Pluripotent cells can be derived from various types of somatic cells by nuclear reprogramming using defined transcription factors. It is however unclear whether human cancer cells can be similarly reprogrammed and subsequently terminally differentiated with abrogation of tumorigenicity. Here, using sarcomas we show that human derived complex karyotype solid tumors: (1) can be reprogrammed into a pluripotent-like state as defined by all in vitro criteria used to define pluripotent stem cells generated from somatic cells; (2) can be terminally differentiated into mature connective tissue and red blood cells; and (3) terminal differentiation is accompanied with loss of both proliferation and tumorigenicity. We go on to perform the first global DNA promoter methylation and gene expression analyses comparing human cancers to their reprogrammed counterparts and report that reprogramming/differentiation results in significant epigenetic remodeling of oncogenes and tumor suppressors; while not significantly altering the differentiation status of the reprogrammed cancer cells, in essence de-differentiating them to a state slightly before the mesenchymal stem cell differentiation stage. Our data demonstrates that direct nuclear reprogramming can restore terminal differentiation potential to human derived cancer cells, with simultaneous loss of tumorigenicity, without the need to revert to an embryonic state. We anticipate that our models would serve as a starting point to more fully assess how nuclear reprogramming overcomes the multitude of genetic and epigenetic aberrancies inherent in human cancers to restore normal terminal differentiation pathways. Finally, these findings suggest that nuclear reprogramming may be a broadly applicable therapeutic strategy for the treatment of cancer.

Expression of Piwi proteins is confined to early development and stem cells during which they suppress transposon migration via DNA methylation to ensure genomic stability. Piwi's genomic protective function conflicts with reports that its human ortholog, Hiwi, is expressed in numerous cancers and prognosticates shorter survival. However, the role of Hiwi in tumorigenesis has not been examined. Here we demonstrate that (1) over-expressing Hiwi in sarcoma precursors inhibits their differentiation in vitro and generates sarcomas in vivo; (2) transgenic mice expressing Hiwi (mesodermally restricted) develop sarcomas; and (3) inducible down-regulation of Hiwi in human sarcomas inhibits growth and re-establishes differentiation. Our data indicates that Hiwi is directly tumorigenic and Hiwi-expressing cancers may be addicted to Hiwi expression. We further show that Hiwi associated DNA methylation and cyclin-dependent kinase inhibitor (CDKI) silencing is reversible along with Hiwi-induced tumorigenesis, via DNA-methyltransferase inhibitors. Our studies reveal for the first time not only a novel oncogenic role for Hiwi as a driver of tumorigenesis, but also suggest that the use of epigenetic agents may be clinically beneficial for treatment of tumors that express Hiwi. Additionally, our data showing that Hiwi-associated DNA hyper-methylation with subsequent genetic and epigenetic changes favoring a tumorigenic state reconciles the conundrum of how Hiwi may act appropriately to promote genomic integrity during early development (via transposon silencing) and inappropriately in adult tissues with subsequent tumorigenesis.

Myxoid round cell liposarcoma (MRCLS) is

Objective Seeking consent for minimal risk research in the ICU poses challenges, especially when the research is time-sensitive. Our aim was to determine the extent to which ICU patients or surrogates support a deferred consent process for a minimal risk study without the potential for direct benefits. Design Prospective cohort study. Setting Five ICUs within a tertiary care hospital. Patients Newly admitted ICU patients ≥18 years old. Interventions We administered an eight-item verbal survey to patients or surrogates approached for consent to participate in a minimal-risk, ICU based study. The parent study involved non-invasive collection of biosamples and clinical data at the time of ICU admission and again 3 days later. If patients had capacity at the time of ICU admission, or if a surrogate was readily available, consent was sought prior to initial sample collection; otherwise, a waiver of consent was granted and deferred consent was sought 3 days later. Quantitative and qualitative data were analyzed. Measurements and Main Results 157 individuals were approached for consent to participate in the parent study; none objected to the consent process. 135/157 (86%) competed the survey, including 94 who consented to the parent study and 41 who declined. 44/60 (73%) individuals approached for deferred consent responded positively to the question “Did we make the right choice in waiting until now to ask your consent?” 3/60 (5%) responded negatively, and 13/60 (22%) made a neutral or unrelated response. The most common reason given for endorsing the deferred consent process was the stress of the early ICU experience 25/44 (61%). Conclusions Most patients and surrogates accept a deferred consent process for minimal risk research in the ICU. For appropriate ICU-based research, investigators and IRBs should consider a deferred consent process if the subject lacks capacity and an appropriate surrogate is not readily available.

Background & Aims Proton pump inhibitors (PPIs) have been associated with increased risk of infection, likely due to changes in intestinal epithelial permeability and the gastrointestinal microbiome. PPIs are frequently given to patients in the intensive care unit (ICU) to prevent stress ulcers. These patients are at risk for bloodstream infections (BSIs), so we investigated the relationship between PPI use and BSIs among patients in the ICU. Methods We performed a retrospective cohort study of adults (≥18 years) admitted to 1 of 14 ICUs within a hospital network of 3 large hospitals from 2008 through 2014. The primary exposure was PPI use for stress ulcer prophylaxis in the ICU. The primary outcome was BSI, confirmed by culture analysis, arising 48 hrs or more after admission to the ICU. Subjects were followed for 30 days after ICU admission or until death, discharge, or BSI. Multivariable Cox proportional-hazards modeling was used to test the association between PPIs and BSI, after controlling for patient comorbidities and other clinical factors. Results We analyzed data from 24,774 patients in the ICU, including 756 patients (3.1%) who developed BSIs while in the ICU. The cumulative incidence of BSI was 3.7% in patients with PPI exposure compared to 2.2% in patients without PPI exposure (log-rank test P<.01). After adjusting for potential confounders, PPI exposure was not associated with increased risk of BSI while in the ICU (adjusted hazard ratio, 1.08; 95% CI, 0.91–1.29). Comorbidities, antibiotic use, and mechanical ventilation were all independently associated with increased risk for BSIs. Conclusion In a retrospective study of patients in the ICU, administration of PPIs to prevent bleeding was not associated with increased risk of BSI. These findings indicate that concern for BSI should not affect decisions regarding use of PPIs in the ICU.