Publications by authors named "Francesco Ciccarese"

17 Publications

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Comprehensive Profiling of Hypoxia-Related miRNAs Identifies miR-23a-3p Overexpression as a Marker of Platinum Resistance and Poor Prognosis in High-Grade Serous Ovarian Cancer.

Cancers (Basel) 2021 Jul 4;13(13). Epub 2021 Jul 4.

Angelo Nocivelli' Institute of Molecular Medicine, ASST Spedali Civili di Brescia, University of Brescia, 25121 Brescia, Italy.

The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance.
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http://dx.doi.org/10.3390/cancers13133358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268862PMC
July 2021

Genetic perturbation of IFN-α transcriptional modulators in human endothelial cells uncovers pivotal regulators of angiogenesis.

Comput Struct Biotechnol J 2020 2;18:3977-3986. Epub 2020 Dec 2.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, via Gattamelata 64, 35128 Padova, Italy.

Interferon-α (IFN-α) comprises a family of 13 cytokines involved in the modulation of antiviral, immune, and anticancer responses by orchestrating a complex transcriptional network. The activation of IFN-α signaling pathway in endothelial cells results in decreased proliferation and migration, ultimately leading to suppression of angiogenesis. In this study, we knocked-down the expression of seven established or candidate modulators of IFN-α response in endothelial cells to reconstruct a gene regulatory network and to investigate the antiangiogenic activity of IFN-α. This genetic perturbation approach, along with the analysis of interferon-induced gene expression dynamics, highlighted a complex and highly interconnected network, in which the angiostatic chemokine C-X-C Motif Chemokine Ligand 10 (CXCL10) was a central node targeted by multiple modulators. IFN-α-induced secretion of CXCL10 protein by endothelial cells was blunted by the silencing of Signal Transducer and Activator of Transcription 1 (STAT1) and of Interferon Regulatory Factor 1 (IRF1) and it was exacerbated by the silencing of Ubiquitin Specific Peptidase 18 (USP18). sprouting assay, which mimics angiogenesis, confirmed STAT1 as a positive modulator and USP18 as a negative modulator of IFN-α-mediated sprouting suppression. Our data reveal an unprecedented physiological regulation of angiogenesis in endothelial cells through a tonic IFN-α signaling, whose enhancement could represent a viable strategy to suppress tumor neoangiogenesis.
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http://dx.doi.org/10.1016/j.csbj.2020.11.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734228PMC
December 2020

Generation of Combinatorial Lentiviral Vectors Expressing Multiple Anti-Hepatitis C Virus shRNAs and Their Validation on a Novel HCV Replicon Double Reporter Cell Line.

Viruses 2020 09 18;12(9). Epub 2020 Sep 18.

Department of Molecular Medicine, University of Padua, 35121 Padua, Italy.

Despite the introduction of directly acting antivirals (DAAs), for the treatment of hepatitis C virus (HCV) infection, their cost, patient compliance, and viral resistance are still important issues to be considered. Here, we describe the generation of a novel JFH1-based HCV subgenomic replicon double reporter cell line suitable for testing different antiviral drugs and therapeutic interventions. This cells line allowed a rapid and accurate quantification of cell growth/viability and HCV RNA replication, thus discriminating specific from unspecific antiviral effects caused by DAAs or cytotoxic compounds, respectively. By correlating cell number and virus replication, we could confirm the inhibitory effect on the latter of cell over confluency and characterize an array of lentiviral vectors expressing single, double, or triple cassettes containing different combinations of short hairpin (sh)RNAs, targeting both highly conserved viral genome sequences and cellular factors crucial for HCV replication. While all vectors were effective in reducing HCV replication, the ones targeting viral sequences displayed a stronger antiviral effect, without significant cytopathic effects. Such combinatorial platforms as well as the developed double reporter cell line might find application both in setting-up anti-HCV gene therapy approaches and in studies aimed at further dissecting the viral biology/pathogenesis of infection.
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http://dx.doi.org/10.3390/v12091044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551853PMC
September 2020

Nanoparticles as Tools to Target Redox Homeostasis in Cancer Cells.

Antioxidants (Basel) 2020 Mar 4;9(3). Epub 2020 Mar 4.

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.

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.
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http://dx.doi.org/10.3390/antiox9030211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139659PMC
March 2020

Oncogenic pathways and the electron transport chain: a dangeROS liaison.

Br J Cancer 2020 01 10;122(2):168-181. Epub 2019 Dec 10.

Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.

Driver mutations in oncogenic pathways, rewiring of cellular metabolism and altered ROS homoeostasis are intimately connected hallmarks of cancer. Electrons derived from different metabolic processes are channelled into the mitochondrial electron transport chain (ETC) to fuel the oxidative phosphorylation process. Electrons leaking from the ETC can prematurely react with oxygen, resulting in the generation of reactive oxygen species (ROS). Several signalling pathways are affected by ROS, which act as second messengers controlling cell proliferation and survival. On the other hand, oncogenic pathways hijack the ETC, enhancing its ROS-producing capacity by increasing electron flow or by impinging on the structure and organisation of the ETC. In this review, we focus on the ETC as a source of ROS and its modulation by oncogenic pathways, which generates a vicious cycle that resets ROS levels to a higher homoeostatic set point, sustaining the cancer cell phenotype.
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http://dx.doi.org/10.1038/s41416-019-0651-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052168PMC
January 2020

Metabolic rewiring and redox alterations in malignant pleural mesothelioma.

Br J Cancer 2020 01 10;122(1):52-61. Epub 2019 Dec 10.

Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Malignant pleural mesothelioma (MPM) is a rare malignancy of mesothelial cells with increasing incidence, and in many cases, dismal prognosis due to its aggressiveness and lack of effective therapies. Environmental and occupational exposure to asbestos is considered the main aetiological factor for MPM. Inhaled asbestos fibres accumulate in the lungs and induce the generation of reactive oxygen species (ROS) due to the presence of iron associated with the fibrous silicates and to the activation of macrophages and inflammation. Chronic inflammation and a ROS-enriched microenvironment can foster the malignant transformation of mesothelial cells. In addition, MPM cells have a highly glycolytic metabolic profile and are positive in F-FDG PET analysis. Loss-of-function mutations of BRCA-associated protein 1 (BAP1) are a major contributor to the metabolic rewiring of MPM cells. A subset of MPM tumours show loss of the methyladenosine phosphorylase (MTAP) locus, resulting in profound alterations in polyamine metabolism, ATP and methionine salvage pathways, as well as changes in epigenetic control of gene expression. This review provides an overview of the perturbations in metabolism and ROS homoeostasis of MPM cells and the role of these alterations in malignant transformation and tumour progression.
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http://dx.doi.org/10.1038/s41416-019-0661-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964675PMC
January 2020

LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective.

Oxid Med Cell Longev 2019 31;2019:8730816. Epub 2019 Oct 31.

Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

Inactivating mutations of the tumor suppressor gene Liver Kinase B1 () are frequently detected in non-small-cell lung cancer (NSCLC) and cervical carcinoma. Moreover, LKB1 expression is epigenetically regulated in several tumor types. LKB1 has an established function in the control of cell metabolism and oxidative stress. Clinical and preclinical studies support a role of LKB1 as a central modifier of cellular response to different stress-inducing drugs, suggesting LKB1 pathway as a highly promising therapeutic target. Loss of LKB1-AMPK signaling confers sensitivity to energy depletion and to redox homeostasis impairment and has been associated with an improved outcome in advanced NSCLC patients treated with chemotherapy. In this review, we provide an overview of the interplay between LKB1 and its downstream targets in cancer and focus on potential therapeutic strategies whose outcome could depend from LKB1.
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http://dx.doi.org/10.1155/2019/8730816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874879PMC
April 2020

The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: A multicenter cohort study.

Liver Int 2019 08 26;39(8):1478-1489. Epub 2019 Jun 26.

Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients.

Patients And Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival.

Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT = 0.19 (0.18-0.20); RES = 0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT = 0.58 (0.55-0.61); SOR = 0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage.

Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage.
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http://dx.doi.org/10.1111/liv.14154DOI Listing
August 2019

Involvement of NADPH Oxidase 1 in Liver Kinase B1-Mediated Effects on Tumor Angiogenesis and Growth.

Front Oncol 2018 4;8:195. Epub 2018 Jun 4.

Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy.

The liver kinase B1 () gene is a tumor suppressor with an established role in the control of cell metabolism and oxidative stress. However, whether dis-regulated oxidative stress promotes growth of LKB1-deficient tumors remains substantially unknown. Through studies, we observed that loss of LKB1 perturbed expression of several genes involved in reactive oxygen species (ROS) homeostasis. In particular, this analysis evidenced strongly up-modulated NADPH oxidase 1 () transcript levels in tumor cells lacking LKB1. NOX1 accounted in part for enhanced cytotoxic effects of HO-induced oxidative stress in A549 LKB1-deficient tumor cells. Notably, genetic and pharmacologic inhibition of NOX1 activity reduced angiogenesis and growth of A549 tumors in mice. These results suggest that NOX1 inhibitors could counteract ROS production and the angiogenic switch in LKB1-deficient tumors.
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http://dx.doi.org/10.3389/fonc.2018.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994402PMC
June 2018

Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting.

Biochim Biophys Acta Mol Cell Res 2018 08 8;1865(8):1114-1129. Epub 2018 May 8.

Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padua, Italy. Electronic address:

Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40 large tumor antigen-derived cNLS (KKRK, P2-5). Indeed, all hydrophobic substitutions in place of R impaired binding to IMPα and nuclear targeting, with the largest effect exerted by a G residue at P4. Substitution of R with neutral hydrophobic residues caused the loss of electrostatic and van der Waals interactions between the P4 residue side chains and IMPα. Detailed bioinformatics analysis confirmed the importance of the P4 residue for cNLS function across the human proteome, with specific residues such as G being associated with low activity. Furthermore, we validate our findings for two additional cNLSs from human cytomegalovirus (HCMV) DNA polymerase catalytic subunit UL54 and processivity factor UL44, where a G residue at P4 results in a 2-3-fold decrease in NLS activity. Our results thus showed that the P4 residue makes a hitherto poorly appreciated contribution to nuclear import efficiency, which is essential to determining the precise nuclear levels of cargoes.
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http://dx.doi.org/10.1016/j.bbamcr.2018.05.006DOI Listing
August 2018

Escaping Death: Mitochondrial Redox Homeostasis in Cancer Cells.

Front Oncol 2017 9;7:117. Epub 2017 Jun 9.

Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.

Reactive oxygen species (ROS) are important signaling molecules that act through the oxidation of nucleic acids, proteins, and lipids. Several hallmarks of cancer, including uncontrolled proliferation, angiogenesis, and genomic instability, are promoted by the increased ROS levels commonly found in tumor cells. To counteract excessive ROS accumulation, oxidative stress, and death, cancer cells tightly regulate ROS levels by enhancing scavenging enzymes, which are dependent on the reducing cofactor nicotinamide adenine dinucleotide phosphate (NADPH). This review focuses on mitochondrial ROS homeostasis with a description of six pathways of NADPH production in mitochondria and a discussion of the possible strategies of pharmacological intervention to selectively eliminate cancer cells by increasing their ROS levels.
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http://dx.doi.org/10.3389/fonc.2017.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465272PMC
June 2017

LKB1 Expression Correlates with Increased Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Chemotherapy and Bevacizumab.

Clin Cancer Res 2017 07 24;23(13):3316-3324. Epub 2017 Jan 24.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

LKB1 is a key sensor of metabolic stress, including hypoxia and glucose deprivation, two features of the tumor microenvironment exacerbated by antiangiogenic therapy. We investigated the role of LKB1 as a potential predictive marker of sensitivity to bevacizumab in advanced non-small cell lung cancer (aNSCLC). We retrospectively analyzed LKB1 expression by IHC in 98 samples from 125 patients with aNSCLC, including 59 patients treated with chemotherapy and 39 treated with chemotherapy plus bevacizumab. IHC intensity was recoded in two classes (negative/weak vs. moderate/intense) and correlated with outcome according to treatment arm. Patient-derived tumor xenografts (PDXs) were used to investigate mechanisms involved in preclinical models. In the whole study population (125), median OS and PFS were 11.7 [95% confidence interval (CI), 9.1-15.3] and 6.7 (95% CI, 5.7-7.2) months, respectively. Differential impact of the marker on outcome of the 98 patients was highlighted according to the treatment. Patients with negative/weak LKB1 status did not have a statistically significant benefit from bevacizumab added to chemotherapy (HR for patients treated with bevacizumab: 0.89; 95% CI, 0.51-1.56; = 0.6803), whereas patients expressing moderate/intense LKB1 and receiving bevacizumab had significant lower risk of death compared with those not receiving bevacizumab (HR, 0.26; 95% CI, 0.10-0.64; = 0.0035). Loss of LKB1 was associated with reduced AMPK activation in PDXs and increased tumor necrosis following bevacizumab administration, highlighting impaired control of the metabolic stress caused by this antiangiogenic drug. Our data hint at a possible predictive impact of LKB1 expression in patients with aNSCLC treated with chemotherapy plus bevacizumab. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-2410DOI Listing
July 2017

Reconstruction of gene regulatory modules from RNA silencing of IFN-α modulators: experimental set-up and inference method.

BMC Genomics 2016 Mar 12;17:228. Epub 2016 Mar 12.

Department of Information Engineering, University of Padova, via Gradenigo 6/B, 35131, Padova, Italy.

Background: Inference of gene regulation from expression data may help to unravel regulatory mechanisms involved in complex diseases or in the action of specific drugs. A challenging task for many researchers working in the field of systems biology is to build up an experiment with a limited budget and produce a dataset suitable to reconstruct putative regulatory modules worth of biological validation.

Results: Here, we focus on small-scale gene expression screens and we introduce a novel experimental set-up and a customized method of analysis to make inference on regulatory modules starting from genetic perturbation data, e.g. knockdown and overexpression data. To illustrate the utility of our strategy, it was applied to produce and analyze a dataset of quantitative real-time RT-PCR data, in which interferon-α (IFN-α) transcriptional response in endothelial cells is investigated by RNA silencing of two candidate IFN-α modulators, STAT1 and IFIH1. A putative regulatory module was reconstructed by our method, revealing an intriguing feed-forward loop, in which STAT1 regulates IFIH1 and they both negatively regulate IFNAR1. STAT1 regulation on IFNAR1 was object of experimental validation at the protein level.

Conclusions: Detailed description of the experimental set-up and of the analysis procedure is reported, with the intent to be of inspiration for other scientists who want to realize similar experiments to reconstruct gene regulatory modules starting from perturbations of possible regulators. Application of our approach to the study of IFN-α transcriptional response modulators in endothelial cells has led to many interesting novel findings and new biological hypotheses worth of validation.
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http://dx.doi.org/10.1186/s12864-016-2525-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788926PMC
March 2016

Hepatitis C virus and host cell nuclear transport machinery: a clandestine affair.

Front Microbiol 2015 19;6:619. Epub 2015 Jun 19.

Department of Molecular Medicine, University of Padua , Padua, Italy.

There is growing evidence that factors encoded by cytoplasmic replicating viruses functionally interact with components of the nucleocytoplasmic transport apparatus. They do so either to access the cell nucleus, thus affecting genes expression, or to interfere with nuclear transport functionality, hindering host immune response. Recent studies revealed that the hepatitis C virus (HCV) makes no exception, interacting with the host cell nuclear transport machinery at two different levels. On the one hand, small amounts of both core and NS5A localize within the host cell nucleus during productive infection, modulating gene expression and signaling functions to promote persistent infection. On the other hand, HCV infection causes a profound redistribution of certain nucleoproteins to the close proximity of endoplasmic reticulum membrane-derived viral replication factories, where viral RNA amplification occurs. These nucleoporins are believed to form nuclear pore complex-like structures, as suggested by their ability to recruit nuclear localization sequence-bearing proteins. Thus, both processes are linked to virus-induced persistence and pathogenesis, representing possible targets for the development of novel anti-HCV therapeutics.
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http://dx.doi.org/10.3389/fmicb.2015.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472997PMC
July 2015

VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells.

Cancer Res 2015 Jan 7;75(1):120-33. Epub 2014 Nov 7.

Istituto Oncologico Veneto, IRCCS, Padova, Italy.

Anti-VEGF therapy perturbs tumor metabolism, severely impairing oxygen, glucose, and ATP levels. In this study, we investigated the effects of anti-VEGF therapy in multiple experimental tumor models that differ in their glycolytic phenotypes to gain insights into optimal modulation of the metabolic features of this therapy. Prolonged treatments induced vascular regression and necrosis in tumor xenograft models, with highly glycolytic tumors becoming treatment resistant more rapidly than poorly glycolytic tumors. By PET imaging, prolonged treatments yielded an increase in both hypoxic and proliferative regions of tumors. A selection for highly glycolytic cells was noted and this metabolic shift was stable and associated with increased tumor aggressiveness and resistance to VEGF blockade in serially transplanted mice. Our results support the hypothesis that the highly glycolytic phenotype of tumor cells studied in xenograft models, either primary or secondary, is a cell-autonomous trait conferring resistance to VEGF blockade. The finding that metabolic traits of tumors can be selected by antiangiogenic therapy suggests insights into the evolutionary dynamics of tumor metabolism.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2037DOI Listing
January 2015

[Successful management of severe unremitting chylothorax after thoraci trauma].

Ann Ital Chir 2007 Mar-Apr;78(2):125-7

Ospedale Luigi Sacco U.O.C Chirurgia Generale I, Milano.

Post-traumatic chylothorax needs surgical approach when conservative treatment is not successful to reduce chyle leakage. Thoracic duct ligation requires thoracoscopic or thoracotomic access. The authors report on a surgical thoracotomic approach to a severe and unremitting thoracic duct lesion after IX and X ribs and vertebral fractures.
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August 2007
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