BackgroundThe tumor suppressor KLF6 and its oncogenic cytoplasmic splice variant KLF6-SV1 represent a paradigm in cancer biology in that their antagonistic cancer functions are encoded within the same gene. As a consequence of splicing, KLF6-SV1 loses both the C-terminus C2H2 three zinc finger (ZF) domain, which characterizes all KLF proteins, as well as the adjacent 5′ basic region (5BR), a putative nuclear localization signal (NLS). It has been hypothesized that this NLS is a functional domain critical to direct the distinct subcellular localization of the tumor suppressor and its splice variant.Methodology/Principal FindingsIn this study, we demonstrate using EGFP fusion constructs that KLF6/KLF6-SV1 nucleo-cytoplasmic transport is not regulated by the 5′ basic region but activated by a novel NLS encoded within the ZF domain, and a nuclear export signal (NES) located in the first 16 amino acids of the shared N-terminus sequence. We demonstrate KLF6 nuclear export to be Crm1-dependent. The dysregulation of nucleo-cytoplasmic transport when disrupting the KLF6 NLS using site-directed mutagenesis showed that its integrity is necessary for appropriate protein stability. Moreover, these mutations impaired transcriptional induction of two KLF6 well-characterized target genes, E-cadherin and p21, as shown by RT-PCR and luciferase promoter assays. The addition of the ZF domain to KLF6-SV1 results in its nuclear localization and a markedly decreased half-life similar to wild type KLF6.Conclusions/SignificanceWe describe the domains that control KLF6 nucleo-cytoplasmic shuttling and how these domains play a role in KLF6 protein half-life and tumor suppressor function. The results begin to mechanistically explain, at least in part, the opposing functions of KLF6 and KLF6-SV1 in cancer.
Left ventricular assisted devices (LVADs) are increasingly used for management of patients with advanced heart failure. However, infection remains one of the most commonly reported complications. Diagnosis, as well as treatment of LVAD infections is challenging. There are multiple diagnostic modalities that have been used to assist with accurate diagnosis of LVAD infections. Treatment of the infection can be especially challenging in these patients, given the presence of the implantable device that cannot be easily replaced or removed. There are no clinical trials assessing the best approach to diagnosis, treatment or long-term management of LVAD infections. In this article we review the most recent diagnostic modalities and treatment approaches, as well as offer our guidance on diagnosis and treatment of LVAD infections.
Background
Solid organ transplant (SOT) recipients are a complex, immunocompromised population in whom greater COVID-19 mortality has been reported as compared to the general population.
Methods
We examined a retrospective cohort of 58 SOT recipients with first-wave COVID-19, comparing patients with severe and non-severe illness. Additionally, SOT patients are compared to general first-wave COVID-19 patients.
Results
Organs transplanted included 38 kidneys, 8 livers, 5 hearts, 3 pancreas. Average SOT patient age was 57.4 years with 62% male, 46.6% African American, 36.2% white. Comorbidities included hypertension (86%), chronic kidney disease (86%), diabetes mellitus (50%), coronary artery disease (26%), COPD (14%). Twenty patients (34.5%) had severe COVID-19 and 38 (65.5%) non-severe disease. Severe disease was more common in older SOT patients with comorbidities and associated with cough, dyspnea, pneumonia, C-reactive protein > 10 mg/L, platelet count < 150/mcL. Gender, race, BMI, time from transplant, baseline immunosuppression and diagnosis month did not differ between those with severe vs non-severe COVID-19. Seventy percent of SOT patients were hospitalized vs 27.2% of general COVID-19 patients and SOT inpatients had a higher mechanical ventilation rate. While trending towards longer length of stay, higher ICU admission and greater inpatient mortality (19.5% vs 14.8%), these differences were not significant.
Conclusions
SARS-CoV-2 has greatly impacted SOT recipients. One-third of our SOT patients seen during the first wave had severe illness with associated standard risk factors for poor outcome. Compared to general first wave patients, more SOT recipients were hospitalized, although inpatient COVID-19 mortality did not significantly differ.
Stopping conventional showering may reduce the rate of Pseudomonas LVAD exit-site infections. Additional, multi-institutional data are needed to further evaluate these findings.
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