Photoacoustic microscopy of arteriovenous shunts and blood diffusion in early-stage tumors

Angiogenesis in a tumor region creates arteriovenous (AV) shunts that cause an abnormal venous blood oxygen saturation (sO_2) distribution. Here, we applied optical-resolution photoacoustic microscopy to study the AV shunting in vivo. First, we built a phantom to image sO_2 distribution in a vessel containing converged flows from two upstream blood vessels with different sO_2 values. The phantom experiment showed that the blood from the two upstream vessels maintained a clear sO_2 boundary for hundreds of seconds, which is consistent with our theoretical analysis using a diffusion model. Next, we xenotransplanted O-786 tumor cells in mouse ears and observed abnormal sO_2 distribution in the downstream vein from the AV shunts in vivo. Finally, we identified the tumor location by tracing the sO_2 distribution. Our study suggests that abnormal sO_2 distribution induced by the AV shunts in the vessel network may be used as a new functional benchmark for early tumor detection

Mikroökonomische Wirkungs- und Effizienzanalyse: Ergebnisse aus dem Untersuchungsfeld 3

Im Untersuchungsfeld 3 wurden unterschiedliche Ansätze zur Eingliederung im Hinblick auf ihre Wirksamkeit verglichen.Wirtschaftliche Effizienz, Verwaltungsreform, Arbeitsverwaltung, Sozialverwaltung, Soziale Mindestsicherung, Berufliche Integration, Arbeitsvermittlung, Deutschland

Multi-contrast photoacoustic microscopy

We developed multi-contrast photoacoustic microscopy (PAM) for in vivo anatomical, functional, metabolic, and molecular imaging. This technical innovation enables comprehensive understanding of the tumor microenvironment. With multi-contrast PAM, we longitudinally determined tumor vascular anatomy, blood flow, oxygen saturation of hemoglobin, and oxygen extraction fraction

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF^(flox/flox) alleles were combined to create TetON-HIF-1:VEGFΔ mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGFΔ mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGFΔ mice. Impaired TetON-HIF-1:VEGFΔ neovascularization could be partially rescued by 12-O-tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF

Tumor glucose metabolism imaged in vivo in small animals with whole-body photoacoustic computed tomography

With the increasing use of small animals for human disease studies, small-animal whole-body molecular imaging plays an important role in biomedical research. Currently, none of the existing imaging modalities can provide both anatomical and glucose molecular information, leading to higher costs of building dual-modality systems. Even with image co-registration, the spatial resolution of the molecular imaging modality is not improved. Utilizing a ring-shaped confocal photoacoustic computed tomography system, we demonstrate, for the first time, that both anatomy and glucose uptake can be imaged in a single modality. Anatomy was imaged with the endogenous hemoglobin contrast, and glucose metabolism was imaged with a near-infrared dye-labeled 2-deoxyglucose

Early-stage tumor detection using photoacoustic microscopy: a pattern recognition approach

We report photoacoustic microscopy (PAM) of arteriovenous (AV) shunts in early stage tumors in vivo, and develop a pattern recognition framework for computerized tumor detection. Here, using a high-resolution photoacoustic microscope, we implement a new blood oxygenation (sO_2)-based disease marker induced by the AV shunt effect in tumor angiogenesis. We discovered a striking biological phenomenon: There can be two dramatically different sO_2 values in bloodstreams flowing side-by-side in a single vessel. By tracing abnormal sO_2 values in the blood vessels, we can identify a tumor region at an early stage. To further automate tumor detection based on our findings, we adopt widely used pattern recognition methods and develop an efficient computerized classification framework. The test result shows over 80% averaged detection accuracy with false positive contributing 18.52% of error test samples on a 50 PAM image dataset

Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas

Neuropilins (NRP) are cell surface receptors for VEGF and SEMA3 family members. The role of NRP in neurons and endothelial cells has been investigated, but the expression and role of NRP in epithelial cells is much less clear. Herein, the expression and localization of neuropilin 1 (NRP1) was investigated in human and mouse skin and squamous cell carcinomas (SCC). Results indicated that NRP1 mRNA and protein was expressed in the suprabasal epithelial layers of skin sections. NRP1 staining did not overlap with that of keratin 14 (K14) or proliferating cell nuclear antigen, but did colocalize with staining for keratin 1, indicating that differentiated keratinocytes express NRP1. Similar to the expression of NRP1, VEGF-A was expressed in suprabasal epithelial cells, whereas Nrp2 and VEGFR2 were not detectable in the epidermis. The expression of NRP1 correlated with a high degree of differentiation in human SCC specimens, human SCC xenografts, and mouse K14-HPV16 transgenic SCC. UVB irradiation of mouse skin induced Nrp1 upregulation. In vitro, Nrp1 was upregulated in primary keratinocytes in response to differentiating media or EGF-family growth factors. In conclusion, the expression of NRP1 is regulated in the skin and is selectively produced in differentiated epithelial cells. NRP1 may function as a reservoir to sequester VEGF ligand within the epithelial compartment, thereby modulating its bioactivity