THE ROLE OF IMAGING BIOMARKERS DERIVED FROM PET/CT STUDIES IN DIAGNOSIS, THERAPY AND PROGNOSIS OF CANCER PATIENTS

Imaging biomarkers are features derived from one or more medical images; when validated, they can be used in the diagnosis, staging, prognosis and evaluation of treatment response of cancer patients. All imaging modalities including PET/CT, CT and MRI can allow the identification and quantitative evaluation of imaging biomarkers. The aim of this thesis was to analyze PET/CT studies performed with 18F-FDG or 68Ga-DOTA-TOC in different groups of cancer patients in order to derive imaging biomarkers and to test their role in the diagnosis, evaluation of treatment response and prognosis of various types of malignancies. The thesis will provide an overview of the studies conducted in each group of patients with non-small cell lung cancer, multiple myeloma and lymphoma, thymic epithelial tumors and neuroendocrine tumors during my PhD program

Apeced in Turkey: a case report and insights on genetic and phenotypic variability

APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies

Load following with Small Modular Reactors (SMR): A real options analysis

Load following is the potential for a power plant to adjust its power output as demand and price for electricity fluctuates throughout the day. In nuclear power plants, this is done by inserting control rods into the reactor pressure vessel. This operation is very inefficient as nuclear power generation is composed almost entirely of fixed and sunk costs; therefore, lowering the power output doesn't significantly reduce generating costs and the plant is thermo-mechanical stressed. A more efficient solution is to maintain the primary circuit at full power and to use the excess power for cogeneration. This paper assesses the technical-economic feasibility of this approach when applied to Small Modular Reactors (SMR) with two cogeneration technologies: algae-biofuel and desalinisation. Multiple SMR are of particular interest due to the fractional nature of their power output. The result shows that the power required by an algae-biofuel plant is not sufficient to justify the load following approach, whereas it is in the case of desalination. The successive economic analysis, based on the real options approach, demonstrates the economic viability of the desalination in several scenarios. In conclusion, the coupling of SMR with a desalination plant is a realistic solution to perform efficient load following

A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11

Meiosis is the biological process that, after a cycle of DNA replication, halves the cellular chromosome complement, leading to the formation of haploid gametes. Haploidization is achieved via two successive rounds of chromosome segregation, meiosis I and II. In mammals, during prophase of meiosis I, homologous chromosomes align and synapse through a recombination-mediated mechanism initiated by the introduction of DNA double-strand breaks (DSBs) by the SPO11 protein. In male mice, if SPO11 expression and DSB number are reduced below heterozygosity levels, chromosome synapsis is delayed, chromosome tangles form at pachynema, and defective cells are eliminated by apoptosis at epithelial stage IV at a spermatogenesis-specific endpoint. Whether DSB levels produced in Spo11 +/− spermatocytes represent, or approximate, the threshold level required to guarantee successful homologous chromosome pairing is unknown. Using a mouse model that expresses Spo11 from a bacterial artificial chromosome, within a Spo11 −/− background, we demonstrate that when SPO11 expression is reduced and DSBs at zygonema are decreased (approximately 40 % below wild-type level), meiotic chromosome pairing is normal. Conversely, DMC1 foci number is increased at pachynema, suggesting that under these experimental conditions, DSBs are likely made with delayed kinetics at zygonema. In addition, we provide evidences that when zygotene-like cells receive enough DSBs before chromosome tangles develop, chromosome synapsis can be completed in most cells, preventing their apoptotic elimination

Pavlovian threat learning shapes the kinematics of action

Prompt response to environmental threats is critical to survival. Previous research has revealed mechanisms underlying threat-conditioned physiological responses, but little is known about how threats shape action. Here we tested if threat learning shapes the kinematics of reaching in human adults. In two different experiments conducted on independent samples of participants, after Pavlovian threat learning, in which a stimulus anticipated the delivery of an aversive shock, whereas another did not, the peak velocity and acceleration of reaching increased for the shocked-paired stimulus, relative to the unpaired one. These kinematic changes appeared as a direct consequence of learning, emerging even in absence of an actual threat to body integrity, as no shock occurred during reaching. Additionally, they correlated with the strength of sympathetic response during threat learning, establishing a direct relationship between previous learning and subsequent changes in action. The increase in velocity and acceleration of action following threat learning may be adaptive to facilitate the implementation of defensive responses. Enhanced action invigoration may be maladaptive, however, when defensive responses are inappropriately enacted in safe contexts, as exemplified in a number of anxiety-related disorders

Molecular beacon-decorated polymethylmethacrylate core-shell fluorescent nanoparticles for the detection of survivin mRNA in human cancer cells.

One of the main goals of nanomedicine in cancer is the development of effective drug delivery systems, primarily nanoparticles. Survivin, an overexpressed anti-apoptotic protein in cancer, represents a pharmacological target for therapy and a Molecular Beacon (MB) specific for survivin mRNA is available. In this study, the ability of polymethylmethacrylate nanoparticles (PMMA-NPs) to promote survivin MB uptake in human A549 cells was investigated. Fluorescent and positively charged core PMMA-NPs of nearly 60nm, obtained through an emulsion co-polymerization reaction, and the MB alone were evaluated in solution, for their analytical characterization; then, the MB specificity and functionality were verified after adsorption onto the PMMA-NPs. The carrier ability of PMMA-NPs in A549 was examined by confocal microscopy. With the optimized protocol, a hardly detectable fluorescent signal was obtained after incubation of the cells with the MB alone (fluorescent spots per cell of 1.90±0.40 with a mean area of 1.04±0.20µm2), while bright fluorescent spots inside the cells were evident by using the MB loaded onto the PMMA-NPs. (27.50±2.30 fluorescent spots per cell with a mean area of 2.35±0.16µm2). These results demonstrate the ability of the PMMA-NPs to promote the survivin-MB internalization, suggesting that this complex might represent a promising strategy for intracellular sensing and for the reduction of cancer cell proliferation

Microgravity Promotes Differentiation and Meiotic Entry of Postnatal Mouse Male Germ Cells

A critical step of spermatogenesis is the entry of mitotic spermatogonia into meiosis. Progresses on these topics are hampered by the lack of an in vitro culture system allowing mouse spermatogonia differentiation and entry into meiosis. Previous studies have shown that mouse pachytene spermatocytes cultured in simulated microgravity (SM) undergo a spontaneous meiotic progression. Here we report that mouse mitotic spermatogonia cultured under SM with a rotary cell culture system (RCCS) enter into meiosis in the absence of any added exogenous factor or contact with somatic cells. We found that isolated Kit-positive spermatogonia under the RCCS condition enter into the prophase of the first meiotic division (leptotene stage), as monitored by chromosomal organization of the synaptonemal complex 3 protein (Scp3) and up-regulation of several pro-meiotic genes. SM was found to activate the phosphatidyl inositol 3 kinase (PI3K) pathway and to induce in Kit-positive spermatogonia the last round of DNA replication, typical of the preleptotene stage. A PI3K inhibitor abolished Scp3 induction and meiotic entry stimulated by RCCS conditions. A positive effect of SM on germ cell differentiation was also observed in undifferentiated (Kit-negative) spermatogonia, in which RCCS conditions stimulate the expression of Kit and Stra8. In conclusion, SM is an artificial environmental condition which promotes postnatal male germ cell differentiation and might provide a tool to study the molecular mechanisms underlying the switch from mitosis to meiosis in mammals

Diagnosis, Management and Theragnostic Approach of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms

Abstract: Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) constitute an ideal target for radiolabeled somatostatin analogs. The theragnostic approach is able to combine diagnosis and therapy by the identification of a molecular target that can be diagnosed and treated with the same radiolabeled compound. During the last years, advances in functional imaging with the introduction of somatostatin analogs and peptide receptor radionuclide therapy, have improved the diagnosis and treatment of GEP-NENs. Moreover, PET/CT imaging with 18F-FDG represents a complementary tool for prognostic evaluation of patients with GEP-NENs. In the field of personalized medicine, the theragnostic approach has emerged as a promising tool in diagnosis and management of patients with GEP-NENs. The aim of this review is to summarize the current evidence on diagnosis and management of patients with GEP-NENs, focusing on the theragnostic approach

The cyclic peptide G4CP2 enables the modulation of galactose metabolism in yeast by interfering with GAL4 transcriptional activity

Genetically-encoded combinatorial peptide libraries are convenient tools to identify peptides to be used as therapeutics, antimicrobials and functional synthetic biology modules. Here, we report the identification and characterization of a cyclic peptide, G4CP2, that interferes with the GAL4 protein, a transcription factor responsible for the activation of galactose catabolism in yeast and widely exploited in molecular biology. G4CP2 was identified by screening CYCLIC, a Yeast Two-Hybrid-based combinatorial library of cyclic peptides developed in our laboratory. G4CP2 interferes with GAL4-mediated activation of galactose metabolic enzymes both when expressed intracellularly, as a recombinant peptide, and when provided exogenously, as a chemically-synthesized cyclic peptide. Our results support the application of G4CP2 in microbial biotechnology and, additionally, demonstrate that CYCLIC can be used as a tool for the rapid identification of peptides, virtually without any limitations with respect to the target protein. The possible biotechnological applications of cyclic peptides are also discussed