Una perspectiva mecánica sobre la estabilidad del enlace químico

Tesis inédita de la Universidad Complutense de Madrid. Facultad de Ciencias Químicas, leída el 16-12-2019This PhD was devoted to demonstrating that the nature and intrinsic features of a given pairwise interaction (covalent, electrostatic, van der Waals, etc.) defines a suitable framework to relate both molecular and bulk properties. To reach this goal, we have considered classical, well-established concepts from the field of condensed matter and translated them into the molecular realm, and vice versa. Pairwise interactions rest on the idea that the physical and chemical properties of a system can be accurately described considering only the potential energy curve between the neighbor atoms or, in other words, how the energy changes with the distance between the interacting particles. Several authors have demonstrated that the shape of the potential energy curve can be considered universal regardless that we consider a molecule or a crystal, implying that its general characteristics are also universally applicable and transferable from one system to the others. This procedure has been profusely applied in chemistry and physics of the solid state, but it has important the important limitation that to transfer the characteristic parameters it is required to fit specific experimental properties. In other words, the shape of the interaction potential is universal, but the characteristic parameters are not. Developing a methodology capable of providing truly universal parameters is one of the major challenges of this PhD thesis and one of its underlying motivations. . Commonly used potential functions include those classical of Lennard-Jones, Born-Mayer and Mie-Grüneisen, or others borrowed from spectroscopy, like Rydberg, Morse and Sutherland. And an example of the success of considering the universality of the potential energy curve was provided in the introduction chapter of this PhD memo with the model relating the stretching forcé constant of diatomic molecules with the bulk modulus of their ionic, metallic and covalent counterpart crystals. The key ideas to put forward such relationship were: to assume that the distance dependence of the diatomic stretching force constant can be universally described, and that they can accurately describe the interaction between the same atoms in the crystal. These two assumptions can be only fulfilled if the pairwise potential shape is universal and its parameters can be universally transferred between molecules and crystals...El objetivo central de Tesis Doctoral ha sido demostrar que las características intrínsecas de una interacción entre pares de átomos dada (covalente, electrostático, van der Waals, etc.) permite establecer un marco interpretativo excelente para relacionar las propiedades mecánicas y químicas de las moléculas y los sólidos cristalinos caracterizadas por dicho tipo de enlace. Para alcanzar este objetivo, hemos tomado como base conceptos clásicos y ampliamente aceptados en materia condensada y los hemos trasladado al campo molecular; pero en otras ocasiones hemos recorrido el camino inverso, con el objetivo de demostrar que dichos conceptos pueden ser -y lo son de hecho- intercambiables entre sistemas materiales muy dispares. Las interacciones entre pares de átomos se fundamental en la idea de que las propiedades físicas y químicas de un sistema pueden describirse con precisión considerando sólo la curva de energía potencial entre los átomos vecinos; en otras palabras, cómo cambia la energía con la distancia entre las partículas que interaccionan. Algunos autores han demostrado en las últimas décadas que la forma de la curva de energía potencial puede considerarse universal, independientemente de que consideremos una molécula o un cristal, lo que implica que las características generales del potencial de interacción son también universalmente aplicables y transferibles de un sistema a otro. A pesar de que esta metodología se ha aplicado de forma exitosa y extensa en las áreas de la Química y la Física del Estado Sólido, tiene la limitación de que para transferir los parámetros característicos entre dos sistemas es necesario ajustar los parámetros característicos del potencial de interacción a propiedades experimentales específicas. En otras palabras, la forma del potencial de interacción es universal, pero los parámetros característicos no lo son. En consecuencia, uno de los mayores retos de esta Tesis Doctoral y una de sus motivaciones originales ha sido el de desarrollar una metodología capaz de proporcionar parámetros verdaderamente universales...Fac. de Ciencias QuímicasTRUEunpu

A Mechanical Insight into the Stability of the Chemical Bond

This PhD was devoted to demonstrating that the nature and intrinsic features of a given pairwise interaction (covalent, electrostatic, van der Waals, etc.) defines a suitable framework to relate both molecular and bulk properties. To reach this goal, we have considered classical, well-established concepts from the field of condensed matter and translated them into the molecular realm, and vice versa. Pairwise interactions rest on the idea that the physical and chemical properties of a system can be accurately described considering only the potential energy curve between the neighbor atoms or, in other words, how the energy changes with the distance between the interacting particles. Several authors have demonstrated that the shape of the potential energy curve can be considered universal regardless that we consider a molecule or a crystal, implying that its general characteristics are also universally applicable and transferable from one system to the others. This procedure has been profusely applied in chemistry and physics of the solid state, but it has important the important limitation that to transfer the characteristic parameters it is required to fit specific experimental properties. In other words, the shape of the interaction potential is universal, but the characteristic parameters are not. Developing a methodology capable of providing truly universal parameters is one of the major challenges of this PhD thesis and one of its underlying motivations. . Commonly used potential functions include those classical of Lennard-Jones, Born-Mayer and Mie-Grüneisen, or others borrowed from spectroscopy, like Rydberg, Morse and Sutherland. And an example of the success of considering the universality of the potential energy curve was provided in the introduction chapter of this PhD memo with the model relating the stretching forcé constant of diatomic molecules with the bulk modulus of their ionic, metallic and covalent counterpart crystals. The key ideas to put forward such relationship were: to assume that the distance dependence of the diatomic stretching force constant can be universally described, and that they can accurately describe the interaction between the same atoms in the crystal. These two assumptions can be only fulfilled if the pairwise potential shape is universal and its parameters can be universally transferred between molecules and crystals..

Charge analysis in (RE)CrO4 scheelites by combined Raman spectroscopy and computer simulations

The quest for structure-property relationships in scheelite-type (RE)CrO4 compounds (where RE is a rare earth element) is a difficult task due to the number of exceptions found in RE empirical trends and the uncommon Cr(V) oxidation state. In this work, we experimentally and computationally analyse how the stretching vibrational frequencies ν1(Ag) and ν3(Eg) associated with the [CrO4] tetrahedral units evolve in the (RE)CrO4 crystal family (RE ¼ Nd, Gd, Dy, Ho, and Lu). Since previously reported Cr–O distances and volume changes along with the RE series are not sufficiently accurate to explain the monotonic decrease observed for the ν1(Ag) and ν3(Eg) frequencies, a deeper analysis was performed involving the well-known fact that the bond strength (force constant) decreases as the interatomic distance increases. Our results demonstrates that structural and spectroscopic parameters can be reconciled with classical solid state chemistry ideas when charge effects are considered. This analysis provides a new method for predicting chromium oxidation states from Raman spectroscopy that can be generalised to the study of other crystal families

Highs and Lows of Bond Lengths: Is There Any Limit?

Two distinct points on the potential energy curve (PEC) of a pairwise interaction, the zero-energy crossing point and the point where the stretching force constant vanishes, allow us to anticipate the range of possible distances between two atoms in diatomic, molecular moieties and crystalline systems. We show that these bond-stability boundaries are unambiguously defined and correlate with topological descriptors of electron-density-based scalar fields, and can be calculated using generic PECs. Chemical databases and quantum-mechanical calculations are used to analyze a full set of diatomic bonds of atoms from the s-p main block. Emphasis is placed on the effect of substituents in C-C covalent bonds, concluding that distances shorter than 1.14 Å or longer than 2.0 Å are unlikely to be achieved, in agreement with ultra-high-pressure data and transition-state distances, respectively. Presumed exceptions are used to place our model in the correct framework and to formulate a conjecture for chained interactions, which offers an explanation for the multimodal histogram of O-H distances reported for hundreds of chemical systems

A Chemical Pressure-Induced Phase Transition Controlled by Lone Electron Pair Activity

The chemical pressure approach offers a new paradigm for property control in functional materials. In this work, we disclose a correlation between the β → α pressureinduced phase transition in SnMoO4 and the substitution process of Mo6+ by W6+ in SnMo1−xWxO4 solid solutions (x = 0-1). Special attention is paid to discriminating the role of the lone pair Sn2+ cation from the structural distortive effect along the Mo/W substitution process, which is crucial to disentangle the driven force of the transition phase. Furthermore, the reverse α → β transition observed at high temperature in SnWO4 is rationalized on the same basis as a negative pressure effect associated with a decreasing of W6+ percentage in the solid solution. This work opens a versatile chemical approach in which the types of interactions along the formation of solid solutions are clearly differentiated and can also be used to tune their properties, providing opportunities for the development of new materials

T cells isolated from G-CSF-treated multiple myeloma patients are suitable for the generation of BCMA-directed CAR-T cells

Autologous cell immunotherapy using B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells is an effective novel treatment for multiple myeloma (MM). This therapy has only been used for relapsed and refractory patients, at which stage the endogenous T cells used to produce the CAR-T cells are affected by the immunosuppressive nature of advanced MM and/or side effects of previous therapies. An alternative pool of fitter T cells is found in leukocytoapheresis products that are routinely collected to obtain hematopoietic progenitor cells for autologous stem cell transplantation (ASCT) early in the treatment of MM. However, to mobilize the progenitor cells, patients are dosed with granulocyte colony-stimulating factor (G-CSF), which is reported to adversely affect T cell proliferation, function, and differentiation. Here, we aimed to first establish whether G-CSF treatment negatively influences T cell phenotype and to ascertain whether previous exposure of T cells to G-CSF is deleterious for anti-BCMA CAR-T cells. We observed that G-CSF had a minimal impact on T cell phenotype when added in vitro or administered to patients. Moreover, we found that CAR-T cell fitness and anti-tumor activity were unaffected when generated from G-CSF-exposed T cells. Overall, we showed that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture

CD229 (Ly9) a Novel Biomarker for B-Cell Malignancies and Multiple Myeloma

CD229 is a cell-surface molecule predominantly expressed on lymphocytes. Its expression in B-cell malignancies is poorly known. We tested the presence of this immunoreceptor on a large number of malignancies and normal tissue using a new monoclonal antibody and tissue microarrays. Our data show that CD229 expression is restricted to hematopoietic cells. It was strongly expressed in myeloma and marginal-zone lymphomas. Because of the high expression on multiple myeloma cells, we also analyze the presence of soluble CD229 in the sera of these patients. We showed that serum levels of soluble CD229 in myeloma patients, at the time of diagnosis, could be useful as a prognostic biomarker. Altogether, our results indicate that CD229 represents not only a useful disease biomarker but also an attractive therapeutic target. CD229 (Ly9) homophilic receptor, which belongs to the SLAM family of cell-surface molecules, is predominantly expressed on B and T cells. It acts as a signaling molecule, regulating lymphocyte homoeostasis and activation. Studies of CD229 function indicate that this receptor functions as a regulator of the development of marginal-zone B cells and other innate-like T and B lymphocytes. The expression on leukemias and lymphomas remains poorly understood due to the lack of CD229 monoclonal antibodies (mAb) for immunohistochemistry application (IHC). In this study, we used a new mAb against the cytoplasmic region of CD229 to study the expression of CD229 on normal tissues and B-cell malignancies, including multiple myeloma (MM), using tissue microarrays. We showed CD229 to be restricted to hematopoietic cells. It was strongly expressed in all cases of MM and in most marginal-zone lymphomas (MZL). Moderate CD229 expression was also found in chronic lymphocyte leukemia (CLL), follicular (FL), classic mantle-cell (MCL) and diffuse large B-cell lymphoma. Given the high expression on myeloma cells, we also analyzed for the presence of soluble CD229 in the sera of these patients. Serum levels of soluble CD229 (sCD229) at the time of diagnosis in MM patients could be useful as a prognostic biomarker. In conclusion, our results indicate that CD229 represents not only a useful biomarker but also an attractive therapeutic target

The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age �60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial

Factors associated with the clinical outcome of patients with relapsed/refractory CD19+acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy

The prognosis of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hema-topoietic cell transplantation (alloHCT). Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT. Chimeric antigen receptors (CAR) targeting CD19 have shown promising results in R/R ALL, and one of these products (tisagenlecleucel) has been approved for the treatment of patients with R/R ALL up to 25 years of age