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Purpose: Pancreatic cancer is characterized by intratumoral hypoxia, early and aggressive local invasion, and metastatic potential. Hypoxia-inducible factor-1 (HIF-1) is the major transcriptional activator of hypoxia-responsive genes and intratumoral hypoxia is associated with increased risk of metastasis. However, the behavior of the cells having HIF-1 activity during the malignant progression in pancreatic cancer has not been tested. Experimental Design: We orthotopically transplanted pancreatic cancer cells stably transfected with a HIF-1-dependent luciferase reporter gene and monitored HIF-1 activity in vivo in control and POP33-treated mice. POP33 is a novel prodrug, which has potential to increase caspase-3 activity and induce apoptosis in HIF-1-active/hypoxic cells. Results: In vivo optical imaging showed that HIF-1 activity proceeded along with local invasion, the peritoneal dissemination, and the liver metastasis. HIF-1-active hypoxic cells were selectively eradicated by POP33. Moreover, selective killing of HIF-1-active hypoxic cells significantly suppressed malignant progression, resulting in a significant improvement in survival rate. Conclusions: These results show that HIF-1-active cells constitute a large proportion of invading and metastatic cells and suggest that eradication of these cells may improve the outcome in advanced pancreatic cancer, a condition for which no effective therapy currently exists.Pancreatic cancer is one of the most lethal solid tumors of the gastrointestinal tract. The high mortality rate of pancreatic cancer is due to the high incidence of metastatic disease at the time of diagnosis, a fulminant clinical course, and the lack of adequate systemic therapies. Peritoneal and extrapancreatic seeding is observed during end-stage pancreatic cancer. Pancreatic cancer is characterized by extensive invasion into surrounding tissues and metastasis to distant organs, even at an early stage. The prognosis of patients is poor (1) and new systemic agents are urgently needed.Intratumoral hypoxia is a major factor contributing to cancer progression (1-4). This situation is exacerbated by the high oxygen demands of rapidly proliferating tumor cells, poor lymphatic drainage resulting in high interstitial pressure, and shunting of blood through immature tumor vasculature (3). The evidence for hypoxia in pancreatic cancers includes their characteristic avascular appearance on computed tomography (5) and low intratumoral oxygen tension measurements (6). Furthermore, the expression of target genes of hypoxia-inducible factor-1 (HIF-1), the major transcription factor activated under hypoxic conditions, is elevated in pancreatic cancers (2, 7-11). They include proangiogenic factors such as vascular endothelial growth factor (VEGF), growth/survival factors such as insulin-like growth factor, and extracellular matrix remodeling proteins such as metalloproteinase-9 (12). Thus, HIF-1 activity may play a crucial role in malignant progression of pancreatic cancers.Orthotopic implantation of h...

Nonionic amphiphilic copolypeptides, which were composed of hydrophilic poly(sarcosine) and hydrophobic poly(gamma-methyl L-glutamate) blocks, were synthesized with varying chain lengths of the blocks. The polypeptides having a suitable hydrophilic and hydrophobic balance were found to form vesicular assemblies of 100 nm size in buffer, which was evidenced by the TEM observation, the DLS analysis, and the encapsulation experiment. The genuine peptide vesicles, peptosomes, were labeled with a near-infrared fluorescence (NIRF) probe. In vivo retention in blood experiment showed long circulation of the peptosome in rat blood as stable as the PEGylated liposome. NIRF imaging of a small cancer on mouse by using the peptosome as a nanocarrier was successful due to the EPR effect of the peptosome. Peptosome is shown here as a novel excellent nanocarrier for molecular imaging.

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Hypoxia-inducible factor-1 (HIF-1) plays an important role in malignant tumor progression and in the development of resistance to radiotherapy. We designed a novel fusion protein (PTD-ODD-SAV [POS]) consisting of a protein transduction domain (PTD), streptavidin (SAV), and a portion of the oxygen-dependent degradation domain (ODD) of HIF-1a that confers the same oxygen-dependent regulation as HIF-1a on POS. (3-123/125 Iiodobenzoyl)norbiotinamide ( 123/125 I-IBB) was conjugated to the SAV moiety of POS to synthesize 123/125 I-IBB-labeled POS ( 123/125 I-IPOS). The purpose of this study was to evaluate the feasibility of 123 I-IPOS as an imaging probe for HIF-1-active tumor hypoxia. Methods: After a 24-h incubation of 125 I-IPOS with various tumor cell lines under either normoxic (20% O 2 ) or hypoxic (0.1% O 2 ) conditions, the intracellular radioactivity was investigated. Then, the biodistribution of 123/125 I-IPOS was examined with tumor-implanted mice, and an in vivo imaging study was performed. The tumoral accumulation of 125 I-IPOS was compared with HIF-1 activity using the mice carrying tumors with the HIF-1-dependent luciferase reporter gene. Furthermore, the intratumoral localization of 125 I-IPOS was examined by the autoradiographic study, and then the same slide was subjected to immunostaining for pimonidazole, which is the hypoxic marker. Results: The ratios of radioactivity in hypoxic cells to that in normoxic cells were more than 2. These results indicate incorporation of 125 I-IPOS into these cells and degradation of 125 I-IPOS by normoxic tumor cells. In the biodistribution study, 125 I-IPOS accumulated in the tumor (1.4 6 0.3 percentage injected dose per gram) 24 h after administration. At that time, 125 I-IPOS showed high tumor-to-blood and tumor-to-muscle ratios (5.1 6 0.3 and 14.0 6 3.9, respectively). The tumors were clearly visualized by in vivo imaging 24 h after 123 I-IPOS injection (tumor-to-muscle ratio was 9.6). The tumoral accumulation of 125 I-IPOS correlated with HIF-1 activity (R 5 0.71, P , 0.05), and its intratumoral distribution coincided with the hypoxic regions. Conclusion: 123 I-IPOS is a potential probe for the imaging of HIF-1 activity in tumors. Given the role of HIF-1 in tumor biology, its detection may be considered an indicator of aggressive cancer phenotypes.

This paper proposes an efficient exact algorithm for the general single-machine scheduling problem where machine idle time is permitted. The algorithm is an extension of the authors' previous algorithm for the problem without machine idle time, which is based on the SSDP (Successive Sublimation Dynamic Programming) method. We first extend our previous algorithm to the problem with machine idle time and next propose several improvements. Then, the proposed algorithm is applied to four types of singlemachine scheduling problems: the total weighted earlinesstardiness problem with equal (zero) release dates, that with distinct release dates, the total weighted completion time problem with distinct release dates, and the total weighted tardiness problem with distinct release dates. Computational experiments demonstrate that our algorithm outperforms existing exact algorithms and can solve instances of the first three problems with up to 200 jobs and those of the last problem with up to 80 jobs.

Hypoxia-inducible factor (HIF) functions as a master transcriptional regulator for adaptation to hypoxia by inducing adaptive changes in gene expression for regulation of proliferation, angiogenesis, apoptosis and energy metabolism. Cancers with high expression of the alpha subunit of HIF (HIFα) are often malignant and treatment-resistant. Therefore, the development of a molecular probe that can detect HIF activity has great potential value for monitoring tumor hypoxia. HIF prolyl hydroxylases (HPHDs) act as oxygen sensors that regulate the fate of HIFα protein through its oxygen-dependent degradation (ODD) domain. We constructed a recombinant protein PTD-ODD-HaloTag (POH) that is under the same ODD regulation as HIFα and contains protein transduction domain (PTD) and an interchangeable labeling system. Administration of near-infrared fluorescently labeled POH (POH-N) to mouse models of cancers allowed successful monitoring of HIF-active regions. Immunohistochemical analysis for intratumoral localization of POH probe revealed its specificity to HIF-active cells. Furthermore, lack of the PTD domain or a point mutation in the ODD domain abrogated the specificity of POH-N to HIF-active cells. Overall results indicate that POH is a practical probe specific to HIF-active cell in cancers and suggest its large potential for imaging and targeting of HIF-related diseases.