RESUMO
Prostate cancer is a heterogeneous disease with a need for new prognostic biomarkers. Human leukocyte antigen (HLA) genes are highly polymorphic genes central to antigen presentation to T-cells. Two alleles, HLA-A*02:01 and HLA-A*24:02, have been associated with prognosis in patients diagnosed with de novo metastatic prostate cancer. We leveraged the next-generation sequenced cohorts CPC-GENE and TCGA-PRAD to examine HLA alleles, antiviral T-cell receptors and prostate cancer disease recurrence after prostatectomy. Carrying HLA-A*02:01 (111/229; 48% of patients) was independently associated with disease recurrence in patients with low-intermediate risk prostate cancer. HLA-A*11 (carried by 42/441; 10% of patients) was independently associated with rapid disease recurrence in patients with high-risk prostate cancer. Moreover, HLA-A*02:01 carriers in which anti-cytomegalovirus T-cell receptors (CMV-TCR) were identified in tumors (13/144; 10% of all patients in the cohort) had a higher risk of disease recurrence than CMV-TCR-negative patients. These findings suggest that HLA-type and CMV immunity may be valuable biomarkers for prostate cancer progression.
Assuntos
Infecções por Citomegalovirus , Neoplasias da Próstata , Antivirais , Citomegalovirus , Infecções por Citomegalovirus/genética , Antígenos HLA-A , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Prostatectomia , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
The RNA integrity number (RIN) is a frequently used quality metric to assess the completeness of rRNA, as a proxy for the corresponding mRNA in a tissue. Current methods operate at bulk resolution and provide a single average estimate for the whole sample. Spatial transcriptomics technologies have emerged and shown their value by placing gene expression into a tissue context, resulting in transcriptional information from all tissue regions. Thus, the ability to estimate RNA quality in situ has become of utmost importance to overcome the limitation with a bulk rRNA measurement. Here we show a new tool, the spatial RNA integrity number (sRIN) assay, to assess the rRNA completeness in a tissue wide manner at cellular resolution. We demonstrate the use of sRIN to identify spatial variation in tissue quality prior to more comprehensive spatial transcriptomics workflows.
Assuntos
RNA Mensageiro/análise , Análise Espacial , Transcriptoma , Linhagem Celular Tumoral , HumanosRESUMO
Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells manifest a limited contribution to cell replacement. We have uncovered a latent potential in neural stem cells to replace large numbers of lost oligodendrocytes in the injured mouse spinal cord. Integrating multimodal single-cell analysis, we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Ectopic expression of the transcription factor OLIG2 unveiled abundant stem cell-derived oligodendrogenesis, which followed the natural progression of oligodendrocyte differentiation, contributed to axon remyelination, and stimulated functional recovery of axon conduction. Recruitment of resident stem cells may thus serve as an alternative to cell transplantation after CNS injury.
Assuntos
Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Oligodendroglia/fisiologia , Regeneração da Medula Espinal/fisiologia , Animais , Astrócitos/fisiologia , Axônios/fisiologia , Linhagem da Célula , Epêndima/citologia , Epêndima/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/citologia , Recuperação de Função Fisiológica/genética , Recuperação de Função Fisiológica/fisiologia , Remielinização/genética , Remielinização/fisiologia , Análise de Célula Única , Traumatismos da Medula Espinal/fisiopatologia , Regeneração da Medula Espinal/genéticaRESUMO
The present protocol describes in detail the steps necessary for executing two highly versatile and minimally invasive surgical approaches for localized delivery of compounds to the central nervous system. The procedures have been designed for use on laboratory mice but can also be tailored for experimentations involving other small rodent models. Following the instructions outlined below, treatments can either be administered through single injections or infused over a longer period of time, at locations identified through stereotaxic coordinates, which ensure efficient targeting of the brain region of interest, as well as increased reproducibility between surgeries. Although the surgical interventions are well tolerated by laboratory animals, it is recommended to closely monitor the mice postoperatively for a few days, and take the necessary measures to prevent stress and discomfort.