Mapping The Excited State Potential Energy Surface Of A Retinal Chromophore Model With Multireference And Equation-of-motion Coupled-cluster 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

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

Multiple Myeloma: Risk Factors, Diagnosis and Treatments

Angiogenesis is a constant hallmark of multiple myeloma progression and has prognostic potential. Multiple myeloma cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype, both at primary and secondary tumor sites. The pathophysiology of multiple myeloma-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. A direct involvement of bone marrow macrophages and mast cells in vasculogenic mimicry has been demonstrated, thus contributing together with circulating endothelial cells and endothelial precursor cells to the multiple myeloma neovascularization. The role of host cells or the niche microenvironment and extracellular matrix represents an intense area of research, finalized at a better understanding of the pathophysiological modifications of the complete tumor entity, i.e. malignant cells and microenvironment

New Drugs and New Strategies for the Treatment of Multiple Myeloma Patients

Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly. Near the old active classes of drugs: alkylators (e.g., melphalan and cyclophosphamide), corticosteroids (e.g., prednisone and dexamethasone), and anthracyclines (e.g., doxorubicin), new drug formulations (e.g., liposomal doxorubicin) and new active classes of drugs such as proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs (e.g., thalidomide and lenalidomide) have been introduced in myeloma therapy. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. High response rates and good quality responses with a long-term disease control can be observed with the introduction of new drugs. Changes in treatment strategies due to the introduction of novel drugs have been able to improve significantly the quality of responses. In fact, if in the past, Complete Remission (CR) in MM was rare to achieve, while the introduction of new treatments have increased the rate in younger patients as well as in non-transplant setting. CR represents a surrogated marker of long survival. It correlates with the long-term Progression-Free Survival (PFS) and Overall Survival (OS). Achieving CR and sustaining CR within a 3-year landmark from the treatment initiation is associated with highly superior survival. Actually, we agree that ―The more profound the remission, the longer the duration of response‖. Moreover, the interactions between tumor cells and their bone marrow microenvironment play a pivotal role in myeloma progression, inducing also drug resistance. This knowledge has improved treatment options leading to the approval of new drugs which target the malignant cell itself and also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control but their use is still not approved outside of clinical trials

Clinical and experimental evidences of anti-myeloma activities of zolendronic acid

The biphosphonate zoledronic acid is indicated for the treatment of patients with osteolytic lesions from multiple myeloma for the prevention of skeletal related events. In patients with multiple myeloma the clonal expansion of plasma cells in the bone marrow results in the disruption of the homeostasis within the bone marrow microenvironment. Interactions between myeloma cells and bone marrow stromal cells directly increase growth and survival of myeloma cells through the dysregulation of growth factors and cytokines and accelerate the destruction of the bone. Thus, most of multiple myeloma patients develop osteolytic bone lesions, which are often associated with bone pain and skeletal-related events which include spinal cord compression, pathologic fractures, or the need for surgery or radiation to the bone. Bisphosphonates are effective inhibitors of osteoclastic bone resorption. In-vitro evidences suggest that bisphosphonates may also have an antimyeloma activity. Furthermore, they may synergize with anticancer agents used in the treatment of myeloma. Recent clinical data show a survival advantage for high-risk patients receiving zoledronic acid concurrently with antimyeloma therapies. This review summerizes the antimyeloma benefits of zoledronic acid combined with new drugs for the treatment of multiple myeloma patients

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