Production of monoclonal antibodies for therapeutic purposes: A review.

Monoclonal antibodies (mAbs) have been used in the development of immunotherapies that target a variety of diseases, such as cancer, autoimmune diseases, and even viral infections; they play a key role in immunization and are expected after vaccination. However, some conditions do not promote the development of neutralizing antibodies. Production and use of mAbs, generated in biofactories, represent vast potential as aids in immunological responses when the organism cannot produce them on their own, these convey unique specificity by recognizing and targeting specific antigen. Antibodies can be defined as heterotetrametric glycoproteins of symmetric nature, and they participate as effector proteins in humoral responses. Additionally, there are different types of mAbs (murine, chimeric, humanized, human, mAbs as Antibody-drug conjugates and bispecific mAbs) discussed in the present work. When these molecules are produced in vitro as mAbs, several common techniques, such as hybridomas or phage display are used. There are several preferred cell lines that function as biofactories, for the production of mAbs, the selection of which rely on the variation of adaptability, productivity and both phenotypic and genotypic shifts. After the cell expression systems and culture techniques are used, there are diverse specialized downstream processes to achieve desired yield and isolation as well as product quality and characterization. Novel perspectives regarding these protocols represent a potential improvement for mAbs high-scale production.

Smoking and pulmonary tuberculosis treatment failure: a case-control study.

OBJECTIVE: To determine the association between smoking and pulmonary tuberculosis treatment failure. METHODS: This was a case-control study conducted at the Brazilian Institute for Tuberculosis Research in the city of Salvador, Brazil, between 2007 and 2015. We evaluated 284 patients treated for pulmonary tuberculosis, comparing 50 cases of treatment failure with 234 control cases in which the final outcome was cure. RESULTS: Treatment failure was attributed to smoking and age rather than to gender, income, level of education, alcohol consumption, or marital status. Therefore, even after adjustment for age, the risk of treatment failure was 2.1 times (95% CI: 1.1-4.1) higher among the patients with a history of smoking. In addition, being over 50 years of age was found to increase the likelihood of treatment failure by 2.8 times (95% CI: 1.4-6.0). CONCLUSIONS: Smoking and aging are both associated with pulmonary tuberculosis treatment failure. Therefore, as part of a tuberculosis control program, health personnel should be prepared to offer strategies to promote smoking cessation and should be more careful with older patients.

Smoking and pulmonary tuberculosis treatment failure: a case-control study / Tabaquismo y fracaso del tratamiento de la tuberculosis pulmonar. Un estudio de casos y controles

ABSTRACT Objective: To determine the association between smoking and pulmonary tuberculosis treatment failure. Methods: This was a case-control study conducted at the Brazilian Institute for Tuberculosis Research in the city of Salvador, Brazil, between 2007 and 2015. We evaluated 284 patients treated for pulmonary tuberculosis, comparing 50 cases of treatment failure with 234 control cases in which the final outcome was cure. Results: Treatment failure was attributed to smoking and age rather than to gender, income, level of education, alcohol consumption, or marital status. Therefore, even after adjustment for age, the risk of treatment failure was 2.1 times (95% CI: 1.1-4.1) higher among the patients with a history of smoking. In addition, being over 50 years of age was found to increase the likelihood of treatment failure by 2.8 times (95% CI: 1.4-6.0). Conclusions: Smoking and aging are both associated with pulmonary tuberculosis treatment failure. Therefore, as part of a tuberculosis control program, health personnel should be prepared to offer strategies to promote smoking cessation and should be more careful with older patients.

RESUMEN Objetivo: Determinar la asociación entre el tabaquismo y el fracaso del tratamiento de la tuberculosis pulmonar. Metodología: Este es un estudio caso - control, realizado en el Instituto Brasilero para la Investigación de la Tuberculosis en Salvador, Brasil entre 2007 y 2015. Se compararon 50 casos de fracaso en el tratamiento con 234 controles de pacientes con diagnóstico de tuberculosis pulmonar y con resultado final de cura. Resultados: Se atribuyó el fracaso del tratamiento al tabaquismo y a la edad, y no al sexo, salario, escolaridad, consumo de alcohol o estado civil. Así, aun después del ajuste por edad, los pacientes con antecedentes de tabaquismo tienen 2,1 (IC95% 1,1-4,1) veces más chance de fracaso en el tratamiento de la tuberculosis. Además, tener una edad mayor de 50 años mostró que la posibilidad de fracaso aumenta 2,8 (IC95% 1,4-6,0) veces más. Conclusiones: El tabaquismo está relacionado con el fracaso del tratamiento de la tuberculosis pulmonar, así como también el envejecimiento. Por tal motivo, como parte del control de la tuberculosis, el personal de salud debe estar preparado para ofrecer estrategias que promuevan la cesación tabáquica y tener un mayor cuidado con pacientes de grupos etarios superiores.

Disrupted Ultradian Activity Rhythms and Differential Expression of Several Clock Genes in Interleukin-6-Deficient Mice.

The characteristics of the cycles of activity and rest stand out among the most intensively investigated aspects of circadian rhythmicity in humans and experimental animals. Alterations in the circadian patterns of activity and rest are strongly linked to cognitive and emotional dysfunctions in severe mental illnesses such as Alzheimer's disease (AD) and major depression (MDD). The proinflammatory cytokine interleukin 6 (IL-6) has been prominently associated with the pathogenesis of AD and MDD. However, the potential involvement of IL-6 in the modulation of the diurnal rhythms of activity and rest has not been investigated. Here, we set out to study the role of IL-6 in circadian rhythmicity through the characterization of patterns of behavioral locomotor activity in IL-6 knockout (IL-6 KO) mice and wild-type littermate controls. Deletion of IL-6 did not alter the length of the circadian period or the amount of locomotor activity under either light-entrained or free-running conditions. IL-6 KO mice also presented a normal phase shift in response to light exposure at night. However, the temporal architecture of the behavioral rhythmicity throughout the day, as characterized by the quantity of ultradian activity bouts, was significantly impaired under light-entrained and free-running conditions in IL-6 KO. Moreover, the assessment of clock gene expression in the hippocampus, a brain region involved in AD and depression, revealed altered levels of cry1, dec2, and rev-erb-beta in IL-6 KO mice. These data propose that IL-6 participates in the regulation of ultradian activity/rest rhythmicity and clock gene expression in the mammalian brain. Furthermore, we propose IL-6-dependent circadian misalignment as a common pathogenetic principle in some neurodegenerative and neuropsychiatric disorders.

The brain-tumor related protein podoplanin regulates synaptic plasticity and hippocampus-dependent learning and memory.

INTRODUCTION: Podoplanin is a cell-surface glycoprotein constitutively expressed in the brain and implicated in human brain tumorigenesis. The intrinsic function of podoplanin in brain neurons remains however uncharacterized. MATERIALS AND METHODS: Using an established podoplanin-knockout mouse model and electrophysiological, biochemical, and behavioral approaches, we investigated the brain neuronal role of podoplanin. RESULTS: Ex-vivo electrophysiology showed that podoplanin deletion impairs dentate gyrus synaptic strengthening. In vivo, podoplanin deletion selectively impaired hippocampus-dependent spatial learning and memory without affecting amygdala-dependent cued fear conditioning. In vitro, neuronal overexpression of podoplanin promoted synaptic activity and neuritic outgrowth whereas podoplanin-deficient neurons exhibited stunted outgrowth and lower levels of p-Ezrin, TrkA, and CREB in response to nerve growth factor (NGF). Surface Plasmon Resonance data further indicated a physical interaction between podoplanin and NGF. DISCUSSION: This work proposes podoplanin as a novel component of the neuronal machinery underlying neuritogenesis, synaptic plasticity, and hippocampus-dependent memory functions. The existence of a relevant cross-talk between podoplanin and the NGF/TrkA signaling pathway is also for the first time proposed here, thus providing a novel molecular complex as a target for future multidisciplinary studies of the brain function in the physiology and the pathology. Key messages Podoplanin, a protein linked to the promotion of human brain tumors, is required in vivo for proper hippocampus-dependent learning and memory functions. Deletion of podoplanin selectively impairs activity-dependent synaptic strengthening at the neurogenic dentate-gyrus and hampers neuritogenesis and phospho Ezrin, TrkA and CREB protein levels upon NGF stimulation. Surface plasmon resonance data indicates a physical interaction between podoplanin and NGF. On these grounds, a relevant cross-talk between podoplanin and NGF as well as a role for podoplanin in plasticity-related brain neuronal functions is here proposed.