Radiation-induced effects on gene expression: an in vivo study on breast cancer.

BACKGROUND AND PURPOSE: Breast cancer is diagnosed worldwide in approximately one million women annually and radiation therapy is an integral part of treatment. The purpose of this study was to investigate the molecular basis underlying response to radiotherapy in breast cancer tissue. MATERIAL AND METHODS: Tumour biopsies were sampled before radiation and after 10 treatments (of 2 Gray (Gy) each) from 19 patients with breast cancer receiving radiation therapy. Gene expression microarray analyses were performed to identify in vivo radiation-responsive genes in tumours from patients diagnosed with breast cancer. The mutation status of the TP53 gene was determined by using direct sequencing. RESULTS AND CONCLUSION: Several genes involved in cell cycle regulation and DNA repair were found to be significantly induced by radiation treatment. Mutations were found in the TP53 gene in 39% of the tumours and the gene expression profiles observed seemed to be influenced by the TP53 mutation status.     

Delayed chronic type A dissection following CABG: implications for evolving techniques of revascularization

BACKGROUND: Postoperative dissection in some patients is related to manipulation of the aorta and accounts for 3% to 5% of deaths after cardiac surgery. METHODS: Between 1987 and 1999, 109 patients with previous cardiac operations were treated for chronic type A dissection. In 31 of the patients, the etiology was related to aortic manipulation. Twenty-one patients (17 men, 4 women; 67+/-13 years of age) had isolated coronary artery bypass grafting (CABG) as their first operation and were reviewed. The interval between operations was 52.9+/-47.3 months. RESULTS: Reoperation was elective in 11 patients, urgent in 10 patients. Median maximal aortic diameter was 6.8+/-2.1 cm; 9 patients had major aortic insufficiency. The intimal tear was at the partial occlusion clamp site in 12 patients (57.1%), at the cross-clamping site in 4 patients (19.1%), and at the proximal anastomosis in 1 patient (4.8%); 4 patients (19.1%) had multiple tears at several sites. Cystic media necrosis was present in 9.5% of the patients, severe atherosclerosis in 47.6% of the patients, and 42.9% of the patients had both. Nine patients (42.9%) underwent a modified Bentall procedure, 12 patients (57.1%) underwent a supracoronary anastomosis, and all had open distal anastomosis. There were two (9.5%) hospital deaths and three (14.3%) postoperative strokes. Freedom from cardiac or aorta-related mortality was 85.7% at a mean follow-up of 49.3 months. CONCLUSIONS: In patients who develop type A dissection of the aorta after previous CABG, the intimal tear most often is at partial occlusion clamp site. This complication is associated with morbidity and mortality. It remains to be seen whether the use of partial occlusion clamps on the pulsating and often diseased aorta during off-pump coronary artery bypass (OPCAB) will increase the risk of delayed iatrogenic dissections.     

A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies.

PURPOSE: The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities. RESULTS: Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that precluded dose escalation. The maximum tolerated dose of ET-743 that could be administered repetitively was 325 microg/m(2)/day. Antitumor activity was noted in three patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas. The pharmacokinetics of ET-743 were dose independent, and drug accumulation over the 5 days of treatment was modest, with the ratio of the area under the plasma-versus-time curve on day 5 to that on day 1 averaging 2.05. The volume of distribution at steady state was large (mean, 1037 liters/m(2)), and the mean terminal half life on day 5 was 26.81 h. CONCLUSIONS: The maximum tolerated dose of ET-743 that can be administered repetitively is 325 microg/m(2)/day daily x 5 every 3 weeks, which is recommended for disease-directed clinical trials. The acceptable toxicity profile of ET-743 on the divided-dose schedule evaluated in this trial, as well as the generally superior antitumor activity associated with divided-dose schedules in preclinical studies, provides a rationale for further evaluation of ET-743 on this administration schedule.     

Coca chewing among high altitude natives: Work and muscular efficiencies of nonhabitual chewers

The leaves of the coca plant (Erythroxylum sp.) have long been chewed by natives of the highland Andes. Folk belief is that the mild stimulant effect is indispensable as an ergogenic aid for strenuous work activities in a high altitude environment. This study explored the exercise responses of 23 nonhabitual coca chewing males who were asked to pedal a bicycle ergometer through a series of submaximal and maximal workloads both with and without coca chewing. The protocol of the exercise test was specifically designed to allow for the determination of work and muscular efficiencies during to submaximal work. The subjects showed no differences between the coca and control work protocols for VO₂max (1/min), VCO₂max (1/min), or maximal work output (watts). Further, there were no differences between coca and control work protocols in oxygen saturation (%), pulmonary ventilation (1/min), or respiratory exchange ratio (VCO₂/VO₂) at any level of work. Coca chewing caused subjects to have a higher heart rate (bpm) and lower oxygen pulse (ml/beat) for most submaximal workloads and higher ventilatory equivalents (VE/VO₂ and VE/VCO₂) above 50% of VO₂max. Although there was a tendency for higher gross efficiencies (GE) during the coca exercise test at lower relative work levels, between 30–40% of the VO₂max, this difference did not reach significance. Mean net efficiency (NE) was higher (P=0.018) at a relative work level of ～32% of the VO₂max for exercise with coca (23.2% vs. 20.8%). This difference was not apparent at any other work level. The mean delta efficiency (DE) was significantly lower (P = 0.012) for exercise with coca (26.7%) than for exercise without coca (28.2%). These efficiency differences suggest a muscle metabolic effect for coca chewing at low workloads whereby less oxygen is consumed by the muscle to perform a given work task. Howeve, given the difficulty of interpreting efficiency values, it is not entirely clear if the differences are indicative of a work performance benefit for coca chewing. © 1995 Wiley-Liss, Inc.     

The neocortical projection to the inferior colliculus in the albino rat

Summary The purpose of the present study was to define the field of termination of the neocortical projection to the inferior colliculus in rat. The study was based on fiber degeneration following large lesions of the cerebral cortex, and anterograde transport of wheat germ agglutinin horseradish peroxidase ejected inotophoretically into more restricted neocortical loci. Neocortical fibers were found to supply the dorsal and external cortices of the inferior colliculus. The central nucleus, in contrast, did not receive such fibers. The results speak in favor of three separate projections, one partly bilateral to the deeper part of the dorsal collicular cortex, a second ipsilateral to the superficial part of this subdivision, and a third ipsilateral to the external collicular cortex.     

A monoclonal antibody to the galactan from Helix pomatia snails recognizes beta-(1,6)-linked D-galactose residues

Using the hybridoma technique, a series of four monoclonal antibodies to the galactan isolated from albumin glands of wine yard snails (Helix pomatia) could be generated. Characterization of the binding properties of one of these antibodies revealed a specificity for beta-(1,6)-glycosidically linked D-galactose residues. This could be demonstrated by reaction of the antibody with beta-(1,6)-D-galactans and by the D-galactose-inhibitable binding to group B streptococci of type II, which possess beta-(1,6)-linked D-galactose as immuno-determinant group.     

Scleroderma-like changes in chronic graft vs host disease.

A case of chronic graft vs host disease had scleroderma-like skin changes. Clinical progression was from poikiloderma to scleroderma, and histopathological changes and results of direct immunofluorescence were noted. It is probable that both cell-mediated (T-cell) and humoral (B-cell) mechanisms contribute to the pathogenesis of the graft vs host reaction.     

A non-living nasal influenza vaccine can induce major humoral and cellular immune responses in humans without the need for adjuvants

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG- and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers>or=40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4+ T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.     

A preclinical comparison between different opioids: antinociceptive versus adverse effects

Reduced side-effect liability of opioids may enhance the patient's quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO(2) was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance. ED(50)'s for the occurrence of side-effects were compared to ED(50)'s in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED(50)'s. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.