3.02 Tesis doctorado

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    Evaluación de la respuesta inmune anti-tumoral mediada por linfocitos T en organoides derivados de pacientes con cáncer de vesícula biliar
    (2024) Obreque Castro, Javiera Constanza; Bizama, Carolina; Roa, Juan Carlos; Montecinos Acuña, Viviana; Pontificia Universidad Católica de Chile. Escuela de Medicina
    El cáncer de vesícula biliar (GBC) es una de las neoplasias más comunes y agresivas dentro del tracto biliar. Particularmente en nuestro país, el GBC se ha reportado como un problema de salud pública, especialmente en mujeres donde contribuye como la quinta causa de muerte por cáncer. Actualmente, el único tratamiento efectivo es la resección quirúrgica de la vesícula en estadios temprano. Sin embargo, la mayoría de los pacientes son diagnosticados en estadios avanzados, donde la única alternativa terapéutica es la quimioterapia con gemcitabina y cisplatino, la cual presenta muy baja respuesta. Es por esto, que la búsqueda de nuevos blancos de terapia y de modelos preclínicos que representen fielmente la respuesta a terapias ha cobrado gran interés en la investigación biomédica con enfoques en medicina personalizada. En los tumores de GBC se ha descrito la presencia de las células iniciadoras de tumor (TICs) o cancer stem cells (CSC), caracterizadas por la expresión doble positiva de los marcadores CD44 y CD133. Una de las características de las TICs, es la evasión de la respuesta inmune antitumoral, a través, de la expresión de los immune checkpoint (o puntos de control inmune) desencadenando la supresión de los linfocitos T citotóxicos, encargados de orquestar la respuesta inmune antitumoral. En los últimos años, la inmunoterapia ha revolucionado el tratamiento del cáncer y actualmente se utiliza con resultados favorables en el tratamiento de diferentes tipos de tumores. Dentro de las inmunoterapias aprobadas por la FDA, se encuentran los inhibidores de los inmune checkpoint, PD-L1/PD-1, CTLA4 y LAG-3. Inicialmente estas terapias fueron aprobados para su uso en melanoma, pero en la actualidad los dos primeros se utilizan en variados tipos de cáncer incluido el gástrico. Por lo tanto, para el análisis de la respuesta y predicción a estas nuevas inmunoterapias se requiere de nuevos modelos in vitro de cáncer, que sean capaces de recapitular la interacción de las células del cáncer con el componente inmune. Dentro de estos modelos, se propone el uso de los cultivos 3D de organoides tumorales derivados de pacientes (PDOs) como una poderosa herramienta que imita las características histológicas, genéticas y fisiopatológicas del tumor del cual derivan. Sin embargo, el principal desafío es enriquecer este modelo de PDOs tumorales con células del componente inmune para poder estudiar la respuesta de los pacientes a la inmunoterapia. Actualmente, el uso de co-cultivo entre organoides y células inmunes, se ha utilizado para generar linfocitos TCD8 reactivos y evaluar la capacidad citotóxica TCD8 en contra de las células tumorales. Tomando todo esto en consideración, el presente proyecto de tesis tuvo como hipótesis: “La interacción directa entre organoides derivados de pacientes con cáncer de vesícula biliar y células inmunes, permite evaluar la respuesta antitumoral mediada por linfocitos T y el efecto de inhibidores de PD-1”.
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    Identification of electroencephalography and psychophysical parameters with potential diagnostic use for suicidal patients
    (2023) Gajardo Gómez, Rosario; Aboitiz, Francisco; Pontificia Universidad Católica de Chile. Facultad de Medicina
    Suicide is a global public health concern, with women showing a higher prevalence of suicidal thoughts and attempts compared to men. The shift from suicidal ideation to suicidal attempts involves individual, social, and environmental factors, with impulsivity playing a significant role. Early detection of suicide risk is vital, and early biological markers are urgently needed. An interesting candidate marker is the Loudness Dependence of Auditory Evoked Potentials (LDAEP). While LDAEP shows promise in characterizing patients with depression and impulsivity, it has been largely used with emotionally neutral stimuli. Thus, its characterization in response to emotional auditory stimuli could represent an improvement as a neuropsychiatric risk marker. This study addresses this gap by examining neural and emotional processing in female patients with depressive episodes, suicidal ideation, and recent suicidal attempts. Our hypothesis posits that female patients with depressive episodes and recent suicide attempts will exhibit greater impairments in neural and emotional processing, but lower levels of impulsivity compared to female patients with depressive episodes and suicidal ideation but no recent suicida attempts. To achieve this, this study explored the interplay between behavior, electrophysiology, and psychology in 19 female patients, including 10 subjects with Suicidal Ideation (SI) and 9 subjects with Suicide Attempt (SA), all admitted to the psychiatric hospitalization service of San Carlos de Apoquindo Clinical Center. Socioeconomic and demographic factors were comparable between groups, emphasizing the role of individual experiences. The LDAEP component was assessed in response to tonal and emotional auditory stimuli. False alarms, accuracy, and response times were analyzed. A multiple correlation matrix with false discovery rate (FDR) correction revealed associations between clinical psychological evaluations and electrophysiological data. Linear regression analysis uncovered mediating factors shaping these relationships. All patients had depressive episodes, with common triggers being suicidal thoughts, interpersonal issues, family conflicts, and academic stressors. Most had received therapy, and self-harm was prevalent, especially in SA. Findings revealed shorter reaction times (RT) in SI the group to neutral stimuli, suggesting impulsive tendencies. RT frequency distributions in the SA group displayed a faster response to negative stimuli, indicating a negative bias associated with depressive states. LDAEP analysis of tonal and emotional stimuli showed no significant differences between groups. However, the SI group demonstrated a tendency towards a greater tonal LDAEP. SI showed increased P2 amplitude, signifying enhanced perceptual attentional processing of emotional information. A deflection in the P3 component suggested reduced attentional allocation, diminished cognitive processing, and a lower level of emotional content evaluation. A consistent plateau in P2-P3 amplitudes was observed for both positive and negative stimuli, indicating a blunted affective response and decreased cognitive and emotional flexibility. SI demonstrated a stronger correlation between impulsivity and depression, while SA showed associations between hopelessness, impulsivity, and depression. Childhood trauma, particularly sexual aggression, exacerbated pathology in SI. Family support was a significant factor influencing depressive symptoms in both groups. SI exhibited a negative correlation between depressive symptoms and hopelessness, influenced by protective factors. Significant correlations were found between electrophysiological and psychological variables. In SI, cognitive factors related to life satisfaction affected neural responses, while hopelessness and childhood trauma influenced depressive symptoms. In SA, depressive symptoms, hopelessness, and impulsivity were strongly correlated, emphasizing the need for clinical intervention. The results highlight the complex interplay of impulsivity, depressive states, cognitive processing, and emotional regulation in shaping suicidal ideation and suicide attempts. Further investigations should continue to explore the intricate mechanisms underlying suicidality, ultimately leading to more effective strategies for identifying and supporting individuals at risk of suicide.
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    Role of neuromuscular electrical stimulation to prevent respiratory muscle weakness in critically ill patients and its association to changes in myokines profile: a randomized clinical trial
    (2024) Jalil Contreras, Yorschua Frederick; Bruhn, Alejandro; Pontificia Universidad Católica de Chile. Facultad de Medicina
    Introduction: Critically ill patients hospitalized at Intensive Care Units (ICU) are characterized by an accelerated muscle wasting, particularly of respiratory muscles, occurring early due to mechanical ventilation (MV). Although active muscle activation may prevent these alterations, it is usually not available at early stages of care because of sedation, favoring a vicious circle. Neuromuscular electrical stimulation (NMES) represents an alternative to achieve muscle contraction in this setting, being able to prevent local muscle wasting, and according to some reports, has the potential to shorten MV time. It has been suggested that this potential benefit might be explained by systemic effects of NMES on distant muscles due to the release of myokines, a diverse range of chemokines secreted by myocytes during contraction. However, no studies have evaluated whether NMES applied to peripheral muscles (quadriceps) in critically ill patients can exert distant muscle effects over the diaphragm, and if such effects are associated to changes in myokine concentrations. Objective: To determine the effects of NMES applied to both quadriceps on myokine plasmatic concentrations, and on peripheral and respiratory muscle function and structure, in mechanical ventilated ICU patients when initiated at an early phase of their critical illness. Methods: Exploratory randomized controlled trial of NMES applied to both quadriceps, twice a day, for 3 days, in comparison to standard care (control group, CG). For myokine characterization (IL-6, BDNF, Myostatin and Decorin), blood samples were obtained at baseline (T0), at the end of the NMES session (T1), and 2 and 6 hours later (T2 and T6). This sampling was repeated on days 1 and 3. For the control group (CG) blood samples were obtained only at T0 and T6. An additional blood sample was also taken on Day 4 (T0) for both groups. Muscle characterization was performed at days 1 and 3 (T0 and T6 respectively). This consisted in ultrasonography of quadriceps muscle layer thickness (MLT), and diaphragmatic thickening fraction (TFdi), along with tracheal tube pressure derived from phrenic nerve magnetic stimulation (Ptr,tw), for diaphragmatic function. Results: 11 patients were randomized: 6 to CG and 5 to NMES. No differences were observed between groups at baseline. No significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) for quadriceps MLT change (p-value of 0.12). However, time as factor had a significant impact on MLT explained by a decrease from 1.92 ± 0.81 cm on day 1 to 1.63 ± 0.85 cm on day 3 in the CG, with a p-value of 0.003, while no change along time was observed in the NMES group (Change from 1.76 ± 0.62 cm on day 1 to 1.66 ± 0.61 cm on day 3, with a p-value of 0.51). Concerning diaphragmatic thickening fraction (TFdi), a significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) (p-value of 0.006). While in the CG there was an absolute TFdi decrease of 8.93% ± 6.4 (-32.6 ± 25.3 % of relative change) along time, in the NMES group TFdi increased 5.14± 6.55 % (+38.15 ± 58.6 % of relative change). Considering Twitch tracheal pressure (Ptr,tw), a significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) (p-value of 0.04). In the control group, Ptr,tw exhibited an absolute change of -1.43 ± 0.68 cmH20, corresponding to a relative decrease of 19.49% ± 16.98 from baseline values to day 3, while the NMES group experienced an absolute change of +2.5 ± 3.8 cmH2O, equivalent to a relative increase of 46.4 ± 45.6 %. Analyzing the raw plasmatic concentrations of myokines, no significant interaction was detected between time (across the 4-day protocol) and intervention (NMES or not) for any of the myokine concentrations (Decorin, Myostatin, IL-6 and BDNF). Moreover, there were no significant changes observed either within or between groups at any time point. Conclusion: The preliminary data analysed supports the notion that peripheral NMES can preserve respiratory muscle function. It appears that this effect is not mediated by changes in any of the myokines included in the present study. Therefore, alternative mechanisms should be considered to explain how NMES may favour respiratory muscle preservation. The results observed on peripheral muscle layer thickness are yet unconclusive with the limited sample size analysed. Data from a larger number of patients is required to confirm these preliminary conclusions.
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    Neural dynamics of creative drawing
    (2023) Cordero Roldán, Evelyn; Rodríguez B., Eugenio; Pontificia Universidad Católica de Chile. Facultad de Medicina; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas; Pontificia Universidad Católica de Chile. Facultad de Ciencias Sociales; Pontificia Universidad Católica de Chile. Facultad de Química
    Creativity is a characteristic element of human cognition. At the brain level, the difference between creative and non-creative problem solving correlates with changes in alpha oscillatory activity. Although interesting, a weakness of these studies is the imbalance between the cognitive demands associated with the creative task (harder) and the control task (easier). This point casts doubt on whether alpha activity is indeed a marker of the creative process or rather is a general index of the cognitive demands of the task. To elucidate this issue, we compared the oscillatory brain response of subjects while performing two cognitively demanding drawing tasks, which differed only in the level of creativity required to execute them. Compared to the ideation of creative drawings, the ideation of conventional drawings induced a greater increase in alpha power, mainly over bilateral frontal and posterior regions. Furthermore, compared to low creative subjects, high creative subjects show a progressive increase in alpha power during the ideation phase, distributed across right frontoparietal and bilateral posterior sites. Taken together, these findings suggest task-specific allocation of cognitive resources over time, with greater cognitve control at the beginning and decreased control towards the end in more structured tasks, and conversely in tasks that demand creative problem solving. Future research should explore these dynamics further, particularly in relation to individual differences in creativity.
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    Tooth loss and depression: epidemiological evidence of causality from the Chilen population
    (2023) Ortuño Borroto, Duniel; Ferreccio Readi, Catterina; Pontificia Universidad Católica de Chile. Escuela de Medicina
    En este estudio, se evaluó la asociación entre pérdida dentaria y depresión con diferentes diseños y poblaciones en Chile. En el marco muestral MAUCO se realizó un análisis longitudinal, con regresiones logísticas binarias y multinomial. Se encontró que los individuos con 19 o menos dientes podrían tener mayor riesgo de depresión, con diferencias entre hombres y mujeres. El edentulismo se asoció a mayor incidencia de depresión a los 4 años de seguimiento, y con mayores niveles de severidad de los síntomas depresivos en mujeres. En los individuos edéntulos al inicio del estudio, el riesgo para cada una de las comparaciones "leve vs no", "moderada vs no", ”moderada severa vs no" y ”severa vs no" fue mayor comparado con aquellos con ≥ 20 dientes. Utilizando el marco muestral ENS 2016-2017, se realizó un análisis de mediación para evaluar el rol de las funciones orales en la asociación entre pérdida de dientes, incluyendo anteriores, y depresión en individuos de 15 años o más. El deterioro de las funciones orales fue un mediador en la asociación entre la pérdida de dientes y el autorreporte o la sospecha de depresión. La sensación de incomodidad al hablar o la incomodidad al comer fueron los mediadores más significativos.