Embrace of a consistent mentoring approach to ensure effective oversight of the mentoring process must be balanced with sufficient flexibility to ensure a mentee-centered approach. Efforts must be made to optimize the key aspects of mentoring relationships in order to ensure successful mentoring processes and outcomes.

The tumor suppressor ARF enhances the SUMOylation of target proteins; however, the physiological function of ARF-mediated SUMOylation has been unclear due to the lack of a known, associated E3 SUMO ligase. Here we uncover TRIM28/KAP1 as a novel ARF-binding protein and SUMO E3 ligase for NPM1/B23. ARF and TRIM28 cooperate to SUMOylate NPM1, a nucleolar protein that regulates centrosome duplication and genomic stability. ARF-mediated SUMOylation of NPM1 was attenuated by TRIM28 depletion and enhanced by TRIM28 overexpression. Coexpression of ARF and TRIM28 promoted NPM1 centrosomal localization by enhancing its SUMOylation and suppressed centrosome amplification; these functions required the E3 ligase activity of TRIM28. Conversely, depletion of ARF or TRIM28 increased centrosome amplification. ARF also counteracted oncogenic Ras-induced centrosome amplification. Centrosome amplification is often induced by oncogenic insults, leading to genomic instability. However, the mechanisms employed by tumor suppressors to protect the genome are poorly understood. Our findings suggest a novel role for ARF in maintaining genome integrity by facilitating TRIM28-mediated SUMOylation of NPM1, thus preventing centrosome amplification. T he INK4a/ARF locus encodes two tumor suppressors, (i) p16INK4a , an inhibitor of cyclin-dependent kinase 4/6 (CDK4/ 6), and (ii) an alternative reading frame (ARF) protein (p14 ARF in humans and p19 ARF in mouse), referred to here as "ARF." This locus is mutated in approximately 40% of human cancers. ARF contributes to p53 stabilization and activation through inhibition of murine double minute 2 (MDM2), leading to cell cycle arrest, apoptosis, or senescence. Oncogenic insults such as mutations in Ras upregulate the expression of ARF to protect cells from tumorigenesis (1).There is substantial evidence that ARF has additional, p53-independent functions (2). For example, a broader spectrum of tumors was observed in ARF/p53-null mice than in p53-null mice (3). ARF is enriched within the nucleolus but also localizes to the mitochondria to induce apoptosis or autophagy in a p53-independent manner (2). These data support a role of ARF in p53-independent tumor-suppressive functions. However, the underlying mechanisms remain elusive.Interestingly, ARF has been shown to promote SUMOylation of MDM2 (4), nucleophosmin (NPM1/B23) (5), and the Werner helicase (WRN) (6) independently of p53. However, ARF did not stimulate SUMOylation in an in vitro reconstitution reaction in the presence of SUMO E1/E2 enzymes (6), suggesting that ARF is not the E3 SUMO ligase. The mechanism and biological impact of ARF-mediated SUMOylation are currently unclear.NPM1 has been shown to be involved in the p53-independent ARF pathway (7). NPM1 usually resides in the nucleolus but also shuttles between the nucleus and cytoplasm (8). SUMOylation of NPM1 contributes to its centrosomal localization (9), and NPM1 has been reported to exert tumor-suppressive function. For example, loss of NPM1 leads to centrosome amplification, resultin...

Background: It is often difficult for patients with advanced heart failure (HF) to decide whether to live with a left ventricular assist device (LVAD) or not. Little is known about their decisional needs prior to LVAD implantation and if these needs were met in the Asian cultural setting. Aims: We aimed to explore the influences, concerns, and needs surrounding the decision-making process of the LVAD implantation among multi-ethnic Asian patients with HF. Methods: Semi-structured interviews with HF patients and caregivers were conducted, based upon the grounded theory approach. Participants were purposively recruited from the inpatient and outpatient setting of the National Heart Centre Singapore. Results: A total of 31 patients and 11 caregivers participated. Mindsets that shaped decision-making ranged from “having no choice,” “being reflective,” “taking a gamble,” and “fighting on.” Instead of making a sole decision, many patients reported that decisions were shared with the family or medical team. Current LVAD patients who acted as patient ambassadors were also strong influences. Spiritual support was pivotal to decision-making for some participants. Goals influencing decision-making including protecting the family and life prolongation improving quality of life. Values held close included sanctity of life, trusting in a higher power, believing in pre-destination or karma, and preserving family harmony. Participants had concerns about cost, employment, and health outcomes. Conclusions: Asian LVAD patients and caregivers had culturally specific mindsets, goals, and values and concerns around decision-making. Our findings have implications for the design of interventions and supportive care models.

No abstract