1,720,995 research outputs found
Biomarker discovery by proteomics-based approaches for early detection and personalized medicine in colorectal cancer
No full textAbout one million people per year develop colorectal cancer (CRC) and approximately half of them die. The extent of the disease (i.e. local invasion at the time of diagnosis) is a key prognostic factor. The 5-year survival rate is almost 90% in the case of delimited CRC and 10% in the case of metastasized CRC. Hence, one of the great challenges in the battle against CRC is to improve early diagnosis strategies. Large-scale proteomic approaches are widely used in cancer research to search for novel biomarkers. Such biomarkers can help in improving the accuracy of the diagnosis and in the optimization of personalized therapy. Herein, we provide an overview of studies published in the last 5 years on CRC that led to the identification of protein biomarkers suitable for clinical application by using proteomic approaches. We discussed these findings according to biomarker application, including also the role of protein phosphorylation and cancer stem cells in biomarker discovery. Our review provides a cross section of scientific approaches and can furnish suggestions for future experimental strategies to be used as reference by scientists, clinicians and researchers interested in proteomics for biomarker discovery
COVIDomics: Metabolomic Views on COVID-19
No full textDuring the COVID-19 pandemic, omics-based methodologies were extensively used to study the pathological mechanisms of SARS-CoV-2 infection and replication in human cells at a large scale [...
Interaction with 14-3-3 θ reduces AF4 transactivation function by inhibiting its nuclear translocation
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14-3-3 θ over-expression increases both the cytosolic amount of AF4 and the expression levels of its target genes.
No full textThe human AF4 gene is involved in the t(4;11)(q21;q23) translocation that causes acute lymphoblastic leukemia. AF4 is a transcriptional activator implicated in early lymphoid development. It is a crucial component of a nuclear protein complex that promotes transcription elongation and chromatin remodeling. Noteworthy, AF4 function is regulated by phosphorylation and its cellular levels by proteasomal degradation. In a previous study aimed to analyze the AF4 function and regulation, we found that AF4 over-expression promotes transcription of several genes (like PTPRA, GRB2, BRD7, etc.) involved in different pathways, in HEK-293 cells. Moreover, we demonstrated that AF4 directly interacts with the scaffold protein 14-3-3 θ, which belongs to a family of proteins that bind phosphorylated target proteins and regulate variously their function. To identify the AF4-responding genes in hematopoietic cell lines, we ectopically expressed AF4 in the K562 mielogenous leukemia cells. Real-time PCR analysis showed increased expression of specific transcripts in K562 as well as in HEK-293 cells. We also evaluated the potential role of 14-3-3 θ in regulating the AF4 function. To this aim, we ectopically expressed 14-3-3 θ in K562 cells and measured transcription levels of the AF4-responding genes previously identified. We observed that 14-3-3 θ over-expression greatly stimulates transcription of these genes. Moreover, we found that the cytosolic amount of AF4 significantly increased, while nuclear levels slightly decreased. These data suggest that 14-3-3 θ binds and stabilizes AF4 in cytosol, probably by impairing its proteasomal degradation. Additional anal
Tools and Avenues for Nanotechnology-based Vectors Exploitation for Biomarker Signature and Therapeutical Drug Delivery
No full textNanomedicine main goal is to ameliorate biodistribution and side effects of therapeutics. Proper Micro (MP) and Nanoparticles (NP) can i) protect therapeutic molecules from reticuloendothelial clearance, ii) transport them to the site of action minimizing their influence on normal tissues and iii) enhance drug concentration and effects in target tissues and cells, allowing the use of lower doses. However a single component nanovector cannot accomplish all those duties; therefore, our efforts are focused on the optimization and performance evaluation of multi-component drug-delivering nanosystems, made of silica, silicon, polymers, lipids and proteins from synthetic and biological sources. In recent years, the groups in Naples and in Houston in cooperation have studied many different strategies which permit MP and NP to overcome one or more biological barriers (BB) that hamper the delivery of therapeutics to the desired site of action. The two research groups have produced a series of results which will be briefly summarized in this report and then discussed in greater detail in the talk.
1) Diverse types of Multistage vector (MSV) were produced and used to enhance the delivery of free and encapsulated drugs in cellular and mice models of cancer. MSV is constituted by a silicon mesoporous microparticle which protect nanoparticles or free drugs from reticuloendothelial clearance, superbly marginates toward vessel walls and preferentially accumulates on inflamed endothelium [1-3].
2) A Biomimetic drug delivery platform was produced with a nanoporous silicon core and and a shell derived from the leukocyte cell membrane. This Leukolike vector (LLV) and it’s therapeutic potentialities were extensively investigated in vitro and in vivo, from a biological and biochemical point of view. LLV shows the ability to: 1) evade the immune system; 2) circulate longer in the blood stream; 3) communicate with endothelial cells through receptor–ligand interactions increasing endothelium permeability; 4) transport and release a payload across inflamed endothelium; 5) accumulate in a tumour [4-7].
3) Innovative microfluidic systems were developed to mimick blood capillary circulation, in order to study and to predict the in flow dynamics and the margination tendency of different types of MP, also in presence of blood cells, using real human blood as circulating solution [8].
4) Enzyme-functionalized silica NPs were conceived and produced to digest tumor extracellular matrix, in vitro and in vivo achieving a better penetration in the tumoral tissue [9].
5) pH-responsive hybrid nanoparticles (HNP) were conceived, produced, characterized and successfully used to achieve efficient siRNA delivery in cell culture and in mice models of human breast cancer. HNP are constituted by a shell of cationic hydrogel able to electrostatically bind siRNA and by a supporting nanostructured core of silica that provides mechanical stability to the system. HNP are able to escape from endolysosomal compartment through a proton sponge effect [5,10].
In the light of what has been briefly outlined, the following avenues will be pursued in the near future and will be discussed:
(i) Production and evaluation of different types of MSV for cancer therapy
(ii) Protein and peptide functionalization of NPs to enhance tumor recognition and penetration
(iii) Production and evaluation of different types of NP for siRNA delivery
(iv) Production of Organ-on-chip microfluidic devices able to study and predict the fluidic and biological performance of MP and NP.
(v) Characterization of plasma Protein Corona (PC) [11] of MP and NP by proteomic approaches and correlations between PC composition and targeting of specific tissues.
References
[1] Tasciotti E, Liu X, Bhavane R, Plant K, Leonard AD, Price BK, Cheng MM, Decuzzi P, Tour JM, Robertson F, Ferrari M. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. Nat Nanotechnol 3, 151-7 (2008).
[2] Martinez JO, Evangelopoulos M, Karun V, Shegog E, Wang JA, Boada C, Liu X, Ferrari M, Tasciotti E. The effect of multistage nanovector targeting of VEGFR2 positive tumor endothelia on cell adhesion and local payload accumulation. Biomaterials 35, 9824-32 (2014).
[3] Martinez JO, Evangelopoulos M, Bhavane R, Acciardo S, Salvatore F, Liu X, Ferrari M, Tasciotti E. Multistage Nanovectors Enhance the Delivery of Free and Encapsulated Drugs. Drug Targets [Epub ahead of print] (2014).
[4] Parodi A, Quattrocchi N, van de Ven AL, Chiappini C, Evangelopoulos M, Martinez JO, Brown BS, Khaled SZ, Yazdi IK, Enzo MV, Isenhart L, Ferrari M, Tasciotti E. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol 8,61-8 (2013).
[5] Parodi A, Corbo C, Cevenini A, Molinaro R, Palomba R, Pandolfi L, Agostini M, Salvatore F, Tasciotti E. Enabling cytoplasmic delivery and organelle targeting by surface modification of nanocarriers. Nanomedicine UK 10,1923-40 (2015).
[6] Corbo C, Parodi A, Evangelopoulos M, Engler DA, Matsunami RK, Engler AC, Molinaro R, Scaria S, Salvatore F, Tasciotti E. Proteomic profiling of a biomimetic drug delivery platform. Curr Drug Targets [Epub ahead of print] (2014).
[7] Palomba R, Parodi A, Evangelopoulos M, Acciardo S, Corbo C, De Rosa E, Yazdi I, Scaria S, Salvatore F, Tasciotti E. A leukolike vector increase the permeability of tumor vasculature. Submitted.
[8] D'Apolito R, Tomaiuolo G, Taraballi F, Minardi S, Kirui D, Liu X, Cevenini A, Palomba R, Ferrari M, Salvatore F, Tasciotti E, Guido S. Red blood cells affect the margination of microparticles in synthetic microcapillaries and intravital microcirculation as a function of their size and shape. J Control Release [Epub ahead of print] (2015).
[9] Parodi A, Haddix SG, Taghipour N, Scaria S, Taraballi F, Cevenini A, Yazdi IK, Corbo C, Palomba R, Khaled SZ, Martinez JO, Brown BS, Isenhart L, Tasciotti E. Bromelain surface modification increases the diffusion of silica nanoparticles in the tumor extracellular matrix. ACS Nano 8,9874-83 (2014).
[10] Khaled SZ, Cevenini A, Yazdi IK, Parodi A, Evangelopoulos M, Corbo C, Scaria S, Hu Y, Chiappini C, Haddix SG, Corradetti B, Salvatore F, Tasciotti E. One-pot synthesis of pH-responsive hybrid nanogel particles for the intracellular delivery of small interfering RNA. Under review for pubblication in Biomaterials.
[11] Corbo C, Molinaro R, Parodi A, Toldeno Furman NE, Salvatore F, Tasciotti E. The impact of the protein corona on nanoparticles and implications for toxicity, immunotoxicity and target drug delivery. Under review for publication in Nanomedicine UK
Interleukin-1 receptor-associated kinase 1 (IRAK1) and Heat shock protein 90 kDa alpha B1 (HSP90) are up-regulated by AF4.
No full textUnraveling the structural and functional features of an aldolase A mutant involved in the hemolytic anemia and severe rhabdomyolysis reported in a child
No full textCorrespondence. No abstract. We demonstrated that a very rare aldolase A natural mutation, which changes a C-terminal amino acid residue, provokes a structural alteration that causes a temperature-dependent enzyme deficiency
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