Phase I chemoprevention study of piroxicam and alpha-difluoromethylornithine

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.     

The HIV-1 nef protein inhibits extracellular signal-regulated kinase-dependent DNA synthesis in a human astrocytic cell line

The role of nonproductive infection of astrocytes by human immunodeficiency virus type 1 (HIV-1), characterized by the overexpression of nef, in brain disease progression is largely unknown. We investigated the consequences of stable expression of nef from the HIV-1 strain LAI in the human astrocytic cell line U373. DNA synthesis induced by endothelin-1 (ET-1) was largely decreased by nef. Stable expression of nef did not affect the ET-1-induced tyrosine phosphorylation of focal adhesion kinase, an adhesion-dependent pathway known to participate in DNA synthesis in astrocytes. Conversely, the activation of extracellular signal-regulated kinase (ERK) by ET-1 was largely inhibited in cells stably or transiently expressing nef. A similar inhibitory action of nef on ERK activation was observed after direct stimulation of G proteins. Furthermore, the inhibitory action of nef did not require protein kinase C (PKC) and affected mainly the PKC-independent pathway of ERK activation. Following chemokine receptor CXCR4-mediated infection of U373 cells stably expressing CXCR4 with the T-tropic HIV-1 strain m7-NDK, ET-1-induced activation of ERK was also inhibited. Altogether, these results indicate that intracellular signaling pathways associated with the growth factor activity of ET-1 are impaired in nef-expressing and HIV-1-infected astrocytes, suggesting that infection of astrocytes may play a significant role in the neuropathogenesis of HIV-1 encephalopathy.     

Epstein-Barr virus (EBV) can immortalize B-cll cells activated by cytokines

B-type of chronic lymphocytic leukemia (B-CLL) cells are inert to the potent transforming action of Epstein-Barr virus (EBV). The mitogenic action of Staphylococcus aureus Cowan I (SAC), MP6-thioredoxin, and interleukin 2 (IL-2), agents previously shown to induce proliferation in normal as well as in B-CLL cells, lifted this block, and EBV-positive cell lines could be established. It was not possible to establish cell lines of leukemic origin from cultures that were incubated with EBV alone or cytokine mix alone. CLL-cells infected with EBV only, expressed the viral nuclear antigen complex (EBNA), but not the viral latent membrane protein (LMP). They were not activated as measured by cell size and 3H-thymidine incorporation. In contrast, cells incubated with EBV and cytokine mix expressed both EBNA and LMP in parallel with enlargement and increased 3H-thymidine incorporation. These results emphasize that LMP expression is a prerequisite for growth transformation and immortalization and that cytokine activation signals are required for its expression in B-CLLs. Cells incubated with SAC/MP6-thioredoxin/IL-2 did not express any of the viral antigens, but were activated with regard to the mentioned parameters. Nine cell lines were established from six patients. From each of the three patients, we obtained 'twin'-pair lines: one corresponding to the malignant cell and the other to a normal B-lymphoblastoid cell. Thus, malignant and normal B-cell counterparts, from the very same donor, are at hand for comparative studies. The cell lines have been carried out for more than 12 months in culture. We conclude that B-CLL that are refractory to EBV-transformation can be rendered susceptible through in vitro cytokine activation.     

Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature

BACKGROUND: Cutaneous angiosarcoma (AS) is a rare, often multicentric vascular tumor of the head and neck region with a rather poor prognosis. The original clinical size of the tumor rarely correlates to the degree of microscopic tissue invasion. Treatment by surgical excision sometimes requires very wide excision. Treatment by radiation or electron beam appears less mutilating but its efficacy is not well documented. OBJECTIVE: To present our experience with a combined surgical delineation of tumor margins followed by radiation treatment. METHODS: We treated three patients with extensive AS of the scalp and face. Prior to radiation, in two cases the tumor margins were determined by grid-pattern punch biopsies. In the third patient, the tumor margins were determined by Mohs mapping system. All three patients then received radiation either by rotational arc electron beam (n = 2) and standard radiation. RESULTS: One patient developed two local recurrences in nonirradiated areas plus a metastatic cervical node, all of which responded to additional electron beam. The patient has no evidence of disease (NED) after 30 months of observation. The other two patients were treated by electron beam and radiation have NED at 5 and 1 years follow-up, respectively. CONCLUSIONS: Local control of AS of the scalp may be achieved by assessment of the tumor margin by peripheral biopsies or Mohs technique followed by electron beam and radiation.     

A ported, proximally-cemented femoral stem for total hip arthroplasty. Development and clinical application

Intracerebroventricular (i.c.v.) administration of glucagon-like peptide-1-(7-37) amide (GLP-1) has been shown to modulate food and water intake. The present studies further characterize the effects of i.c.v. GLP-1 in the regulation of energy balance in lean and obese animals. In both obese and lean Zucker rats, a single i.c.v. infusion of GLP-1 (1-30 microg) resulted in a dose-dependent reduction of food intake and decrease in respiratory quotient relative to the saline control during the first 2 h of the nocturnal cycle. In obese Zucker rats, the food intake was reduced by 73 +/- 11% of the control at the 30 microg dose, whereas a modest 45 +/- 18% reduction was observed in lean rats. Despite the large reduction in food intake seen with GLP-1, there was no compensatory decrease in nocturnal oxygen consumption in the obese Zucker rats. Interestingly, low doses of GLP-1 (1 microg) in lean Zucker rats, which had minimal effects on food intake, caused a 19 +/- 7% increase in O2 consumption during the first 2 h of the nocturnal cycle. These data suggest that central GLP-1 may be an important factor controlling negative energy balance in both the lean and obese Zucker rats.     

The chain that saves life. Prehospital treatment of myocardial infarction

A 53-year old woman living in a rural area 220 km from the nearest hospital experienced an acute myocardial infarction. The local doctor contacted the emergency service and requisitioned an air ambulance. 29 minutes later the physician-manned helicopter arrived, and thrombolytic treatment was started after 15 minutes. The patient arrived at the county hospital 35 minutes later, after having been electroconverted three times because of ventricular fibrillation. The patient was discharged from hospital ten days later with no cerebral sequelae, and left ventricular ejection fraction 49%. This example shows that active use of emergency communications systems and air ambulances enables both prompt thrombolytic treatment and the effective treatment of complications associated with myocardial infarction to be accomplished.     

Supramolecular organization of immature and mature murine leukemia virus revealed by electron cryo-microscopy: implications for retroviral assembly mechanisms

We have used electron cryo-microscopy and image analysis to examine the native structure of immature, protease-deficient (PR-) and mature, wild-type (WT) Moloney murine leukemia virus (MuLV). Maturational cleavage of the Gag polyprotein by the viral protease is associated with striking morphological changes. The PR- MuLV particles exhibit a rounded central core, which has a characteristic track-like shell on its surface, whereas the WT MuLV cores display a polygonal surface with loss of the track-like feature. The pleomorphic shape and inability to refine unique orientation angles suggest that neither the PR- nor the WT MuLV adheres to strict icosahedral symmetry. Nevertheless, the PR- MuLV particles do exhibit paracrystalline order with a spacing between Gag molecules of approximately 45 A and a length of approximately 200 A. Because of the pleomorphic shape and paracrystalline packing of the Gag-RNA complexes, we raise the possibility that assembly of MuLV is driven by protein-RNA, as well as protein-protein, interactions. The maturation process involves a dramatic reorganization of the packing arrangements within the ribonucleoprotein core with disordering and loosening of the individual protein components.     

Active control of supersonic/hypersonic aeroelastic flutter for a two-dimensional airfoil with flap

The flutter, post-flutter and active control of a two-dimensional airfoil with control surface operating in supersonic/hypersonic flight speed regions are investigated in this paper. A three-degree-of-freedom dynamic model is established, in which both the cubic nonlinear structural stiffness and the nonlinear aerodynamic load are accounted for. The third order Piston Theory is employed to derive the aerodynamic loads in the supersonic/hypersonic airflow. Nonlinear flutter happens with a phenomenon of limit...     

Smart RTD for multiphase flow systems

A relatively new concept is presented for evaluation of the fluid age distribution a = a(x,t) within the interior of an apparatus. In the standard RTD approach, the tracer study is performed and the residence time distribution is obtained. In the new approach denoted as SRTD, the fluid age is considered as the field quantity and the governing equation is formulated for its spatio-temporal distribution within the flow domain. There are only few studies devoted to this alternative approach, which typically concern only the single-phase flow systems. In this contribution we investigate its applicability also to multiphase systems. In the case of a bubble column, both the RTD and SRTD concepts are employed and discussed. The results are calculated numerically and compared with the experimental observations.