Citations

Our aim was to determine the effect of the initial pattern of fracture and the displacement of fragments on the outcome of proximal humeral fractures treated conservatively. We followed 93 consecutive patients prospectively for one year. Final movement and strength were compared with those of the contralateral side. The final American Shoulder and Elbow Society score and the Disabilities of Arm, Shoulder and Hand and Short-Form 36 questionnaires were compared with those provided by the patient on the day of the injury. Radiographs and CT scans with three-dimensional reconstruction were obtained in all patients. The pattern of the fracture and the displacement of individual fragments were analysed and correlated with the final outcome. There were two cases of nonunion and six of avascular necrosis. The majority of the fractures (84 patients; 90%) followed one of the following four patterns: posteromedial (varus) impaction in 50 patients (54%), lateral (valgus) impaction in 13 (14%), isolated greater tuberosity in 15 (16%), and anteromedial impaction fracture in six (6%). Head orientation, impaction of the surgical neck and displacement of the tuberosity correlated strongly with the outcome. In fractures with posteromedial impaction, a poor outcome was noted as the articular surface displaced inferiorly increasing its distance from the acromion. A poorer outcome was noted as a fractured greater tuberosity displaced medially overlapping with the posterior articular surface. Lateral impaction fractures had a worse outcome than other patterns of fracture.

OBJECTIVE Investigating the dynamics of pancreatic β-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that β-cell proliferation and glucose homeostasis were controlled by Δ40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. RESEARCH DESIGN AND METHODS We phenotyped metabolic parameters in Δ40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine β-cell proliferation. RESULTS Transgenic mice with an ectopic p53 gene encoding Δ40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from ∼14 months of age. Consistent with a dramatic decrease in β-cell mass and reduced β-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. CONCLUSIONS These data indicate a significant and novel role for Δ40p53 in β-cell proliferation with implications for the development of age-dependent diabetes.

Abstract The molecular mechanisms underlying the initiation of innate and adaptive proallergic Th2-type responses in the airways are not well understood. IL-33 is a new member of the IL-1 family of molecules that is implicated in Th2-type responses. Airway exposure of naive mice to a common environmental aeroallergen, the fungus Alternaria alternata, induces rapid release of IL-33 into the airway lumen, followed by innate Th2-type responses. Biologically active IL-33 is constitutively stored in the nuclei of human airway epithelial cells. Exposing these epithelial cells to A. alternata releases IL-33 extracellularly in vitro. Allergen exposure also induces acute extracellular accumulation of a danger signal, ATP; autocrine ATP sustains increases in intracellular Ca2+ concentration and releases IL-33 through activation of P2 purinergic receptors. Pharmacological inhibitors of purinergic receptors or deficiency in the P2Y2 gene abrogate IL-33 release and Th2-type responses in the Alternaria-induced airway inflammation model in naive mice, emphasizing the essential roles for ATP and the P2Y2 receptor. Thus, ATP and purinergic signaling in the respiratory epithelium are critical sensors for airway exposure to airborne allergens, and they may provide novel opportunities to dampen the hypersensitivity response in Th2-type airway diseases such as asthma.

Abstract Purpose: Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether soluble B7-H1 (sB7-H1) levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. Experimental Design: We developed an ELISA for quantification of sB7-H1 in biological fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein microsequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T-cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. Results: sB7-H1 was detected in the cell supernatants of some B7-H1–positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver proapoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (P < 0.001), tumors of advanced stage (P = 0.017) and grade (P = 0.044), and tumors with necrosis (P = 0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (P = 0.010). Conclusion: Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome. Clin Cancer Res; 17(7); 1915–23. ©2011 AACR.

Abstract Hepatocellular carcinoma (HCC), the primary malignancy of the liver, is the fourth leading cause of cancer deaths worldwide, with a 5-year survival rate of∼10%. Recently, a new multikinase inhibitor, sorafenib (Nexavar®), which mainly targets the VEGFR and the Raf/Mek/Erk pathways, has shown limited response rate and modest survival benefits in patients with advanced stage HCC. We hypothesize that there exist genetic alterations or contexts of vulnerability (COV) in cancer cells that dictate sensitivity to sorafenib. In order to identify specific COVs and obtain an increased understanding of drug's mechanism of action, we performed a custom chemosensitization high-throughput siRNA screen. We developed and optimized a sorafenib chemosensitization assay in 3 HCC cell lines, one of which, Hep3B, a AFP and HBsAg positive cell line, was selected for primary RNAi screening with a kinase siRNA library, which covers 700 genes (4 siRNA sequences per gene). Primary screen data was rigorously evaluated for multiple quality control metrics (transfection efficiency, CV values, accessing plate-to-plate and set-to-set variation) and found to exceed all expected performance parameters. The top sorefenib sensitizing hits were identified and supplemented with additional genes selected based on related biological concepts. This sensitization effect of the genes was further tested and compared in two additional HCC cell lines (HepG2 and PLC). Additionally, based on the sensitizer list from the RNAi screening, 11 chemical compounds were tested for synergistic combination with sorafenib. Notable synergism with sorafenib was observed in the combination with erlotinib or doxorubicin. More strikingly, we also observed synergy between sorafenib and multiple MEK inhibitors as well as gemcitabine in the selected HCC cell lines. Our data suggest that MEK inhibitors might improve the efficacy of sorafenib in HCC treatment in the clinic. Further mechanistic studies are being conducted for this particular combination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-285.