Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer.

Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (< 0.3 fold of the control) was associated with invasiveness of oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter -132 to -125 bp and -343 to -336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1-mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy.

Target therapy using a small molecule inhibitor against angiogenic receptors in pancreatic cancer.

PURPOSE: PD173074, a small molecule inhibitor of VEGF-RII and FGF-RI, targets neoangiogenesis and mitogenesis. This study aimed to analyze a single-compound-driven inhibition of FGF and VEGF receptors in pancreatic cancer. EXPERIMENTAL DESIGN: RT-PCR and Western blots were performed to quantify protein expression and phosphorylation. Anchorage dependent and independent growth assays were used to study cell growth. With flow cytometry, cell cycle analysis and apoptosis were studied. In vivo HPAF-II and MIA PaCa-2 cells were xenografted. Animals were treated daily for 10 weeks. Immunohistochemistry was used to quantify microvessel density and apoptosis. RESULTS: Highest levels of FGF-RI were detectable in MIA PaCa-2 cells, lowest in HPAF-II cells. PD173074 inhibited cell growth most prominently in cells expressing high levels of FGF-RI. Cell cycle progression was inhibited by blocking transition in the G(0)/G(1) phase, and consequently, apoptosis was increased. In vivo significant inhibition of orthotopic tumor growth was achieved by a combination effect of inhibition of mitogenesis, induction of apoptosis, and reduction of angiogenesis in PD173074-treated animals. CONCLUSIONS: These data highlight VEGF-RII and FGF-RI as therapeutic targets and suggest a potential role for the combined use of tyrosine kinase inhibitors in the management of inoperable pancreatic cancer patients.

Pain scores improve analgesic administration patterns for trauma patients in the emergency department.

OBJECTIVE: To determine the efficacy of pain scores in improving pain management practices for trauma patients in the emergency department (ED). METHODS: A prospective, observational study of analgesic administration to trauma patients was conducted over a nine-week period following educational intervention and introduction of verbal pain scores (VPSs). All ED nursing and physician staff in an urban Level I trauma center were trained to use the 0-10 VPS. Patients younger than 12 years old, having a Glasgow Coma Scale score (GCS) <8, or requiring intubation were excluded from analysis. Demographics, mechanism of injury, vital signs, pain scores, and analgesic data were extracted from a computerized ED database and patients' records. The staff was blinded to the ongoing study. RESULTS: There were 150 patients studied (183 consecutive trauma patients seen; 33 patients excluded per criteria). Pain scores were documented for 73% of the patients. Overall, 53% (95% confidence interval [CI] = 45% to 61%) of the patients received analgesics in the ED. Of the patients who had pain scores documented, 60% (95% CI = 51% to 69%) received analgesics, whereas 33% (95% CI = 18% to 47%) of the patients without pain scores received analgesics. No patient with a VPS < 4 received analgesics, whereas 72% of patients with a VPS > 4 and 82% with a VPS > 7 received analgesics. Mean time to analgesic administration was 68 minutes (95% CI = 49 to 87). CONCLUSIONS: Pain assessment using VPS increased the likelihood of analgesic administration to trauma patients with higher pain scores in the ED.

Patterns of analgesic use in trauma patients in the ED.

The objective was to describe patterns of analgesic use for trauma patients treated in our emergency department (ED). We reviewed analgesic use in consecutive patients meeting American College of Surgeons (ACS) Trauma Center Guidelines. A comprehensive database was abstracted from this institution's Trauma Registry and medical records of each patient. A total of 38% (95% CI: 31-46%) of patients received analgesics. Time to administration of first dose of analgesia was 109 minutes (95% CI: 85-133). Women, patients with long bone and pelvic fractures, and those with a longer ED stay were most likely to receive analgesics. Patients with head trauma and those admitted to the intensive care unit were least likely to receive analgesics. Morphine was the most frequent analgesic used with an average total dose of 14 milligrams. A majority of patients meeting ACS Trauma Center Guidelines did not receive analgesics in the ED.