A Review of Distributions on the String Landscape

We review some basic flux vacua counting techniques and results, focusing on the distributions of properties over different regions of the landscape of string vacua and assessing the phenomenological implications. The topics we discuss include: an overview of how moduli are stabilized and how vacua are counted; the applicability of effective field theory; the uses of and differences between probabilistic and statistical analysis (and the relation to the anthropic principle); the distribution of various parameters on the landscape, including cosmological constant, gauge group rank, and SUSY-breaking scale; "friendly landscapes"; open string moduli; the (in)finiteness of the number of phenomenologically viable vacua; etc. At all points, we attempt to connect this study to the phenomenology of vacua which are experimentally viable.Comment: Invited review, IJMP A. LaTeX. 39 pages. References adde

Ionizing Radiation-Induced Oxidative Stress Alters miRNA Expression

). treatment, and 45 after etoposide treatment. Substantial overlap between the miRNA expression changes between agents was observed suggesting a signature miRNA response to cell stress. Changes in the expression of selected miRNA species varied in response to radiation dose and time. Finally, production of reactive oxygen species (ROS) increased with increasing doses of radiation and pre-treatment with the thiol antioxidant cysteine decreased both ROS production and the miRNA response to radiation., and etoposide. Additionally, pre-treatment with cysteine prevented radiation-induced alterations in miRNA expression which suggests that miRNAs are responsive to oxidative stress. Taken together, these results imply that miRNAs play a role in cellular defense against exogenous stress and are involved in the generalized cellular response to genotoxic oxidative stress

PHF6 suppresses self-renewal of leukemic stem cells in AML

Acute myeloid leukemia is characterized by uncontrolled proliferation of self-renewing myeloid progenitors accompanied by a differentiation arrest. PHF6 is a chromatin-binding protein mutated in myeloid leukemias, and its isolated loss increases mouse HSC self-renewal without malignant transformation. We report here that Phf6 knockout increases the aggressiveness of Hoxa9-driven AML over serial transplantation, and increases the frequency of leukemia initiating cells. We define the in vivo hierarchy of Hoxa9-driven AML and identify a population that we term the “LIC-e” (leukemia initiating cells enriched) population. We find that Phf6 loss expands the LIC-e population and skews its transcriptome to a more stem-like state; concordant transcriptome shifts are also observed on PHF6 knockout in a human AML cell line and in PHF6 mutant patient samples from the BEAT AML dataset. We demonstrate that LIC-e accumulation in Phf6 knockout AML occurs not due to effects on cell cycle or apoptosis, but due to an increase in the fraction of its progeny that retain LIC-e identity. Our work indicates that Phf6 loss increases AML self-renewal through context-specific effects on leukemia stem cells

PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55 alpha/PP2A reconstitution that triggers centrosome destabilization

The PPP2R2A gene encodes the B55 alpha regulatory subunit of PP2A. Here, we report that PPP2R2A is hemizygously lost in similar to 42% of prostate adenocarcinomas, correlating with reduced expression, poorer prognosis, and an increased incidence of hemizygous loss (>75%) in metastatic disease. Of note, PPP2R2A homozygous loss is less common (5%) and not increased at later tumor stages. Reduced expression of B55 alpha is also seen in prostate tumor tissue and cell lines. Consistent with the possibility that complete loss of PPP2R2A is detrimental in prostate tumors, PPP2R2A deletion in cells with reduced but present B55 alpha reduces cell proliferation by slowing progression through the cell cycle. Remarkably, B55 alpha-low cells also appear addicted to lower B55 alpha expression, as even moderate increases in B55 alpha expression are toxic. Reconstitution of B55 alpha expression in prostate cancer (PCa) cell lines with low B55 alpha expression reduces proliferation, inhibits transformation and blocks xenograft tumorigenicity. Mechanistically, we show B55 alpha reconstitution reduces phosphorylation of proteins essential for centrosomal maintenance, and induces centrosome collapse and chromosome segregation failure; a first reported link between B55 alpha/PP2A and the vertebrate centrosome. These effects are dependent on a prolonged metaphase/anaphase checkpoint and are lethal to PCa cells addicted to low levels of B55 alpha. Thus, we propose the reduction in B55 alpha levels associated with hemizygous loss is necessary for centrosomal integrity in PCa cells, leading to selective lethality of B55 alpha reconstitution. Such a vulnerability could be targeted therapeutically in the large pool of patients with hemizygous PPP2R2A deletions, using pharmacologic approaches that enhance PP2A/B55 alpha activity