Prognostic and therapeutic role of angiogenic microenvironment in thyroid cancer

Thyroid cancer is the most common endocrine malignancy, with a typically favorable prognosis following standard treatments, such as surgical resection and radioiodine therapy. A subset of thyroid cancers progress to refractory/metastatic disease. Understanding how the tumor microenvironment is transformed into an angiogenic microenvironment has a role of primary importance in the aggressive behavior of these neoplasms. During tumor growth and progression, angiogenesis represents a deregulated biological process, and the angiogenic switch, characterized by the formation of new vessels, induces tumor cell proliferation, local invasion, and hematogenous metastases. This evidence has propelled the scientific community’s effort to study a number of molecular pathways (proliferation, cell cycle control, and angiogenic processes), identifying mediators that may represent viable targets for new anticancer treatments. Herein, we sought to review angiogenesis in thyroid cancer and the potential role of proangiogenic cytokines for risk stratification of patients. We also present the current status of treatment of advanced differentiated, medullary, and poorly differentiated thyroid cancers with multiple tyrosine kinase inhibitors, based on the rationale of angiogenesis as a potential therapeutic target

Comparison of the isomerization mechanisms of human melanopsin and invertebrate and vertebrate rhodopsins

Comparative modeling and ab initio multiconfigurational quantum chemistry are combined to investigate the reactivity of the human nonvisual photoreceptor melanopsin. It is found that both the thermal and photochemical isomerization of the melanopsin 11-cis retinal chromophore occur via a space-saving mechanism involving the unidirectional, counterclockwise twisting of the =C11H-C12H= moiety with respect to its Lys340-linked frame as proposed by Warshel for visual pigments [Warshel A (1976) Nature 260(5553):679–683]. A comparison with the mechanisms documented for vertebrate (bovine) and invertebrate (squid) visual photoreceptors shows that such a mechanism is not affected by the diversity of the three chromophore cavities. Despite such invariance, trajectory computations indicate that although all receptors display less than 100 fs excited state dynamics, human melanopsin decays from the excited state ∼40 fs earlier than bovine rhodopsin. Some diversity is also found in the energy barriers controlling thermal isomerization. Human melanopsin features the highest computed barrier which appears to be ∼2.5 kcal mol(−1) higher than that of bovine rhodopsin. When assuming the validity of both the reaction speed/quantum yield correlation discussed by Warshel, Mathies and coworkers [Weiss RM, Warshel A (1979) J Am Chem Soc 101:6131–6133; Schoenlein RW, Peteanu LA, Mathies RA, Shank CV (1991) Science 254(5030):412–415] and of a relationship between thermal isomerization rate and thermal activation of the photocycle, melanopsin turns out to be a highly sensitive pigment consistent with the low number of melanopsin-containing cells found in the retina and with the extraretina location of melanopsin in nonmammalian vertebrates

Mapping the excited state potential energy surface of a retinal chromophore model with multireference and EOM-CC methods

The photoisomerization of the retinal chromophore of visual pigments proceeds along a complex reaction coordinate on a multidimensional surface that comprises a hydrogen-out-of-plane (HOOP) coordinate, a bond length alternation (BLA) coordinate, a single bond torsion and, finally, the reactive double bond torsion. These degrees of freedom are coupled with changes in the electronic structure of the chromophore and, therefore, the computational investigation of the photochemistry of such systems requires the use of a methodology capable of describing electronic structure changes along all those coordinates. Here, we employ the penta-2,4-dieniminium (PSB3) cation as a minimal model of the retinal chromophore of visual pigments and compare its excited state isomerization paths at the CASSCF and CASPT2 levels of theory. These paths connect the cis isomer and the trans isomer of PSB3 with two structurally and energetically distinct conical intersections (CIs) that belong to the same intersection space. MRCISD+Q energy profiles along these paths provide benchmark values against which other ab initio methods are validated. Accordingly, we compare the energy profiles of MRPT2 methods (CASPT2, QD-NEVPT2, and XMCQDPT2) and EOM-SF-CC methods (EOM-SF-CCSD and EOM-SF-CCSD(dT)) to the MRCISD+Q reference profiles. We find that the paths produced with CASSCF and CASPT2 are topologically and energetically different, partially due to the existence of a “locally excited” region on the CASPT2 excited state near the Franck–Condon point that is absent in CASSCF and that involves a single bond, rather than double bond, torsion. We also find that MRPT2 methods as well as EOM-SF-CCSD(dT) are capable of quantitatively describing the processes involved in the photoisomerization of systems like PSB3

Characterization and model parameters of large commercial supercapacitor cells

The paper reports the results of the test and modelling activities carried out on large commercial supercapacitor cells at high current. Four commercials cells, with rated capacitance of 3000 F and rated voltage of 2.7 V, are considered. All cells are submitted to consecutive charge/discharge cycles at constant current. A test current in the range 80-130 A is used, which is comparable with the maximum operating current (up to 150 A) that the cells can reach in practical operations. A circuit model of the cells, able to reproduce the most relevant dynamic behavior, with a good compromise between accuracy, simplicity and robustness of the model’s parameters, is also developed and validated against the experimental data. It is shown that all the investigated commercial cells are characterized by similar phenomena and comply with the same circuit model. Moreover, it is shown that the circuit parameters of the cells are in the same range and are weakly dependent on the test current. The obtained circuit parameters are accurately reported for all the cells and made fully accessible to user

Telemedicine DSS-AI Multi Level Platform for Monoclonal Gammopathy Assistance

The proposed work describes preliminary results of a research project based on the realization of a Decision Support System -DSS- platform embedding medical and artificial intelligence -AI- algorithms. Specifically the telemedicine platform is suitable for the optimization of assistance processes of patients affected by Monoclonal Gammopaty. The results are related to the whole design of the platform implementing a DSS based on a multi-level decision making process. Starting from the main architecture specifications, is formulated a flowchart based on different alerting levels of patient risk including artificial intelligence -AI- decision supporting facilities. Finally, the perspectives of the performed research are discussed

Shape of Multireference, EOM-CC, and DFT Potential Energy Surfaces at a Conical Intersection

We report and characterize ground-state and excited-state potential energy profiles using a variety of electronic structure methods along a loop lying on the branching plane associated with a conical intersection (CI) of a reduced retinal model, the penta-2,4-dieniminium cation (PSB3). Whereas the performance of the equation-of-motion coupled-cluster, density functional theory, and multireference methods had been tested along the excited and ground state paths of PSB3 in our earlier work, the ability of these methods to correctly describe the potential energy surface shape along a CI branching plane has not yet been investigated. This is the focus of the present contribution. We find, in agreement with earlier studies by others, that standard TDDFT does not yield the correct two-dimensional (i.e., conical) crossing along the branching plane but rather a one-dimensional (i.e., linear) crossing along the same plane. The same type of behavior is found for SS-CASPT2(IPEA=0), SS-CASPT2(IPEA=0.25), spin-projected SF-TDDFT, EOM-SF-CCSD and, finally, for the reference MRCISD+Q method. In contrast, we found that MRCISD, CASSCF, MS-CASPT2(IPEA=0), MS-CASPT2(IPEA=0.25), XMCQDPT2, QD-NEVPT2, non spin-projected SF-TDDFT, and SI-SA-REKS yield the expected conical crossing. To assess the effect of the different crossing topologies (i.e., linear or conical) on the PSB3 photoisomerization efficiency, we discuss the results of 100 semi-classical trajectories computed by CASSCF and SS-CASPT2(IPEA=0.25) for a PSB3 derivative. We show that for the the same initial conditions, the two methods yield similar dynamics leading to isomerization quantum yields that differ by only a few percent

Effect of thyroidectomy on circulating angiogenic cytokines in papillary thyroid carcinoma and benign goiter: Potential for new biomarkers?

Background: Circulating angiogenic factors have been associated with clinical outcomes of papillary thyroid carcinoma, although they may also be released in the context of benign multinodular goiter. We sought to investigate the effect of thyroidectomy on the activity and importance of multiple circulating angiogenic factors in papillary thyroid carcinoma and benign multinodular goiter. Methods: Between May 2015 and December 2016, patients scheduled for total thyroidectomy for papillary thyroid carcinoma or benign multinodular goiter were offered to enroll in this study. Serum levels of angiopoietin-2, fibroblast growth factor-2, hepatocyte growth factor, platelet-derived growth factor-BB, placenta growth factor, heparin-binding epidermal growth factor, and vascular endothelial growth factor-A and -C were collected preoperatively and 2 weeks postsurgery. These levels were measured by enzyme-linked immunosorbent assay and compared with those of 35 healthy control subjects. Results: Sixty patients with a median age of 52 years, 37 of whom were females, were included: 36 had papillary thyroid carcinoma, and 24 had benign multinodular goiter. In both benign multinodular goiter and papillary thyroid carcinoma, preoperative, circulating angiogenic factors levels were increased with respect to controls (P < .0001), and a decrease after total thyroidectomy was observed in the levels of angiopoietin-2 (P < .0001), fibroblast growth factor-2 (P < .0001), hepatocyte growth factor (P < .001), and heparin-binding epidermal growth factor (P < .01 each). Only patients with papillary thyroid carcinomas, however, showed decrease in the postoperative levels of platelet-derived growth factor-BB and vascular endothelial growth factor-A (P = .001 each). Conclusion: Results from this study raise the potential for vascular endothelial growth factor-A and platelet-derived growth factor-BB to be used as biomarkers of the effectiveness of treatment of papillary thyroid carcinoma. These results warrant further investigation and may have potential prognostic implications