Citations

Advances in the understanding of neonatal pain have created interest in the use of medications during commonly performed procedures in the neonatal intensive care unit. A number of small studies have examined the role of sedatives, narcotics, miscellaneous anesthetics, and neuromuscular blockers in providing a more comfortable experience for the patient during nonemergent tracheal intubation. However, the most effective combination and doses of these medications is currently unknown. This review discusses the findings of selected studies that have been used to improve the intubating experience of patient and clinician.

Abstract Purpose: Prosurvival Bcl-2 proteins inhibit the mitochondrial and death receptor-mediated apoptotic pathways. Obatoclax is a small-molecule antagonist of the BH3-binding groove of Bcl-2 proteins that may enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity and efficacy. Experimental Design: Human pancreatic cancer cell lines were incubated with obatoclax and/or TRAIL and cell viability, Annexin V labeling, caspase cleavage, and cytochrome c release were measured. In drug-treated cell lines, protein-protein interactions were studied by immunoprecipitation. Bax/Bak activation was analyzed using conformation-specific antibodies. Lentiviral short hairpin RNA was used to knockdown Bim, Bid, and apoptosis-inducing factor (AIF) expression. Results: Obatoclax reduced the viability of PANC-1 and BxPC-3 cell lines and synergistically enhanced TRAIL-mediated cytotoxicity. Obatoclax enhanced TRAIL-mediated apoptosis, as shown by Annexin V labeling, which was accompanied by caspase activation (caspase-8, -9, and -3) and cleavage of Bid. Obatoclax potentiated TRAIL-mediated Bax/Bak activation and the release of mitochondrial cytochrome c, Smac, and AIF. Mechanisms underlying the apoptotic effect of obatoclax include displacement of Bak from its sequestration by Bcl-xL or Mcl-1 and release of Bim from Bcl-2 or Mcl-1. Bid knockdown by short hairpin RNA attenuated caspase cleavage and cytotoxicity of obatoclax plus TRAIL. Bim knockdown failed to inhibit the cytotoxic effect of obatoclax alone or combined with TRAIL yet attenuated TRAIL-mediated cytotoxicity. AIF knockdown attenuated cytotoxicity of the drug combination. Conclusions: Obatoclax potentiates TRAIL-mediated apoptosis by unsequestering Bak and Bim from Bcl-2/Bcl-xL or Mcl-1 proteins. This drug combination enhances Bid-mediated cross-talk between the mitochondrial and death receptor-mediated apoptotic pathways and may represent a novel therapeutic strategy against pancreatic cancer.

Abstract Purpose: Patients with hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) that are refractory to standard therapies are difficult to manage and have significantly shortened life expectancy. Experimental Design: CD52 is a surface glycoprotein highly expressed on eosinophils. We treated 11 patients with advanced HES/CEL with alemtuzumab, a humanized anti-CD52 monoclonal antibody. Alemtuzumab was administered, in general, first in escalating doses (5, 10, 30 mg i.v. on days 1-3), then at the tolerated dose thrice per week for a total of 12 doses. Patients with complete hematologic response (CHR; normal percent and absolute eosinophil count) were allowed to continue therapy once weekly as maintenance. Results: Ten patients (91%) achieved CHR after a median of 2 weeks (0.5-5 weeks) of therapy. Bone marrow eosinophilia resolved in four of seven evaluable patients. The median duration of CHR was 3 months (1.5-17+ months). Seven of the 10 CHR patients relapsed, five while off-therapy. Two patients achieved second CHR upon alemtuzumab rechallenge. Three patients experienced mild infusion-related symptoms, two developed cytomegalovirus reactivation requiring therapy, and one developed orbital lymphoma that was successfully treated. Conclusions: Our limited experience suggests alemtuzumab to be a valuable therapy for advanced HES or CEL, refractory to standard therapies, and supports the clinical evaluation of alemtuzumab in a larger trial.

Abstract Transforming growth factor-β (TGF-β) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-β signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-β has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-β signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-β. We show that TGF-β activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2–dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-β–mediated anchorage-independent growth without affecting TGF-β transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-β action. mTORC2 promotes TGF-β–induced morphologic transformation and is required for TGF-β–induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-β–mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-β and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia. [Cancer Res 2009;69(1):84–93]

BackgroundWe evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer's disease (AD) pathology.MethodsAmyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects.ResultsPlasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease‐free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ.ConclusionsEfforts to use plasma levels of Aβ peptides as AD biomarkers or disease‐staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long‐range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered.

Abstract Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

Abstract Ice hockey is a fast-paced, aggressive sport whose participants are subject to relatively high rates of injury. Although there is a growing emphasis on the epidemiology of ice hockey research and its application towards reducing injuries, the literature has never been organized into an accessible database. Ice hockey is played in North America, Europe, Scandinavia, the U.K., and several other non-English speaking countries, yet injury reports not written in English are often ignored in review articles. The purpose of this project was to synthesize the existing world literature on ice hockey injuries into a framework of epidemiologic criteria, accessible in an organized, retrievable library. An extensive search of the following databases was done: MEDLINE, BIOSIS, EMBASE, NTIS, CURRENT CONTENTS, DISSERTATION ABSTRACTS, SPORT DISCUS, CINAHL, and WEB OF SCIENCE. Key words used were “ice hockey” and “injuries,” and the search range was 1966 to July 2007. Endnote X (Thompson Corp., Stamford, CT) was used for reference compilation. Eight hundred sixty seven documents were catalogued, from 27 countries in 8 languages. Documents were first categorized by type, including injury (226), equipment (45), case reports (94), review articles (294), editorials (39), or as focusing on the physiological, psychological, or medical aspects of ice hockey (169). Documents were then subdivided by study type and whether they were prospective (117) or retrospective (109). Further subdivisions beyond these levels were based on the inclusion of certain critical epidemiological criteria, including exposure time, a clear definition of “injury,” and the level of play, among others. This comprehensive database should make future ice hockey research more efficient, as well as promote sound epidemiology and a more global perspective.