Mammalian sirtuins have emerged in recent years as critical modulators of multiple biological processes, regulating cellular metabolism, DNA repair, gene expression, and mitochondrial biology. As such, they evolved to play key roles in organismal homeostasis, and defects in these proteins have been linked to a plethora of diseases, including cancer, neurodegeneration, and aging. In this review, we describe the multiple roles of SIRT6, a chromatin deacylase with unique and important functions in maintaining cellular homeostasis. We attempt to provide a framework for such different functions, for the ability of SIRT6 to interconnect chromatin dynamics with metabolism and DNA repair, and the open questions the field will face in the future, particularly in the context of putative therapeutic opportunities.
Highlights d The histone deacetylase SIRT6 binds to Pol II and promotes transcriptional pausing d SIRT6 retains NELF by deacetylating intragenically H3K9 and H3K56 d Removal of SIRT6 from chromatin increases K9/K56 acetylation d Recruitment of elongation factors promotes transcriptional elongation of SIRT6 targets
Oncogenic "driver" mutations are theoretically attractive targets for the immunotherapy of lymphoid cancers, yet the proportion that can be recognized by T cells remains poorly defined. To address this issue without any confounding effects of the patient's immune system, we assessed T cells from 19 healthy donors for recognition of three common driver mutations in lymphoma: , and . Donors collectively expressed the 10 most prevalent HLA class I alleles, including HLA-A*02:01. Peripheral blood T cells were primed with peptide-loaded dendritic cells (DC), and reactive T cells were assessed for recognition of naturally processed mutant versus wild type full-length proteins. After screening three driver mutations across 17-26 HLA class I alleles and 3 × 10-3 × 10 T cells per donor, we identified CD4 T cells against EFISECGEII from EZH2 (presented by HLA-DRB1*13:02) and CD8 T cells against RIPIKYKA from MYD88 (presented by HLA-B*07:02). We failed to detect RIPIKYKA-specific T cells in seven other HLA-B*07:02-positive donors, including two lymphoma patients. Thus, healthy donors harbor T cells specific for common driver mutations in lymphoma. However, such responses appear to be rare due to the combined limitations of antigen processing, HLA restriction, and T cell repertoire size, highlighting the need for highly individualized approaches for selecting targets.
A fundamental challenge in cancer genomics is to design effective, personalized treatments based on the mutational profiles of tumors. Pharmacological targeting of the numerous aberrant pathways found in individual tumors remains exceedingly challenging, but T cellbased therapies are an attractive alternative because of the enormous diversity and exquisite specificity of antigen recognition. We assessed the immunogenicity of three common driver mutations in human lymphoma -MYD88 L265P , EZH2 Y641N , and EZH2 Y641Fto evaluate their suitability as targets for immunotherapy. Antigen presenting cells were loaded with overlapping peptide libraries containing each mutation and used to stimulate autologous T cells from healthy donors and lymphoma patients. Stimulated T cells were screened by interferongamma ELISPOT for reactivity to mutant versus wildtype peptides as well as full-length proteins. All three peptide libraries elicited T cell responses from multiple donors representing diverse HLA haplotypes. Moreover, we identified peptides from MYD88 L265P and EZH2 Y641N that were naturally processed and presented, and the corresponding T cell responses were specific for mutant proteins. Thus, MYD88 L265P and EZH2 Y641N both represent compelling antigens for immunotherapy of lymphoma patients.
ObjectiveThe purpose of this study was to characterize the impact of adolescent pregnancy on families and describe the needs of adolescent mothers and their infants in order to assess the need for intervention and identify potential intervention targets.BackgroundAdolescent mothers and their offspring face an increased risk of mental health problems. Adolescent mothers and their families also face significant resource constraints; 95% live in low‐ and middle‐income countries (LMICs). Cost‐effective interventions are needed to improve outcomes for this vulnerable group.MethodThis qualitative study conducted in Lima, Peru, consisted of four clinician focus groups and 18 in‐depth interviews with adolescent mothers and their family members. Data were coded thematically, and direct content analysis was employed.ResultsThe study identified the following issues facing adolescent parents: the transition to parenthood, the need for family support, difficulty accessing support, the difficulty for family members of providing support, and ideas about responsibility and adolescent autonomy.ConclusionOverall, these findings demonstrate the need for interventions that engage families and address barriers to accessing support, including relationship conflict and differing beliefs about responsibility and autonomy.ImplicationsInterventions are needed for adolescent mothers in LMICs that mobilize family support. Clinicians who care for these patients need to be aware of the family context and the resources available where they practice.
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