The tumour microenvironment, treatment resistance and recurrence in glioblastoma.

The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, with many clinical trials, GBM patients rely on standard treatments including surgery followed by radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure to improve treatments is undoubtedly a result of insufficient models which fail to incorporate components of the human brain TME. Research has increasingly uncovered mechanisms of tumour-TME interactions that correlate to worsened patient prognoses, including tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling and immunosuppression. This tumour hijacked TME is highly implicated in driving therapy resistance, with further alterations within the TME and tumour resulting from therapy exposure inducing increased tumour growth and invasion. Recent developments improving organoid models, including aspects of the TME, are paving an exciting future for the research and drug development for GBM, with the hopes of improving patient survival growing closer. This review focuses on GBMs interactions with the TME and their effect on tumour pathology and treatment efficiency, with a look at challenges GBM models face in sufficiently recapitulating this complex and highly adaptive cancer.

Information, Motivation, Behavioral Skills Model in Youth Newly Starting Antiretroviral Treatment.

An understanding of adherence among youth newly starting antiretroviral therapy (ART) is critical but understudied. The information-motivation-behavioral skills (IMB) model is often used to understand health behaviors, but has rarely been studied in youth with HIV. In a multi-site sample of 153 youth newly starting ART, structural equation modeling was utilized to test this model. The model was generally supported with information and behavioral skills directly related to the decision to adhere, while motivation was indirectly related through behavioral skills. Results suggest that interventions focusing on improving IMB constructs for medication adherence are important for preventing non-adherence in youth newly starting ART.

RESUMEN: El entendimiento de la adherencia en jóvenes que recién comienzan ART es fundamental, pero se ha estudiado poco. El modelo de información-motivación-habilidades conductuales (IMB, por sus siglas en inglés) se usa a menudo para comprender los comportamientos de salud, pero rara vez se ha estudiado en jóvenes que viven con el VIH. En una muestra de múltiples sitios de 153 jóvenes que recién comenzaban ART, se utilizó el análisis de ecuaciones estructurales para probar este modelo. En general, el modelo fue apoyado con información y habilidades conductuales directamente relacionadas con la decisión de adherirse, mientras que la motivación se relacionó indirectamente a través de las habilidades conductuales. Los resultados sugieren que las intervenciones que se enfocan en mejorar los aspectos del modelo IMB para la adherencia al medicamento son importantes para prevenir la falta de adherencia en los jóvenes que recién comienzan ART.

The role of histone lysine demethylases in cancer cells' resistance to tyrosine kinase inhibitors.

Current cancer therapies are often associated with treatment failure and reduced patients' survival due to drug resistance. There are various mechanisms involved in the acquisition of cancer drug resistance, including the selection of advantageous mutations, overexpression of transporter proteins and epigenetic alterations. In this context, epigenetic alterations refer to chromatin-mediated regulation of gene expression that results in heritable changes in the cellular phenotype. There is an ever-growing body of evidence suggesting that epigenetic mechanisms play an important role in bringing about drug resistance in cancer cells. While the relationship between chemotherapy and epigenetics has been widely discussed, emerging evidence indicates that specific epigenetic effectors are also crucial for the development of resistance to tyrosine kinase inhibitors (TKIs). One particular gene that encodes the histone lysine demethylase KDM5A is overexpressed in several cancers. In breast cancer tissues, cells with KDM5A gene amplification were found to be more resistant to erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), when compared to cells without the same amplification. KDM5A was also shown to mediate resistance to a second EGFR inhibitor called gefitinib, in EGFR-mutant lung cancer cell lines. This evidence indicates that KDM5A could activate alternative survival pathways involved in overcoming EGFR inhibition. In line with these results, another histone demethylase (i.e., KDM1A) promotes liver cancer cells' resistance to the TKI sorafenib. Current evidence provides a suitable rationale to consider the use of specific KDMs inhibitors to sensitize cells to tyrosine kinase targeted therapies and thus, presents an opportunity to prevent the further development of drug resistance. This review discusses the involvement of histone lysine demethylases in the development of resistance to TKI and highlights the importance to develop new cancer treatment regimens to counteract this phenomenon.