A personalized molecular approach in multiple myeloma: the possible use of RAF/RAS/MEK/ERK and BCL-2 inhibitors.

Multiple myeloma (MM) is a blood cancer that derives from plasma cells (PCs), which will accumulate in the bone marrow (BM). Over time, several drugs have been developed to treat this disease that is still uncurable. The therapies used to treat the disease target immune activity, inhibit proteasome activity, and involve the use of monoclonal antibodies. However, MM is a highly heterogeneous disease, in fact, there are several mutations in signaling pathways that are particularly important for MM cell biology and that are possible therapeutic targets. Indeed, some studies suggest that MM is driven by mutations within the rat sarcoma virus (RAS) signaling cascade, which regulates cell survival and proliferation. The RAS/proto-oncogene, serine/threonine kinase (RAF)/mitogen-activated extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling pathway is deregulated in several cancers, for which drugs have been developed to inhibit these pathways. In addition to the signaling pathways, the disease implements mechanisms to ensure the survival and consequently a high replicative capacity. This strategy consists in the deregulation of apoptosis. In particular, some cases of MM show overexpression of anti-apoptotic proteins belonging to the B cell lymphoma 2 (BCL-2) family that represent a possible druggable target. Venetoclax is an anti-BCL-2 molecule used in hematological malignancies that may be used in selected MM patients based on their molecular profile. We focused on the possible effects in MM of off-label drugs that are currently used for other cancers with the same molecular characteristics. Their use, combined with the current treatments, could be a good strategy against MM.

Metabolic features of myeloma cells in the context of bone microenvironment: Implication for the pathophysiology and clinic of myeloma bone disease.

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of malignant plasma cells (PCs) into the bone marrow (BM). The complex interaction between the BM microenvironment and MM PCs can lead to severe impairment of bone remodeling. Indeed, the BM microenvironment exerts a critical role in the survival of malignant PCs. Growing evidence indicates that MM cells have several metabolic features including enhanced glycolysis and an increase in lactate production through the upregulation of glucose transporters and enzymes. More recently, it has been reported that MM cells arehighly glutamine addicted. Interestingly, these metabolic changes in MM cells may affect BM microenvironment cells by altering the differentiation process of osteoblasts from mesenchymal stromal cells. The identification of glutamine metabolism alterations in MM cells and bone microenvironment may provide a rationale to design new therapeutic approaches and diagnostic tools. The osteolytic lesions are the most frequent clinical features in MM patients, often characterized by pathological fractures and acute pain. The use of the newer imaging techniques such as Magnetic Resonance Imaging (MRI) and combined Positron Emission Tomography (PET) and Computerized Tomography (CT) has been introduced into clinical practice to better define the skeletal involvement. Currently, the PET/CT with 18F-fluorodeoxyglucose (FDG) is the diagnostic gold standard to detect active MM bone disease due to the high glycolytic activity of MM cells. However, new tracers are actively under investigation because a portion of MM patients remains negative at the skeletal level by 18F-FDG. In this review, we will summarize the existing knowledge on the metabolic alterations of MM cells considering their impact on the BM microenvironment cells and particularly in the subsequent formation of osteolytic bone lesions. Based on this, we will discuss the identification of possible new druggable targets and the use of novel metabolic targets for PET imaging in the detection of skeletal lesions, in the staging and treatment response of MM patients.

Immune response to SARS-CoV-2 mRNA vaccination and booster dose in patients with multiple myeloma and monoclonal gammopathies: impact of Omicron variant on the humoral response.

The humoral and cellular response to SARS-CoV-2 mRNA full vaccination and booster dose as well as the impact of the spike variants, including Omicron, are still unclear in patients with multiple myeloma (MM) and those with pre-malignant monoclonal gammopathies. In this study, involving 40 patients, we found that MM patients with relapsed-refractory disease (MMR) had reduced spike-specific antibody levels and neutralizing titers after SARS-CoV-2 vaccination. The five analyzed variants, remarkably Omicron, had a significant negative impact on the neutralizing ability of the vaccine-induced antibodies in all patients with MM and smoldering MM. Moreover, lower spike-specific IL-2-producing CD4+ T cells and reduced cytotoxic spike-specific IFN-γ and TNF-α-producing CD8+ T cells were found in MM patients as compared to patients with monoclonal gammopathy of undetermined significance. We found that a heterologous booster immunization improved SARS-CoV-2 spike humoral and cellular responses in newly diagnosed MM (MMD) patients and in most, but not all, MMR patients. After the booster dose, a significant increase of the neutralizing antibody titers against almost all the analyzed variants was achieved in MMD. However, in MMR patients, Omicron retained a negative impact on neutralizing ability, suggesting further approaches to potentiating the effectiveness of SARS-CoV-2 vaccination in these patients.

Social interaction, languaging and the operational conditions for the emergence of observing.

In order to adequately understand the foundations of human social interaction, we need to provide an explanation of our specific mode of living based on linguistic activity and the cultural practices with which it is interwoven. To this end, we need to make explicit the constitutive conditions for the emergence of the phenomena which relate to language and joint activity starting from their operational-relational matrix. The approach presented here challenges the inadequacy of mentalist models to explain the relation between language and interaction. Recent empirical studies concerning joint attention and language acquisition have led scholars such as Tomasello et al. (2005) to postulate the existence of a universal human "sociocognitive infrastructure" that drives joint social activities and is biologically inherited. This infrastructure would include the skill of precocious intention-reading, and is meant to explain human linguistic development and cultural learning. However, the cognitivist and functionalist assumptions on which this model relies have resulted in controversial hypotheses (i.e., intention-reading as the ontogenetic precursor of language) which take a contentious conception of mind and language for granted. By challenging this model, I will show that we should instead turn ourselves towards a constitutive explanation of language within a "bio-logical" understanding of interactivity. This is possible only by abandoning the cognitivist conception of organism and traditional views of language. An epistemological shift must therefore be proposed, based on embodied, enactive and distributed approaches, and on Maturana's work in particular. The notions of languaging and observing that will be discussed in this article will allow for a bio-logically grounded, theoretically parsimonious alternative to mentalist and spectatorial approaches, and will guide us towards a wider understanding of our sociocultural mode of living.

Sistema para digitalización del electrocardiograma e historia médica computarizada aplicada a cardiología

Este trabajo presenta el desarrollo de un sistema formado por dos partes. La primera parte consiste en un módulo hardware diseñado para digitalizar el electrocardiograma (ECG) de cualquier electrocardiógrafo con salida analógica, y transmitir los datos a un computador personal (PC). La segunda parte del sistema consiste en un software programado en el computador, que tiene por finalidad manipular y almacenar los datos del paciente y el registro del ECG obtenido, en un formato de historia médica computarizada aplicada a cardiología. Entre las tareas que realiza el sistema se pueden nombrar: adquisición y muestreo de la señal ECG proveniente del electrocardiógrafo analógico, transmisión en forma serial al computador, visualización de la señal en tiempo real, almacenamiento digital de la historia médica de cada paciente, así como de cada una de las consultas y registros de ECG realizados, y generación de reporte para la impresión en papel de las 12 derivaciones electrocardiográficas. Como resultado de este trabajo se construyó un prototipo, el cual se encuentra actualmente en validación clínica en el Hospital Universitario de Los Andes. Este sistema ayuda a modernizar los antiguos electrocardiógrafos analógicos, transformándolos en electrocardiógrafos digitales de bajo costo, con todas las ventajas de los equipos de última generación. Además, permite el almacenamiento ordenado de las historias médicas de los pacientes, con fácil acceso a cada una de las consultas y los registros de ECG realizados con anterioridad.

This work presents the development of a system formed by two parts. The first part consists on a module hardware designed to digitize the electrocardiogram (ECG) of any electrocardiograph with analog exit and to transmit the data to a personal computer (PC). The second part of the system consists on a software programmed in the computer that has the purpose of manipulate and store the patient’s data and also perform the registration of the obtained ECG, this data is taken in a format of on-line medical history applied to cardiology. Among the tasks that carries the system can be named: Acquisition and sampling of the sign ECG coming from the analog electrocardiograph, transmission in serial form to the computer, visualization of the sign in real time, digital storage of each patient’s medical history, as well as of each one of the consultations and registrations of carried ECG, and report generation for the impression in paper of the 12 derivations of ECG. As result of this work, a prototype was built, which is at the moment in clinical validation in the University Hospital of The Andes. This system helps to modernize the old analogical electrocardiographs, transforming them in digital electrocardiographs of low cost, with all the advantages of the teams of last generation. It also allows the orderly storage of the medical histories of the patients with easy access to each one of the consultations and the registrations of ECG carried out previously.

Bomba de perfusión programable para uso biomédico

Este trabajo presenta el funcionamiento de un instrumento biomédico, diseñado y construido para cubrir los requerimientos de un grupo de investigadores en el área de bioquímica. El instrumento desarrollado tiene como propósito inyectar un fluido biológico a un sistema específico en una secuencia definida y programable, cuyo compuesto químico lo define el investigador. Dicha secuencia permite establecer diferentes velocidades de inyección del fluido en función del tiempo; todo ello, en un mismo ciclo de trabajo. Para cumplir con las características de funcionamiento se diseñó un sistema electrónico con microcontroladores y un sistema mecánico de precisión, que puede manejar una o dos inyectadoras de 3 centímetros cúbicos (cc) de uso comercial. La acción del sistema mecánico sobre las inyectadoras se encarga de inyectar el líquido en el medio o cuerpo de experimentación. El prototipo de este instrumento se está utilizando en el estudio del metabolismo de los atletas durante el ejercicio, en el laboratorio de investigación del Departamento de Bioquímica de la Facultad de Medicina de la Universidad de Los Andes.

This work presents the operation of a biomedical instrument, designed and built to cover the requirements of investigators group at the biochemistry area. The developed instrument has as purpose to inject a biological fluid, to a specific system in a defined and programmable sequence whose chemical compound the investigator defines. This sequence allows to establish different speeds of injection of the fluid in function of the time; everything it, in oneself work cycle. To fulfill the operation characteristics an electronic system it was designed with microcontrolers and a mechanical system of precision that it can manage an or two syringes of 3 cubic centimeters (cc) of commercial use. The action of the mechanical system on the syringes takes charge of inject the liquid in the means or experimentation body. The prototype of this instrument is used in the study of the metabolism of the athletes during the exercise, at the laboratory of investigation of the department of Biochemistry of the Ability of Medicine at the University of The Andes.