Predictive Biomarkers of Severe Immune-Related Adverse Events With Immune Checkpoint Inhibitors: Prevention, Underlying Causes, Intensity, and Consequences.

Immune checkpoint inhibitors (ICIs) have dramatically transformed oncology by prolonging overall survival and yielding better patient tolerance compared to other chemotherapeutic agents. However, numerous questions remain unanswered about the toxicity profile of ICIs, its relationship with the treatment response, and causes underlying the excellent treatment response in some patients, while recalcitrance in others. Research groups have continued to seek biomarkers that may permit the identification of treatment responders and predict toxicity to facilitate cessation of immunotherapy before the development of severe toxicity. However, some studies have found associations between serious adverse events and longer survivorship. The research question entailed determining whether a biomarker is needed to predict severe immune-related adverse events prior to their development or whether providing early treatment for toxicity would inhibit the immune system from attaining a long-lasting anti-tumor effect. Therefore, this review conducted an in-depth analysis into the molecular basis of these observations.

Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors -A Review.

People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.

Máster en Oncología Molecular. Un conocimiento indispensable en la práctica clínica / Master in Molecular Oncology: An indispensable knowledge in clinical practice

La formación que reciben los especialistas vinculados con la enfermedad oncológica no aborda en profundidad el conocimiento de las bases moleculares del cáncer. Hoy no se concibe una práctica clínica de excelencia sin el conocimiento de las bases moleculares de la enfermedad. Consecuentemente, resulta necesaria una formación específica en oncología molecular que le aporte al especialista médico una herramienta óptima en el diagnóstico y tratamiento. El cáncer tiene unas bases genéticas y moleculares estudiadas en profundidad por los mejores laboratorios del mundo. El diagnóstico, pronóstico y tratamiento se basa cada vez más en los marcadores moleculares de cada paciente. De esta necesidad surgió el Máster en Oncología Molecular: Bases Moleculares del Cáncer que se presenta en este artículo, y que es considerado en muchos servicios de oncología de hospitales españoles y latinoamericanos una formación esencial para sus residentes y especialistas. Este máster se imparte íntegramente online, permitiendo al especialista médico compaginar la formación con su trabajo, siguiendo las clases desde su propio ordenador. Otras ventajas para el alumno son el establecimiento de redes profesionales con otros especialistas y la adquisición de nuevas capacidades para participar en proyectos de investigación y colaboraciones científicas

The training received by the MDs in oncology does not allow enough time to look into the molecular basis of cancer. Nowadays, a clinical practice of excellence cannot be conceived without knowledge of the molecular basis of the disease. Consequently, specific training in molecular oncology will provide the MD with an optimal tool in the diagnosis and treatment of cancer. The genetic and molecular basis of cancer have been studied in detail by the best laboratories in the world. The diagnosis, prognosis and treatment are increasingly based on the molecular markers of each patient. The Master in Molecular Oncology: Molecular Basis of Cancer has been created for this need, which is presented in the following article. This course is considered an essential training for oncology residents and fellows in most Spanish and Latin-American hospitals. The full program is online. This allows medical specialists to combine their training with their clinical practice, following the courses from their own computers. Other advantages for the students are: creation of professional networks with other specialists from all over the world and the acquisition of new skills to participate in research projects and scientific collaborations

Doxazosin induces apoptosis in LNCaP prostate cancer cell line through DNA binding and DNA-dependent protein kinase down-regulation.

Doxazosin is a quinazoline-based compound acting as an alpha-1-adrenergic inhibitor shown to induce apoptosis in prostate cancer cell lines via an alpha-1-adrenergic receptor-independent mechanism. To better understand the mechanism of doxazosin-induced apoptosis in prostate cancer, we performed cDNA microarray to analyze gene expression changes produced by doxazosin in the androgen-dependent human prostate cancer cell line, LNCaP. We found that 70 and 92 genes were deregulated after 8 and 24 h of doxazosin treatment, respectively. These genes are involved in several cellular processes such as cell-cycle regulation, cell adhesion and signal transduction pathways. Strikingly, we found that doxazosin induces deregulation of genes implicated in DNA replication and repair, such as GADD45A, XRCC5 and PRKDC. These facts, together with the demonstration of the ability of doxazosin to bind DNA, allowed us to propose a novel mechanism of action for doxazosin in prostate cancer cells that implies DNA-damage mediated apoptosis by down-regulation of XRCC5 and PRKDC genes.

Inhibition of proliferation and expression of T1 and cyclin D1 genes by thyroid hormone in mammary epithelial cells.

The relationship between thyroid hormone (triiodothyronine, T(3)) and breast cancer is unclear. We studied the effect of the c-erbA/TR alpha proto-oncogene encoding a functional T(3) receptor (TR alpha 1), of its ligand T(3), and of its retroviral, mutated counterpart, the v-erbA oncogene, on the proliferation capacity of nontumorigenic mammary epithelial cells (EpH4). We found that EpH4 cells expressing ectopically TR (EpH4 + TR alpha 1) or v-erbA (EpH4 + v-erbA) proliferated faster than parental EpH4 cells that contained low levels of endogenous TR. T(3) inhibited DNA synthesis and proliferation in EpH4 + TR alpha 1 cells but not EpH4 or EpH4 + v-erbA cells. The study of cell-cycle genes showed that T(3) decreased cyclin D1 RNA and protein levels in EpH4 + TR alpha 1 cells. In addition, T(3) downregulated the expression of T1, a gene that is overexpressed in human breast adenocarcinomas and is induced by mitogens, serum, and several oncogenes and cytokines. Inhibition of the T1 gene by T(3) required both de novo mRNA and protein synthesis. Furthermore, T(3) abolished the induction of T1 by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and inhibited the activity of an activation protein 1-dependent promoter (-73-Col-CAT) in EpH4 + TR alpha 1 cells, suggesting that interference with activation protein 1 transcription factor plays a part in the inhibition of the T1 gene. Our results showed that T(3) reduced the proliferation of mammary epithelial cells and inhibited the expression of cyclin D1 and T1 genes.