No abstract

Intraoperative injection of the pectoralis muscle with botulinum toxin is not an effective method to improve pain control in tissue expander reconstruction.

Androgen withdrawal induces the regression of human prostate cancers, but such cancers eventually become androgen-independent and metastasize. Thus, deciphering the mechanism of androgen withdrawalinduced apoptosis is critical to designing new therapies for prostate cancer. Previously, we showed that in the rat, castration-induced apoptosis is accompanied by a reduction in the expression of the apical caspase inhibitor FLICE-like inhibitory protein (FLIP). To test the functional role of FLIP in inhibiting prostate epithelial cell apoptosis, we employed the rat prostate epithelial cell line NRP-152, which differentiates to a secretory phenotype in a low-mitogen medium and then undergoes apoptosis following the addition of transforming growth factor B1 (TGFB1), mimicking androgen withdrawal -induced apoptosis. FLIP levels decline with TGFB1 treatment, suggesting that apoptosis is mediated by caspase-8 and indeed the caspase inhibitor crmA blocks TGFB1-induced apoptosis. Small interfering RNA -mediated knockdown of FLIP recapitulates and enhances TGFB1-induced cell death. NRP-152 cells stably transfected with constitutively expressed FLIP were refractory to TGFB1-induced apoptosis. TGFB1-induced caspase-3 activity is proportional to the level of cell death and inversely proportional to the level of FLIP expression in various clones. Moreover, neither caspase-3 nor PARP is cleaved in clones expressing high levels of FLIP. Furthermore, insulin, which inhibits differentiation, increases FLIP and inhibits TGFB-induced death in a FLIP-dependent manner. Although neither Fas-Fc, sTNFRII-Fc, nor DR5-Fc blocked TGFB1-induced cell death, there is a significant increase in tumor necrosis factor mRNA following TGFB stimulation, suggesting both an unexpected role for tumor necrosis factor in this model system and the possibility that FLIP blocks another unknown caspase-dependent mediator of apoptosis. (Mol Cancer Res 2008;6(2):231 -42)

Background Intense debate continues in the search of the optimal ratio of blood components to deliver preemptively in the critically injured patient anticipated to require a massive transfusion. A major challenge is distinguishing patients with refractory coagulopathy versus those with overwhelming injuries who will perish irrespective of blood component administration. The hypothesis of this clinical study is that a predominant number of early deaths from hemorrhage are irretrievable despite an aggressive transfusion policy. Materials and Methods During the 7-yr period ending in December 2009, there were 772 in-hospital trauma deaths. Each of these deaths had been assigned a cause of death via concurrent review by the multi-disciplinary hospital trauma QI committee. ED deaths and patients arriving from outside facilities were excluded from this study. Results Of the 382 patients (49.5%) who died secondary to acute blood loss, (84/22.0 %) survived beyond the ED; (68/82%) were male, mean age was 31, and (30/36%) sustained blunt trauma. Cause of death was determined to be exsanguination in (63/75 %), coagulopathy in (13/15 %), metabolic failure in (5/6%), and indeterminate in (3/3.7%) patients. Conclusion These data indicate that 75% of patients who succumb to postinjury acute blood loss are bleeding because they are dying rather than dying because they are bleeding. Conversely, only 13 (2%) of hospital deaths were attributed to refractory coagulopathy. These critical facts need to be considered in designing studies to determine optimal massive transfusion protocols.

Background Intercellular adhesion molecule-1 (ICAM-1) modulates cell–cell adhesion and is a receptor for cognate ligands on leukocytes. Upregulation of ICAM-1 has been demonstrated in malignant transformation of adenomas and is associated with poor prognosis for many malignancies. ICAM-1 is upregulated on the invasive front of pancreatic metastases and melanomas. These data suggest that the upregulated ICAM-1 expression promotes malignant progression. We hypothesize that the downregulation of ICAM-1 will mitigate tumor progression. Methods Mouse colon adenocarcinoma cells (MC38) were evaluated for the expression of ICAM-1 using Western immunoblot analysis. Short hairpin RNA (shRNA) transduction was used to downregulate ICAM-1. Tumor invasion determined via a modified Boyden chamber was used as a surrogate of tumor progression examining MC38 cells, MC38 ICAM-1 knockdowns, and MC38 transduced with vehicle control. The cells were cultured in full media for 24 h and serum-starved for 24 h. A total of 5 × 104 cells were plated and allowed to migrate for 24 h using full media with 10% fetal bovine serum as a chemoattractant. Inserts were fixed and stained with crystal violet. Blinded investigators counted the cells using a stereomicroscope. Statistical analysis was performed by analysis of variance with Fischer protected least significant difference and a P value of <0.05 was considered statistically significant. Results ICAM-1 was constitutively expressed on MC38 cells. Transduction with anti–ICAM-1 shRNA vector downregulated ICAM-1 protein expression by 30% according to the Western blot analysis (P < 0.03) and decreased ICAM-1 messenger RNA expression by 70% according to the reverse transcription–polymerase chain reaction. shRNA knockdown cells had a significant reduction in invasion >45% (P < 0.03). There were no significant differences between the invasion rates of MC38 and MC38 vehicle controls. Conclusions Downregulation of ICAM-1 mitigates MC38 invasion. These data suggest that targeted downregulation of tumor ICAM-1 is a potential therapeutic target.

Background Perioperative blood transfusion in pancreatic cancer patients is linked to decreased survival; however, a causal mechanism has not been determined. Previously we have shown that the plasma fraction of stored packed red blood cells (pRBCs) promotes pancreas cancer progression and associated morbidity. We hypothesize these untoward effects will be mitigated by use of a hemoglobin-based oxygen carrier (HBOC). Methods Cytokines and growth factors were measured in the plasma fraction from stored pRBCs and in an HBOC via cytokine array followed by formal enzyme-linked immune-sorbent assay (ELISA). In an immunocompetent murine model, pancreas cancer progression was determined in vivo by bioluminescence, tumor weight, and number of metastases. Results Elevated levels of epidermal growth factor (EGF), platelet-derived growth factor BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) were present in the plasma fraction of stored pRBCs, but were not found in the HBOC. Intravenous delivery of plasma fraction to mice with pancreatic cancer resulted in increased bioluminescence activity compared with mice that received HBOC. Metastatic events and pancreatic primary tumor weights were significantly higher in animals receiving plasma fraction from stored pRBCs compared with animals receiving HBOC. Conclusions Intravenous receipt of the acellular plasma fraction of stored pRBCs promotes pancreatic cancer progression in an immunocompetent mouse model. These untoward events are mitigated by use of an HBOC.

No abstract

No abstract