preferential virus replication in PDA cells over that in a nontransformed pancreatic ductal cell line. Finally, at early time points posttreatment, infection with IAVs caused higher levels of apoptosis in PDA cells than gemcitabine and cisplatin, which are the cornerstone of current therapies for PDA. In the BxPC-3 PDA cell line, apoptosis resulted from the engagement of the intrinsic mitochondrial pathway. Importantly, IAVs did not induce apoptosis in nontransformed pancreatic ductal HPDE6 cells. Using a model based on the growth of a PDA cell line as a xenograft in SCID mice, we also show that a slightly pathogenic avian IAV significantly inhibited tumor growth following intratumoral injection. Taken together, these results are the first to suggest that IAVs may hold promise as future agents of oncolytic virotherapy against pancreatic ductal adenocarcinomas. IMPORTANCE: Despite intensive studies aimed at designing new therapeutic approaches, PDA still retains the most dismal prognosis among human cancers. In the present study, we provide the first evidence indicating that avian IAVs of low pathogenicity display a tropism for human PDA cells, resulting in viral RNA replication and a potent induction of apoptosis in vitro and antitumor effects in vivo. These results suggest that slightly pathogenic IAVs may prove to be effective for oncolytic virotherapy of PDA and provide grounds for further studies to develop specific and targeted viruses, with the aim of testing their efficacy in clinical contexts.

Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases.

OBJECTIVE: Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood. METHODS: Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy. RESULTS: The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells. CONCLUSIONS: SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

Kinetics and intracellular compartmentalization of HTLV-1 gene expression: nuclear retention of HBZ mRNAs.

Human T-cell leukemia virus type 1 (HTLV-1) codes for 9 alternatively spliced transcripts and 2 major regulatory proteins named Tax and Rex that function at the transcriptional and posttranscriptional levels, respectively. We investigated the temporal sequence of HTLV-1 gene expression in primary cells from infected patients using splice site-specific quantitative RT-PCR. The results indicated a two-phase kinetics with the tax/rex mRNA preceding expression of other viral transcripts. Analysis of mRNA compartmentalization in cells transfected with HTLV-1 molecular clones demonstrated the strict Rex-dependency of the two-phase kinetics and revealed strong nuclear retention of HBZ mRNAs, supporting their function as noncoding transcripts. Mathematical modeling underscored the importance of a delay between the functions of Tax and Rex, which was supported by experimental evidence of the longer half-life of Rex. These data provide evidence for a temporal pattern of HTLV-1 expression and reveal major differences in the intracellular compartmentalization of HTLV-1 transcripts.

Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus.

New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL.

Redox regulation of T-cell turnover by the p13 protein of human T-cell leukemia virus type 1: distinct effects in primary versus transformed cells.

The present study investigated the function of p13, a mitochondrial protein of human T-cell leukemia virus type 1 (HTLV-1). Although necessary for viral propagation in vivo, the mechanism of function of p13 is incompletely understood. Drawing from studies in isolated mitochondria, we analyzed the effects of p13 on mitochondrial reactive oxygen species (ROS) in transformed and primary T cells. In transformed cells (Jurkat, HeLa), p13 did not affect ROS unless the cells were subjected to glucose deprivation, which led to a p13-dependent increase in ROS and cell death. Using RNA interference we confirmed that expression of p13 also influences glucose starvation-induced cell death in the context of HTLV-1-infected cells. ROS measurements showed an increasing gradient from resting to mitogen-activated primary T cells to transformed T cells (Jurkat). Expression of p13 in primary T cells resulted in their activation, an effect that was abrogated by ROS scavengers. These findings suggest that p13 may have a distinct impact on cell turnover depending on the inherent ROS levels; in the context of the HTLV-1 propagation strategy, p13 could increase the pool of "normal" infected cells while culling cells acquiring a transformed phenotype, thus favoring lifelong persistence of the virus in the host.

MiR-150 in HTLV-1 infection and T-cell transformation.

Human T-cell leukemia virus-1 (HTLV-1) is a retrovirus that persistently infects CD4+ T-cells, and is the causative agent of adult T-cell leukemia/lymphoma (ATLL), tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and several inflammatory diseases. T-cell transformation by HTLV-1 is driven by multiple interactions between viral regulatory proteins and host cell pathways that govern cell proliferation and survival. Studies performed over the last decade have revealed alterations in the expression of many microRNAs in HTLV-1-infected cells and ATLL cells, and have identified several microRNA targets with roles in the viral life cycle and host cell turnover. This review centers on miR-150-5p, a microRNA whose expression is temporally regulated during lymphocyte development and altered in several hematological malignancies. The levels of miR-150-5p are reduced in many HTLV-1-transformed- and ATLL-derived cell lines. Experiments in these cell lines showed that downregulation of miR-150-5p results in activation of the transcription factor STAT1, which is a direct target of the miRNA. However, data on miR-150-5p levels in freshly isolated ATLL samples are suggestive of its upregulation compared to controls. These apparently puzzling findings highlight the need for more in-depth studies of the role of miR-150-5p in HTLV-1 infection and pathogenesis based on knowledge of miR-150-5p-target mRNA interactions and mechanisms regulating its function in normal leukocytes and hematologic neoplasms.

mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells.

mTOR activation is a hallmark of T-cell acute lymphoblastic leukemia (T-ALL) and is associated with resistance to glucocorticoid (GC)-based chemotherapy. We previously showed that altering redox homeostasis primes T-ALL cells to GC-induced apoptosis. Here we investigated the connection between the mTOR pathway and redox homeostasis using pharmacological inhibitors and gene silencing. In vitro studies performed on T-ALL cell lines and CG-resistant patient-derived T-ALL xenograft (PDX) cells showed that the mTOR inhibitor everolimus increased reactive oxygen species (ROS) levels, augmented lipid peroxidation, and activated the ROS-controlled transcription factor NRF2. These effects were accompanied by a decrease in the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), which is a major source of cytosolic NADPH needed for maintaining the cellular ROS-scavenging capacity. The mTOR inhibitor everolimus induced mitochondrial inner membrane depolarization and dose-dependent apoptosis of T-ALL cells, but did not kill normal T-cells. Importantly, the combination of everolimus and the GC dexamethasone had a synergistic effect on killing T-ALL cells. The effects of mTOR inhibition were blunted by ROS scavengers and phenocopied by siRNA-mediated G6PD silencing. In vivo studies of NOD/SCID mice inoculated with refractory T-ALL PDX demonstrated that everolimus overcame dexamethasone resistance in conditions of high tumor burden that mimicked the clinical setting of acute leukemia. These findings provide insight into the crosstalk between mTOR and ROS homeostasis in T-ALL cells and furnish mechanistic evidence to support the combination of glucocorticoids with mTOR inhibitors as a therapeutic avenue for treating refractory T-ALL.

Near infrared photoimmunotherapy targeting the cutaneous lymphocyte antigen for mycosis fungoides.

Background: Mycosis fungoides (MF) is a low-grade T-cell lymphoma with primary cutaneous involvement accounting for more than half of all primary cutaneous lymphomas. The treatment of MF is very challenging due to the limited therapies available. Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and highly selective cancer treatment that employs a monoclonal antibody conjugated to a photo-absorber dye, the hydrophilic phthalocyanine IRdye 700DX® (IR700), and near infrared light. In this study, we investigated the effect of NIR-PIT on MF targeting the cell-surface antigen cutaneous lymphocyte antigen (CLA)Matherial and methods: MF derived My-La CD4+ cells were incubated with the anti-CLA antibody conjugated to IR700 and then irradiated with a 690 nm near-infrared light. Cell death was evaluated by propidium iodide staining and flow cytometry 24 hours after irradiation.Results: Treatment with anti-CLA or light irradiation exhibited very modest pro-death effects, whereas treatment with the anti-CLA antibody conjugated to IR700 and then irradiation with a 690 nm near-infrared light induced a substantial increase in death in the MF cell line.Conclusions: NIR-PIT targeting CLA to treat MF showed marked antitumour effects. As such, CLA-targeted NIR-PIT could be a promising treatment for MF and, possibly, other cutaneous diseases characterized by CLA+ skin infiltrating T-cells.

The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers.

The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.

Modulation of mitochondrial K(+) permeability and reactive oxygen species production by the p13 protein of human T-cell leukemia virus type 1.

Human T-cell leukemia virus type-1 (HTLV-1) expresses an 87-amino acid protein named p13 that is targeted to the inner mitochondrial membrane. Previous studies showed that a synthetic peptide spanning an alpha helical domain of p13 alters mitochondrial membrane permeability to cations, resulting in swelling. The present study examined the effects of full-length p13 on isolated, energized mitochondria. Results demonstrated that p13 triggers an inward K(+) current that leads to mitochondrial swelling and confers a crescent-like morphology distinct from that caused by opening of the permeability transition pore. p13 also induces depolarization, with a matching increase in respiratory chain activity, and augments production of reactive oxygen species (ROS). These effects require an intact alpha helical domain and strictly depend on the presence of K(+) in the assay medium. The effects of p13 on ROS are mimicked by the K(+) ionophore valinomycin, while the protonophore FCCP decreases ROS, indicating that depolarization induced by K(+) vs. H(+) currents has different effects on mitochondrial ROS production, possibly because of their opposite effects on matrix pH (alkalinization and acidification, respectively). The downstream consequences of p13-induced mitochondrial K(+) permeability are likely to have an important influence on the redox state and turnover of HTLV-1-infected cells.

Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal adenocarcinoma.

Loss of menin, a tumor suppressor coded by the MEN1 gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MEN1 gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MEN1 microsatellite markers. Methylation of CpG sites in the MEN1 promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MEN1 gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.

Nanoparticles as Tools to Target Redox Homeostasis in Cancer Cells.

Reactive oxygen species (ROS) constitute a homeostatic rheostat that modulates signal transduction pathways controlling cell turnover. Most oncogenic pathways activated in cancer cells drive a sustained increase in ROS production, and cancer cells are strongly addicted to the increased activity of scavenging pathways to maintain ROS below levels that produce macromolecular damage and engage cell death pathways. Consistent with this notion, tumor cells are more vulnerable than their normal counterparts to pharmacological treatments that increase ROS production and inhibit ROS scavenging. In the present review, we discuss the recent advances in the development of integrated anticancer therapies based on nanoparticles engineered to kill cancer cells by raising their ROS setpoint. We also examine nanoparticles engineered to exploit the metabolic and redox alterations of cancer cells to promote site-specific drug delivery to cancer cells, thus maximizing anticancer efficacy while minimizing undesired side effects on normal tissues.

Targeting the cutaneous lymphocyte antigen (CLA) in inflammatory and neoplastic skin conditions.

Introduction: The cutaneous lymphocyte antigen interacts with E-selectin on endothelial cells and is expressed on 15% of circulating T-cells. Skin-homing T-cells express the cutaneous lymphocyte antigen and play a role in local cutaneous immunity in inflammatory reactions and neoplastic conditions.Areas covered: Lymphocyte extravasation is the essential para-physiological mechanism enabling immune surveillance of tissues for tumors as well as effector cell recruitment to inflammatory sites.The authors focused on skin inflammatory disorders, on cutaneous lymphoproliferative disease, and on other skin malignancies.Expert opinion: Interfering with leukocyte extravasation has been regarded as an attractive strategy in skin disorders, in the past for inflammatory conditions and more recently for cutaneous T-cell lymphomas. Therapeutic blocking of skin-homing interactions has been attempted in psoriasis and atopic dermatitis and has been achieved in the treatment of cutaneous T-cell lymphomas. Cutaneous lymphocyte antigen is a potential molecular target for both systemic and skin-directed therapy for cutaneous T-cell lymphomas.

Rewiring of Lipid Metabolism and Storage in Ovarian Cancer Cells after Anti-VEGF Therapy.

Anti-angiogenic therapy triggers metabolic alterations in experimental and human tumors, the best characterized being exacerbated glycolysis and lactate production. By using both Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) analysis, we found that treatment of ovarian cancer xenografts with the anti-Vascular Endothelial Growth Factor (VEGF) neutralizing antibody bevacizumab caused marked alterations of the tumor lipidomic profile, including increased levels of triacylglycerols and reduced saturation of lipid chains. Moreover, transcriptome analysis uncovered up-regulation of pathways involved in lipid metabolism. These alterations were accompanied by increased accumulation of lipid droplets in tumors. This phenomenon was reproduced under hypoxic conditions in vitro, where it mainly depended from uptake of exogenous lipids and was counteracted by treatment with the Liver X Receptor (LXR)-agonist GW3965, which inhibited cancer cell viability selectively under reduced serum conditions. This multi-level analysis indicates alterations of lipid metabolism following anti-VEGF therapy in ovarian cancer xenografts and suggests that LXR-agonists might empower anti-tumor effects of bevacizumab.

Mitochondrial Proteins Coded by Human Tumor Viruses.

Viruses must exploit the cellular biosynthetic machinery and evade cellular defense systems to complete their life cycles. Due to their crucial roles in cellular bioenergetics, apoptosis, innate immunity and redox balance, mitochondria are important functional targets of many viruses, including tumor viruses. The present review describes the interactions between mitochondria and proteins coded by the human tumor viruses human T-cell leukemia virus type 1, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, human hepatitis viruses B and C, and human papillomavirus, and highlights how these interactions contribute to viral replication, persistence and transformation.