Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer

BACKGROUND: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone. METHODS: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy. RESULTS: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group. CONCLUSIONS: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.     

Clavaric acid and steroidal analogues as Ras- and FPP-directed inhibitors of human farnesyl-protein transferase

We have identified a novel fungal metabolite that is an inhibitor of human farnesyl-protein transferase (FPTase) by randomly screening natural product extracts using a high-throughput biochemical assay. Clavaric acid [24, 25-dihydroxy-2-(3-hydroxy-3-methylglutaryl)lanostan-3-one] was isolated from Clavariadelphus truncatus; it specifically inhibits human FPTase (IC50 = 1.3 microM) and does not inhibit geranylgeranyl-protein transferase-I (GGPTase-I) or squalene synthase activity. It is competitive with respect to Ras and is a reversible inhibitor of FPTase. An alkaline hydrolysis product of clavaric acid, clavarinone [2,24,25-trihydroxylanostan-3-one], lacking the 3-hydroxy-3-methylglutaric acid side chain is less active as a FPTase inhibitor. Similarly, a methyl ester derivative of clavaric acid is also inactive. In Rat1 ras-transformed cells clavaric acid and lovastatin inhibited Ras processing without being overtly cytotoxic. Excess mevalonate reversed the effects of lovastatin but not of clavaric acid suggesting that the block on Ras processing by clavaric acid was due to inhibition of FPTase and not due to inhibition of HMG-CoA reductase. Despite these results, the possibility existed that clavaric acid inhibited Ras processing by directly inhibiting HMG-CoA reductase. To directly examine the effects of clavaric acid and clavarinone on HMG-CoA reductase, cholesterol synthesis was measured in HepG2 cells. No inhibition of HMG-CoA reductase was observed indicating that the inhibition of Ras processing by this class of compounds is due to inhibition of FPTase. To date, clavaric acid is the second reported nitrogen-free compound that competes with Ras to inhibit FPTase activity. A series of related compounds derived from computer-based similarity searches and subsequent rational chemical synthetic design provided compounds that exhibited a range of activity (0.04 --> 100 microM) against FPTase. Modest changes in the structures of these inhibitors dramatically change the inhibitory activity of these inhibitors.     

Structural integrity of implanted WMT infinity hip and Osteonics Omnifit hip in fresh cadaveric femurs

OBJECTIVES: To evaluate the role of proton MR spectroscopy (1H-MRS) in detecting metabolic changes in diffuse or focal lesions in the brain of patients infected with HIV. METHODS: Sixty HIV seropositive patients (25 with HIV related encephalopathies, 20 with toxoplasmosis, eight with progressive multifocal leukoencephalopathies (PMLs), and seven with lymphomas) and 22 HIV seronegative neurological controls were examined with a combined MRI and 1H-MRS technique using a Siemens 1.5 Tesla Magnetom. Spectra (Spin Echo sequence, TE 135 ms) were acquired by single voxel, localised on focal lesions in toxoplasmosis, PML, lymphomas, and HIV encephalopathies and on the centrum semiovale of neurological controls. Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate, and lipids were evaluated in each spectrum and NAA/Cr, NAA/Cho, and Cho/Cr ratios were calculated. RESULTS: A significant decrease in NAA/Cr and NAA/Cho ratios were found in all HIV diagnostic groups in comparison with neurological controls (p<0.003), suggesting neuronal or axonal damage independent of brain lesion aetiology. However, the NAA/Cr ratio was significantly lower in PML and lymphomas than in HIV encephalopathies (p<0.02) and toxoplasmosis (p<0.05). HIV encephalopathies, lymphomas, and toxoplasmosis showed a significant increase in the Cho/Cr ratio in comparison with neurological controls (p<0.03) without between group differences. The presence of a lipid signal was more frequent in lymphomas (71%) than in other HIV groups (Fisher's test, p=0.00003). The presence of mobile lipid resonance together with a high Cho/Cr ratio in lymphomas may be related to an increased membrane synthesis and turnover in tumour cells. A lactate signal (marker of inflammatory reaction), was found in all but one patient with PML lesions (75%), but had a lower incidence in the other HIV diagnostic groups (Fisher's test, p=0.00024). CONCLUSION: 1H-MRS shows a high sensitivity in detecting brain involvement in HIV related diseases, but a poor specificity in differential diagnosis of HIV brain lesions. Nevertheless, the homogeneous metabolic pattern that characterises PML suggests the usefulness of 1H-MRS as an adjunct to MRI in differentiating CNS white matter lesions, such as HIV encephalopathies, from PML.     

Enthalpy relaxation in binary amorphous mixtures containing sucrose

PURPOSE: To compare the enthalpy relaxation of amorphous sucrose and co-lyophilized sucrose-additive mixtures near the calorimetric glass transition temperature, so as to measure the effects of additives on the molecular mobility of sucrose. METHODS: Amorphous sucrose and sucrose-additive mixtures, containing poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl-acetate) (PVPNA) dextran or trehalose, were prepared by lyophilization. Differential scanning calorimetry (DSC) was used to determine the area of the enthalpy recovery endotherm following aging times of up to 750 hours for the various systems. This technique was also used to compare the enthalpy relaxation of a physical mixture of amorphous sucrose and PVP. RESULTS: Relative to sucrose alone, the enthalpy relaxation of co-lyophilized sucrose-additive mixtures was reduced when aged for the same length of time at a comparable degree of undercooling in the order: dextran approximately PVP > PVPNA > trehalose. Calculated estimates of the total enthalpy change required for sucrose and the mixtures to relax to an equilibrium supercooled liquid state (deltaHinfinity) were essentially the same and were in agreement with enthalpy changes measured at longer aging times (750 hours). CONCLUSIONS: The observed decrease in the enthalpy relaxation of the mixtures relative to sucrose alone indicates that the mobility of sucrose is reduced by the presence of additives having a Tg that is greater than that of sucrose. Comparison with a physically mixed amorphous system revealed no such effects on sucrose. The formation of a molecular dispersion of sucrose with a second component, present at a level as low as 10%, thus reduces the mobility of sucrose below Tg, most likely due to the coupling of the molecular motions of sucrose to those of the additive through molecular interactions.     

The course of childhood bronchiectasis: a case report and considerations of hospital use

Using an inhibitory synthetic peptide (DP-178) from HIV-1 gp41, we have trapped HIV-1 envelope glycoprotein (Env) undergoing conformational changes during virus entry. Our data show that DP-178 binds gp41 and inhibits Env-mediated membrane fusion after gp120 interacts with cellular receptors, indicating that conformational changes involving the coiled coil domain of gp41 are required for entry. Capture of this fusion-active conformation of Env provides insights into the early events leading to Env-mediated membrane fusion.     

Eosinophil surface antigen expression and cytokine production vary in different ocular allergic diseases

OBJECTIVES: Improving methods of donor heart preservation may permit prolonged storage and remote procurement of cardiac allografts. We hypothesized that continuous, sanguineous perfusion of the donor heart in the beating, working state may prolong myocardial preservation. METHODS: We developed a portable perfusion apparatus for use in donor heart preservation. Contractile, metabolic, and vasomotor functions were monitored simultaneously in an isolated swine heart. The metabolic state was monitored by myocardial tissue pH. Vasomotor function was assessed in isolated coronary ring chambers. Hearts were randomized into 3 groups: group I (n = 5), cardioplegic arrest, 12-hour storage at 4 degrees C with modified Belzer solution, and 2-hour sanguineous reperfusion in the working state; group II (n = 6), 12-hour continuous perfusion in the beating working state, 30 minutes of arrest (to simulate re-implantation time), and 2 hours of reperfusion, as above; group III (n = 7), coronary ring control hearts. RESULTS: At 2 hours of reperfusion, left ventricular developed pressure in group II was higher than in group I (mean +/- standard deviation: 90 +/- 6 mm Hg, 53 +/- 15 mm Hg, P = .005). Significantly less myocardial edema was observed in group II than in group I (73% +/- 4%, 80% +/- 1% water content, P = .01). Significantly less myocardial acidosis was noted in group II than in group I during preservation (pH 7.3 +/- 0.01, 6.1 +/- 0.03, P < .001) and reperfusion (pH 7.3 +/- 0.008, 6.8 +/- 0.05, P < .001). Coronary endothelial vasomotor function was better preserved in group II than in group I as evidenced by dose-response relaxation of coronary rings to 10(-8) mol/L bradykinin (37%, 55% delta baseline, P = .01). CONCLUSION: This new method extends the current preservation limit and avoids time-dependent ischemic injury, thereby allowing for distant procurement of donor organs.     

Transient gene transfer of IL-12 regulates chemokine expression and disease severity in experimental arthritis

Murine collagen-induced arthritis (CIA) is characterized by pannus formation, cell infiltration, and cartilage erosion, and shares histologic and immunologic features with rheumatoid arthritis. Numerous cytokines are reportedly associated with RA and/or CIA; however, their mechanistic role is not clear. To determine the role of IL-12 in CIA, DBA/1 LacJ mice were administered 3 x 10(8) plaque-forming units of mIL-12 i.p. in a nonreplicating adenoviral vector (AdIL-12) on day 25 following primary type II collagen immunization. Our studies demonstrated that systemic transient overexpression of IL-12 accelerated disease progression and augmented the arthritis severity relative to mice expressing a replication-deficient, E1-deleted Ad5 construct. A likely mechanism for this increase in pathology was the increase in the expression of cytokines and chemokines known to play a proinflammatory role in disease. In particular, levels of murine IFN-gamma were significantly increased in mice overexpressing AdIL-12 relative to the replication-deficient, E1-deleted Ad5 construct. Interestingly, the C-X-C chemokine murine macrophage inflammatory protein-2, as well as the C-C chemokines murine monocyte chemoattractant protein-1 and murine macrophage inflammatory protein-1alpha were up-regulated by AdIL-12 relative to controls. In an additional set of studies, neutralization of endogenous IL-12 in CIA mice was shown to delay disease onset and attenuate disease severity. IFN-gamma levels in the mice receiving anti-IL-12 were significantly decreased in joint homogenates. These studies demonstrate that IL-12 is an important cytokine involved in controlling the production of chemokines/cytokines leading to the evolution of experimental arthritis.