The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC

The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe

As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic o

"Significados asociados a la actividad delictiva” en hombres que se encuentran privados de libertad, por delito de robo, en Centro de Detención Preventiva Santiago Sur

The following Seminar is orientated to understand the meanings that people outside the law give to their own criminal activities, primarily stealing, through the identification and connection between the emerging issues and the theoretical constructs made through this study. The identification and understanding of this topic is developed focusing on Occupational Therapy general views.To develop this qualitative research, the project takes place in Centro de Detención Preventiva ( Preventive detention center) Santiago Sur, Chile, with men between the ages of 27 and 35 years old, which are convicted for robbery. The information was collected from five semi-structured interviews, and analyzed with the Grounded Theory. This allows the review of emerging phenomena and compares them with the theoretical approach.The results indicate that the meanings related to stealing are correlated with different phenomena, like: psychosocial risk factors, criminal initiation and the influence of being part of social networks, exploratory behavior, psychosocial development, symbolic interaction and meaningful map, personal identity, premeditated action and motivation for stealing, self-concept and self-efficiency.After discovering and understanding the phenomena from the participant's point of view, it is clear to see two different ways for understanding the act of stealing, which differ from the meaning that the person gives to the act. On one hand, they see themselves as thieves and participate with the role. And on the other, they do not see themselves as thieves, they find an identity with the job, becoming the main activity in their lives.The analysis and results of the meanings associated to the act of robbery can be interesting for Occupational Therapy. This research includes key elements for this discipline and its development, including the motivation and personal subjectivity, bounds, relationships and the context for their development, making all together the meanings of each person.El presente estudio pretende comprender los significados que las personas transgresoras de ley, le otorgan a su propia actividad delictiva, específicamente al robo, mediante la identificación y relación de los temas emergentes durante este estudio, con constructos teóricos. La identificación y comprensión de estos temas, se realiza en torno a una visión general de Terapia Ocupacional.Para abordar esta investigación, de carácter cualitativo, se contextualiza el tema a estudiar en Centro de Detención Preventiva Santiago Sur, siendo los participantes hombres entre 27 y 35 años, que cumplen condena por delito de robo. La información recopilada, se extrae a partir de cinco entrevistas semi estructuradas, para ser luego analizadas a través de la Teoría Fundada, que permite revisar los fenómenos emergentes y ponerlos en discusión con los planteamientos teóricos.Los hallazgos obtenidos, señalan que los significados asociados al robo, se pueden relacionar a distintos fenómenos como; factores psicosociales de riesgo, inicio delictual e influencia y pertenencia a redes sociales, conducta exploratoria, procesos psicosociales, interacción simbólica y mapa significativo propio, identidad personal, acción preconcebida y motivaciones del robo, autoconcepto y autoeficacia.Al descubrir y analizar los fenómenos desde los participantes, emergieron dos formas de significar el robo, las cuales se diferencian según la relación que tiene el entrevistado con   este. En una de las categorías, se consideran ladrones, asumen este rol y se auto perciben como tales. En la otra, no se consideran a si mismos ladrones, identificándose con el trabajo, siendo esta la principal actividad en sus vidas.Al conocer y profundizar sobre los significados asociados al robo, se puede aportar a Terapia Ocupacional, ya que se consideran en la investigación elementos claves para esta disciplina y su desempeño, como son las motivaciones y la subjetividad de cada persona, los vínculos, relaciones y el contexto en que estas se dan, formando en conjunto los significados de cada persona