Energy expenditure during activity in the American lobster Homarus americanus: Correlations with body acceleration.

How animals manage time and expend energy has implications for survivorship. Being able to measure key metabolic costs of animals under natural conditions is therefore an important tool in behavioral ecology. One method for estimating activity-specific metabolic rate is via derived measures of acceleration, often 'overall dynamic body acceleration' (ODBA), recorded by an instrumented acceleration logger. ODBA has been shown to correlate well with rate of oxygen consumption (V˙o2) in a range of species during activity in the laboratory. This study devised a method for attaching acceleration loggers to decapod crustaceans and then correlated ODBA against concurrent respirometry readings to assess accelerometry as a proxy for activity-specific energy expenditure in a model species, the American lobster Homarus americanus. Where the instrumented animals exhibited a sufficient range of activity levels, positive linear relationships were found between V˙o2 and ODBA over 20min periods at a range of ambient temperatures (6, 13 and 20°C). Mixed effect linear models based on these data and morphometrics provided reasonably strong predictive power for estimating activity-specific V˙o2 from ODBA. These V˙o2-ODBA calibrations demonstrate the potential of accelerometry as an effective predictor of behavior-specific metabolic rate of crustaceans in the wild during periods of activity.

Stable isotopes challenge the perception of ocean sunfish Mola mola as obligate jellyfish predators.

Evidence is provided from stable isotope analysis that aggregations of small ocean sunfish Mola mola (total length <1 m) feed broadly within coastal food webs and their classification as obligate predators of gelatinous zooplankton requires revision.

Human neuroepithelial cells express NMDA receptors.

L-glutamate, an excitatory neurotransmitter, binds to both ionotropic and metabotropic glutamate receptors. In certain parts of the brain the BBB contains two normally impermeable barriers: 1) cerebral endothelial barrier and 2) cerebral epithelial barrier. Human cerebral endothelial cells express NMDA receptors; however, to date, human cerebral epithelial cells (neuroepithelial cells) have not been shown to express NMDA receptor message or protein. In this study, human hypothalamic sections were examined for NMDA receptors (NMDAR) expression via immunohistochemistry and murine neuroepithelial cell line (V1) were examined for NMDAR via RT-PCR and Western analysis. We found that human cerebral epithelium express protein and cultured mouse neuroepithelial cells express both mRNA and protein for the NMDA receptor. These findings may have important consequences for neuroepithelial responses during excitotoxicity and in disease.

Ratio of 2'-deoxyadenosine-5'-triphosphate/thymidine-5'-triphosphate influences the commitment of human colon carcinoma cells to thymineless death.

In colon cancers induction of a thymineless state following inhibition of thymidylate synthase (TS) by 5-fluorouracil combined with leucovorin can initiate a cytotoxic response. Using a 5-fluorouracil-leucovorin-treated human colon carcinoma cell line (GC3/cl) and a clonally derived TS- mutant, initiation events that dictate the onset of and commitment to thymineless death have been examined. Initial events related to a temporally associated decrease in dTTP and elevation in the dATP pools; no depletion of dGTP or elevation in dCTP was detected. Nucleosomal degradation of DNA commenced at 24 h in TS- and 49 h in GC3/c1, and was associated with the more rapid development of an imbalance in the dATP and dTTP pools and a higher dATP:dTTP ratio in TS- cells. The contribution of elevated dATP or depleted dTTP pools to thymineless death was subsequently determined by treatment of GC3/cl or TS- cells with deoxyadenosine to elevate the dATP pool either under thymidine-replete or thymineless conditions. Thus, deoxyadenosine supplementation under dTTP-replete conditions elevated the dATP pool for 16 h and was cytotoxic to cells. During dTTP depletion elevated dATP was maintained, and cytotoxicity was significantly and rapidly enhanced by deoxyadenosine but could be reversed by thymidine. Data suggest that maintenance of elevated dATP and the dATP:dTTP ratio are essential initiation events in the commitment of colon carcinoma cells to thymineless death.

Biochemical markers of bone turnover in women with surgically treated carcinoma of the breast.

Biochemical markers of bone turnover were measured in fasting urine and blood samples obtained from 38 postmenopausal women with previous surgical treatment of breast cancer combined with adjuvant chemotherapy, tamoxifen, or placebo. Significantly elevated urinary pyridinoline as nmol mmol-1 creatinine (47.5 and 42.5 in tamoxifen and placebo treated patients compared with 26.3 in normal controls, both P < 0.001) and deoxypyridinoline (11.9 and 10.5 compared with 6.3, P < 0.001 and P = 0.002 respectively) were found with unchanged urinary hydroxyproline, serum alkaline phosphatase and procollagen I carboxyterminal peptide (PICP). These findings suggest enhanced bone resorption resulting from the humoral osteoclast activating effect of the previous breast cancer or underlying carcinoma recurrence. Alternatively the raised pyridinium excretion might indicate an altered crosslinking composition of bone collagen. No specific effect on bone metabolism was found with tamoxifen treatment as all measured parameters were similar in both tamoxifen ex-users and non-users. This confirmed the safety of tamoxifen therapy with respect to bone.

Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors.

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4dx4)] or daily p.o. or i.p. administration 5 days per week for up to 20 courses. On a q4dx4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in approximately 5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18-21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being < 0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (> or = 84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13-20 weeks (1.0-1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines.(ABSTRACT TRUNCATED AT 400 WORDS)

Is there a role for perioperative adjuvant therapy in the treatment of early breast cancer?

Despite having been investigated for many years, the role of adjuvant perioperative chemotherapy in the treatment of early breast cancer has still to be fully defined. This paper reviews the early trials of perioperative cytotoxic therapy and overviews the two largest trials; the Scandinavian Adjuvant Chemotherapy Study Group (SACSG) Trial, which began in 1965 and recruited 1026 patients, and the Cancer Research Campaign (CRC) Adjuvant Trial with 2230 patients entered between 1981 and 1985. Overview analysis of these two trials clearly shows a small but highly significant increase in time to first event (P less than 0.001). Increased survival, although significant in the SACSG trial, has not yet been demonstrated in the CRC study, but at this stage of follow-up (median 2.5 years) this is not surprising.

Role of murine tumor models in cancer treatment research.

Two major factors have contributed to a widely held disenchantment with murine tumor models for drug screening in cancer research: (a) the higher costs of these models in comparison to studies performed with tumor cells in vitro; and (b) the perception that these models have failed to demonstrate satisfactory correlation of chemosensitivity with analogous human tumor types; i.e., murine tumors generally have proved to be sensitive to many more agents than are found to be active in the clinic. The perceived failure of the murine models is discussed with particular reference to the difference in criteria used for evaluating drug sensitivity in murine tumor models versus clinical trials, and we conclude that the perception about murine models is not tenable in light of present information. The very important role of murine tumor models in optimizing dosage and administration schedules and, most importantly, in the development of a new drug to its most useful potential in combination chemotherapy is discussed. The value of this in vivo methodology is stressed.

Chemotherapy of childhood rhabdomyosarcomas growing as xenografts in immune-deprived mice.

Xenografts derived from the neoplastic tissues of children with rhabdomyosarcoma have been used in immune-deprived mice to examine the efficacy of agents known to be active against this disease, and in others that received either limited or no clinical evaluation. Two models were derived; xenografts were established from tumors obtained from either (a) untreated patients or (b) from patients who had become refractory to conventional therapy. Model a identified as being effective each of these clinically used agents: vincristine, dactinomycin, cyclophosphamide, and doxorubicin; mitomycin C and 5-(3,3-dimethyl-1-triazeno)-2-methylimidazole-4-carboxamide also showed activity, as did busulfan in one tumor line. Tumors derived from refractory patients were significantly less responsive to all agents examined.

Light-dependent cytochrome P-450 changes in mung beans (Phaseolus aureus).

Maximum concentrations of microsomal cytochrome P-450 are present in 3-4 day-old mung beans (Phaseolus aureus). On illumination of dark-grown seedlings, cytochrome P-450 and later cytochrome P-450 undergo a rapid decrease in concentration in vivo, with an apparent half-time of about 6 h. Conversely light-grown seedlings, transferred to darkness, show a slow accumulation of cytochrome P-450, doubling time of about 30 h, with a later accumulation of cytochrome P-420. Microsomal cytochromes b559, b560.5 and b562.5 do not significantly alter on light-dark transitions. Possible functions for dark-induced cytochrome P-450 are discussed.

The cytochromes in microsomal fractions of germinating mung beans.

Detailed studies of microsomal cytochromes from mung-bean radicles showed the presence of cytochrome P-420, particularly in dark-grown seedlings, accompanied by smaller quantities of cytochrome P-450. Similar proportions of cytochrome P-420 to cytochrome P-450 were found spectrophotometrically in vivo with whole radicles and hypocotyls. Assayed in vitro, maximum concentrations of both cytochromes were attained after 4 days of growth, before undergoing rapid degradation. Illumination of seedlings stabilized cytochrome P-450 and decreased the amount of cytochrome P-420. Three b cytochromes were present in the microsomal fraction, namely cytochromes b-562.5 (Em + 105 +/- 23 mV), b-560.5 (Em + 49 +/- 13 mV) and b5 (Em - 45 +/- 14 mV), all at pH 7.0. Of the b cytochromes, cytochrome b5 alone undergoes a rapid degradation after day 4, Changes in cytochrome b concentrations were confined to the microsomal fraction: mitochondrial b cytochrome concentrations were unaltered with age. Protohaem degradation (of exogenous methaemalbumin) was detected in microsomal fractions of mung beans. The rates of degradation were highest in extracts of young tissue and declined after day 4. The degradation mechanism and products did not resemble those of mammalian haem oxygenase.

Cancer growth, response to treatment and survival time in mice: beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen.

Adult mice were injected subcutaneously with cells from a syngeneic metastasizing mammary cancer. Daily treatment with flurbiprofen starting before injection of the cancer cells reduced tumour growth and lengthened the survival of mice whose tumours were excised at 3 weeks. When low doses of radiotherapy and chemotherapy were given, additional treatment with flurbiprofen starting 25 days after injecting the cancer cells substantially inhibited tumour growth.