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...

We investigated the onset of paternal gene expression in the early mouse embryo. We obtained transgenic mouse embryos by fertilizing BD (C57BL/6N x DBA) F1 hybrid female oocytes in vitro, with sperm from homozygous transgenic males carrying integrated chicken beta-actin promoter-driven firefly luciferase cDNA. We then examined the RNA and protein synthesis of the luciferase gene in embryos from the 1- to 2-cell stage. RNA transcripts of the luciferase gene were first detected in the 1-cell stage embryos as early as 13 hr postinsemination, just prior to elongation. By photon-count imaging, functional luciferase was identified at the 2-cell stage 23 hr postinsemination. These findings indicate that the paternal endogenous gene is already transcribed in the late 1-cell embryos, although paternally derived protein is not synthesized until the 2-cell stage. Therefore, these results suggest that the embryonic gene is activated as early as the late 1-cell stage.

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Background: Evidence as to the benefits of nonpharmacological interventions for the boundary state between normal aging and dementia [mild cognitive impairment or a Clinical Dementia Rating (CDR) of 0.5] remains weak due to a lack of positive controls. Aims: To directly compare the effects of cognitive interventions (CI), physical activities (PA) and a group reminiscence approach (GRA), we conducted a pilot study on the basis of a cluster randomized controlled trial design. Method: A total of 127 participants aged >74 years with a CDR of 0.5 were cluster randomized into three groups for CI, PA and GRA. The intervention lasted 12 weeks and consisted of weekly group sessions and home assignments. Mini-Mental State Examination (MMSE), Trail Making Test part A (TMT-A), word fluency (WF), 6-meter walk time and Quality of Life (QOL) Face Scale scores were evaluated as primary outcomes. Results: Methodology-related benefits of CI and PA were found for MMSE scores and walk time, respectively. TMT-A, WF and QOL Face Scale scores improved irrespective of the methodologies used. Conclusions: Our findings suggest that CI and PA may be beneficial to cognitive and physical abilities, respectively. Executive functions and QOL may improve irrespective of the intervention methodologies used.