The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors.

Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.

G9a controls pluripotent-like identity and tumor-initiating function in human colorectal cancer.

Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of cancer stemness phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in cancer stem cells by establishing embryonic stem-like transcriptional programs, thus impacting the balance between self-renewal and differentiation. We identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, we observed that G9a activity is essential for the maintenance of embryonic-like transcriptional signature promoting self-renewal, tumorigenicity, and undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. Finally, by integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, we identified the canonical Wnt pathway, epithelial-to-mesenchyme transition, and extracellular matrix organization as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Overall, our findings provide novel insights on the role of G9a as a driver of cancer stem cell phenotype, promoting self-renewal, tumorigenicity, and undifferentiated state.

Micro-concentrators for a microsystems-enabled photovoltaic system.

A 100X magnification, ± 2.5° field of view micro-concentrating optical system has been developed for a microsystems-enabled photovoltaic (MEPV) prototype module using 250 µm diameter multi-junction "stacked" PV cells.

Splenic artery aneurysms and pseudoaneurysms: clinical distinctions and CT appearances.

OBJECTIVE: Aneurysms of the splenic artery are being diagnosed with greater frequency as incidental findings on cross-sectional imaging. Splenic artery pseudoaneurysms are even more rare than true aneurysms. This article reviews the clinical features and management of splenic artery aneurysms and pseudoaneurysms. A variety of cases are presented to show the range of CT appearances. CONCLUSION: Radiologists who identify either type of splenic artery lesion should recognize the clinical and pathophysiologic distinctions between these two forms of splenic vascular pathology and understand the differences in management.

Multidetector row CT of superior mesenteric artery syndrome.

GOALS: The purpose of this case series is to illustrate the diagnostic criteria of superior mesenteric artery syndrome (SMAS) using 16-slice multidetector row computed tomography (MDCT) angiography with multiplanar and 3-dimensional reconstructions. BACKGROUND: SMAS is a rare condition causing functional obstruction of the third portion of the duodenum. When suspected, diagnostic imaging can be performed with upper gastrointestinal, arteriography, or CT. STUDY: Four patients with clinical symptoms and correlative CT evidence of SMAS are described. Axial, multiplanar, and 3-dimensional rendered MDCT images were retrospectively reviewed by 1 investigator, who measured the aortomesenteric angle and aortomesenteric distance on a sagittal maximum intensity projection rendering, and compared these values with normal ranges described in the literature. RESULTS: In each patient, MDCT demonstrated gastric and proximal duodenal dilatation with abrupt narrowing of the third portion of the duodenum between the aorta and SMA. Sagittal maximum intensity projection images reliably demonstrated the decreased aortomesenteric angle (mean in subjects 13.5 degrees, normal range 28 to 65 degrees) and distance (mean in subjects 4.4 mm, normal range 10 to 34 mm) in all 4 patients. CONCLUSIONS: As opposed to traditional imaging modalities like upper gastrointestinal and mesenteric arteriography, which depict either the bowel or vasculature respectively, CT enables direct visualization of obstructed bowel owing to duodenal compression by the SMA. Multiplanar MDCT with 3-dimensional rendering provides sagittal reconstructions that can be used to confirm the CT criteria of decreased aortomesenteric angle and distance in SMAS.