Oncogenic miRNAs and the Perils of Losing Control of a Stem Cell’s Epigenetic Identity

Pathways that regulate epigenetic control of stem cell identity are critical to the molecular etiology of cancer. In back-to-back articles in Cell and Cell Stem Cell, Song et al. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system

Regulation of p53 localization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65260/1/j.1432-1327.2001.02227.x.pd

Identification of histological features to predict MUC2 expression in colon cancer tissues

Colorectal cancer (CRC) is the third-most common form of cancer among Americans. Like normal colon tissue, CRC cells are sustained by a subpopulation of “stem cells” that possess the ability to self-renew and differentiate into more specialized cancer cell types. In normal colon tissue, the enterocytes, goblet cells and other epithelial cells in the mucosa region have distinct morphologies that distinguish them from the other cells in the lamina propria, muscularis mucosa, and submucosa. However, in a tumor, the morphology of the cancer cells varies dramatically. Cancer cells that express genes specific to goblet cells significantly differ in shape and size compared to their normal counterparts. Even though a large number of hematoxylin and eosin (H&E)-stained sections and the corresponding RNA sequencing (RNASeq) data from CRC are available from The Cancer Genome Atlas (TCGA), prediction of gene expression patterns from tissue histological features has not been attempted yet. In this manuscript, we identified histological features that are strongly associated with MUC2 expression patterns in a tumor. Specifically, we show that large nuclear area is associated with MUC2-high tumors (p < 0.001). This discovery provides insight into cancer biology and tumor histology and demonstrates that it may be possible to predict certain gene expressions from histological features

New Oncolytic Adenoviruses with Hypoxia- and Estrogen Receptor-Regulated Replication

Oncolytic adenoviruses with restricted replication can be produced if the expression of crucial transcription units of the virus is controlled by tissue- or tumor-specific promoters. Here we describe a method for the rapid incorporation of exogenous promoters into the E1A and E4 regions of the human adenovirus type 5 genome. Using this system, we have generated AdEHT2 and AdEHE2F, two conditionally replicative adenoviruses for the treatment of breast cancer. The expression of the E1A gene in both viruses is controlled by a minimal dual-specificity promoter that responds to estrogens and hypoxia. The tight regulation of E1A expression correlated with the ability of these viruses to replicate and kill human cancer cells that express estrogen receptors, or are maintained under hypoxic conditions. The telomerase reverse transcriptase (TERT) promoter and the E2F-1 promoter are preferentially activated in cancer cells. They were introduced into the E4 region of AdEHT2 and AdEHE2F, respectively. The telomerase core promoter failed to block the replication of the virus in telomerase-negative cells. In contrast, AdEHE2F was attenuated in nontransformed quiescent cells growing under normoxic conditions, suggesting that an intact pRB pathway with low levels of E2F transcription factors acts as a negative modulator for the virus. These data indicate that the simultaneous regulation of E1A and E4 viral transcription units by the appropriate combination of promoters can increase the tumor selectivity of oncolytic adenoviruses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63195/1/104303402760293574.pd

Serially transplantable mammary epithelial cells express the Thy-1 antigen

Abstract Background Recent studies in murine mammary tissue have identified functionally distinct cell populations that may be isolated by surface phenotype or lineage tracing. Previous groups have shown that CD24medCD49fhigh cells enriched for long-lived mammary epithelial cells can be serially transplanted. Methods Flow cytometry-based enrichment of distinct phenotypic populations was assessed for their gene expression profiles and functional proliferative attributes in vitro and in vivo. Results Here, we show Thy-1 is differentially expressed in the CD24medCD49fhigh population, which allowed us to discern two functionally different populations. The Thy-1+CD24medCD49fhigh phenotype contained the majority of the serially transplantable epithelial cells. The Thy-1−CD24medCD49fhigh phenotype contains a rare progenitor population that is able to form primary mammary outgrowths with significantly decreased serial in vivo transplantation potential. Conclusions Therefore, Thy-1 expression in the immature cell compartment is a useful tool to study the functional heterogeneity that drives mammary gland development and has implications for disease etiology.https://deepblue.lib.umich.edu/bitstream/2027.42/145730/1/13058_2018_Article_1006.pd

Stem cells, cancer, and cancer stem cells

Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells'-rare cells with indefinite potential for self-renewal that drive tumorigenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62862/1/414105a0.pd

A Method of Limited Replication for the Efficient In Vivo Delivery of Adenovirus to Cancer Cells

Overview summary Replication-defective viral vectors are limited in their ability to diffuse through tissue. This poses a problem for treating tumors in vivo using gene transfer. This article demonstrates that limited replication of adenovirus leads to greater gene transfer efficiency in vitro and in vivo without introducing additional safety concerns beyond traditional adenovirus administration. This has implications for the improvement of current gene transfer methods for treating cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63280/1/hum.1998.9.8-1209.pd

Oral dosing for antenatal corticosteroids in the Rhesus macaque.

Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6-8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses

The Bcl-2 family of proteins: regulators of cell death and survival

The Bcl-2 protein inhibits apoptosis induced by a variety of signals, in a range of cell types and in diverse organisms, and it is implicated in both normal development and oncogenesis. Despite this central role, the mechanism of action of Bcl-2 is not yet clear. Recent studies have uncovered a number of Bcl-2-related gene products that regulate apoptosis either negatively or positively, and Bcl-2 forms heterodimers with at least one of these proteins, Bax. This article discusses the role of the Bcl-2 family of proteins in the light of these findings.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31217/1/0000119.pd

Real time imaging, forecasting and management of human-induced seismicity at Preston New Road, Lancashire, England

Earthquakes induced by subsurface fluid injection pose a significant issue across a range of industries. Debate continues as to the most effective methods to mitigate the resulting seismic hazard. Observations of induced seismicity indicate that the rate of seismicity scales with the injection volume and that events follow the Gutenberg-Richter distribution. These two inferences permit us to populate statistical models of the seismicity and extrapolate them to make forecasts of the expected event magnitudes as injection continues. Here, we describe a shale gas site where this approach was used in real time to make operational decisions during hydraulic fracturing operations. Microseismic observations revealed the intersection between hydraulic fracturing and a pre-existing fault or fracture network that became seismically active. Although "red light" events, requiring a pause to the injection program, occurred on several occasions, the observed event magnitudes fell within expected levels based on the extrapolated statistical models, and the levels of seismicity remained within acceptable limits as defined by the regulator. To date, induced seismicity has typically been regulated using retroactive traffic light schemes. This study shows that the use of high-quality microseismic observations to populate statistical models that forecast expected event magnitudes can provide a more effective approach