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With advances in modern technologies and growing understanding of cellular biology, a variety of new mechanisms and molecular antagonists are currently being pursued in the fight against cancer. The result of these advances has spawned dozens of new exciting small molecula agents which are slowly progressing through the arduous process of clinical trials. We attempt in this review to highlight some of the new and exciting molecules representing previously unexplored targets. While it is by no means certain that novelty in a molecular target assures that it is a good one, our reading of the current literature would suggest that the seven molecules discussed in this review represent potentially new therapies which may add to the much needed armamentarium of cancer drugs.

Background. A major barrier to effective tuberculosis control is our limited understanding of risk factors for tuberculosis disease progression. This study examined the role of apoptosis in immunity to tuberculosis. Methods. Cell subsets from tuberculosis cases and tuberculin skin test-positive (TST⁺) and TST-negative (TST⁻) household contacts (HHCs) were analyzed for expression of annexin-V and propidium iodide by flow cytometry. RNA microarrays were used to determine differences in apoptotic gene expression levels and multiplex ligationdependent probe amplification was used to analyze gene expression in HHCs who progressed to active tuberculosis. Results. T cells from TST⁺HHC exhibited higher levels of apoptosis than tuberculosis cases; however, tuberculosis cases had a higher proportion of late apoptotic cells within the CD3⁺ PD-1⁺ subset. Tuberculosis cases had reduced levels of antiapoptotic genes compared to HHCs with a significant reduction in BCL2 associated with disease progression at least 1 year prior to progression. Conclusions. While T cells are clearly able to mount a robust immune response to Mycobacterium tuberculosis, there are increased levels of apoptosis seen in effector T cells from tuberculosis patients. Dysregulation of several apoptotic genes suggest that apoptosis is a major functional pathway that could be targeted for future host-directed therapeutics.

Multicomponent therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. We have developed a high-throughput screening method for identifying effective combinations of therapeutic compounds. We report here that systematic screening of combinations of small molecules reveals unexpected interactions between compounds, presumably due to interactions between the pathways on which they act. Through systematic screening of ≈120,000 different two-component combinations of reference-listed drugs, we identified potential multicomponent therapeutics, including (i) fungistatic and analgesic agents that together generate fungicidal activity in drug-resistant Candida albicans, yet do not significantly affect human cells, (ii) glucocorticoid and antiplatelet agents that together suppress the production of tumor necrosis factor-α in human primary peripheral blood mononuclear cells, and (iii) antipsychotic and antiprotozoal agents that do not exhibit significant antitumor activity alone, yet together prevent the growth of tumors in mice. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways and, when performed with reference-listed drugs, may result in the discovery of new combination drug regimens.

Caribou (Rangifer tarandus), elk (Cervus canadensis), moose (Alces alces), and Stone's sheep (Ovis dalli stonei) were either decreasing or stable in numbers in two areas in northeastern British Columbia in 1981-1982, prior to reductions in wolf (Canis lupus) numbers. Following the reduction of wolf numbers, recruitment improved 2-5 times for all four species, and all populations increased, based on either hunting statistics, census results, and (or) recruitments greater than 24 offspring at 9 months of age per 100 females. Recruitment of offspring at 9 months of age, when regressed against wolf numbers, declined with decelerating slopes for all four species. This inverse functional response is hypothesized to result from the preparturient spacing of females to reduce predation risk, and in this regard moose seem the least secure and sheep the most effectively spaced. For the four species, mean recruitment at 9 months of age that balanced adult mortality and provided a finite rate of increase of 1.00 was 24.16 ± 0.91 offspring/100 females (n = 11, coefficient of variation = 12.5%). The predicted recruitment rate for all four species in the absence of wolves was 53-57 offspring/100 females. But the birth rate of moose was much higher than those of the other species, indicating greater loss to other factors of which bear predation may be the greatest. Following wolf reductions of 60-86% of entire travelling packs, the wolves quickly recolonized the removal zones, with rates of increase ranging from 1.5 to 5.6.

The ubiquitin proteasome pathway is a highly conserved intracellular pathway for the degradation of proteins. Many of the short-lived regulatory proteins which govern cell division, growth, activation, signaling and transcription are substrates that are temporally degraded by the proteasome. In recent years, new and selective inhibitors of the proteasome have been employed in cell culture systems to examine the anti-tumor potential of these agents. This review covers the chemistry of selected proteasome inhibitors, possible mechanisms of action in cell culture and the in vivo examination of proteasome inhibitors in murine and human xenograft tumor models in mice. One inhibitor, PS-341, has recently entered Phase I clinical trials in cancer patients with advanced disease to further test the potential of this approach.

Five steers (mean BW 526 kg) fitted with ruminal, duodenal, and ileal cannulas were used in a 5 x 6 Youden square design with 14-d periods. Diets contained chopped alfalfa hay, corn silage, and concentrate (25:35:40, DM basis). Treatments were 1) control (no added fat); 2) tallow (T), iodine value (IV) = 51.5; 3) partially hydrogenated tallow (PHT), IV = 30.7; 4) hydrogenated tallow (HT), IV = 6.9; 5) blend (1: 1) of HT and hydrogenated free fatty acids (HTHFA), IV = 9.0; and 6) hydrogenated free fatty acids (HFA), IV = 11.2. Fats replaced cornstarch in the control diet to supply 5% added fatty acids. Intake was restricted to 90% of ad libitum; DMI was similar among diets (mean 9 kg/d). Total fatty acid intake averaged 170, 500, 506, 525, 489, and 491 g/d for treatments 1 to 6, respectively. Flows of total C16, total C18, and total fatty acids to the duodenum were increased by supplemental fat; flows of total C18 and total fatty acids were greater than their intake for all treatments. Flow of total fatty acids associated with ruminal bacteria accounted for 50 and 17% of the total duodenal fatty acid flow for the control and fat-supplemented diets, respectively. Digestibility of total fatty acids entering the small intestine (74, 71, 62, 39, 53, and 63% for treatments 1 to 6, respectively) was greater for the control diet than for fat-supplemented diets and decreased as either saturation (T < PHT < HT) or esterification (HFA < HTHFA < HT) increased. Digestibilities of fatty acids in the total tract followed similar patterns. Ruminal lipolysis of dietary triglycerides decreased linearly as the degree of saturation of fat sources increased. Small intestinal disappearance of triglycerides (89, 75, 51, 44, 64, and 73% of duodenal flow for treatments 1 to 6, respectively) decreased linearly as either saturation or esterification increased. Flows and digestion of gross energy followed patterns similar to those for fatty acids and triglycerides. Resistance to ruminal and small intestinal lipolysis is a major factor contributing to the poor digestibility of highly saturated triglycerides.

Background: The recognition that early diagnosis and intervention, prior to ischemic neurologic injury, has the potential to improve outcome following blunt cerebrovascular injuries (BCVI), led to a policy of aggressive screening for these injuries. The resultant epidemic of BCVI has created a dilemma, as widespread screening is impractical. We sought to identify independent predictors of BCVI, to focus resources. Methods: Cerebral arteriography was performed based on signs or symptoms of BCVI, or in asymptomatic patients with high-risk mechanisms (hyperextension, hyperflexion, direct blow) or injury patterns. Logistic regression analysis identified independent predictors. Results: A total of 249 patients underwent arteriography; 85 (34%) had injuries. Independent predictors of carotid arterial injury were Glasgow coma score ≤6, petrous bone fracture, diffuse axonal brain injury, and LeFort II or III fracture. Having one of these factors in the setting of a high-risk mechanism was associated with 41% risk of injury. Of patients with cervical spine fracture, 39% had vertebral arterial injury. Conclusions: Patients sustaining high-risk injury mechanisms or patterns should be screened for BCVI. In the face of limited resources, screening efforts should be focused on those with high-risk predictors.

Objectives: To estimate exposures to cadmium (Cd) received by the United Kingdom population as a result of the dispersion of zinc Cd sulfide (ZnCdS) by the Ministry of Defence between 1953 and 1964, as a simulator of biological warfare agents. Methods: A retrospective risk assessment study was carried out on the United Kingdom population during the period 1953–64. This determined land and air dispersion of ZnCdS over most of the United Kingdom, inhalation exposure of the United Kingdom population, soil contamination, and risks to personnel operating equipment that dispersed ZnCdS. Results: About 4600 kg ZnCdS were dispersed from aircraft and ships, at times when the prevailing winds would allow large areas of the country to be covered. Cadmium released from 44 long range trials for which data are available, and extrapolated to a total of 76 trials to allow for trials with incomplete information, is about 1.2% of the estimated total release of Cd into the atmosphere over the same period. “Worst case” estimates are 10 μg Cd inhaled over 8 years, equivalent to Cd inhaled in an urban environment in 12–100 days, or from smoking 100 cigarettes. A further 250 kg ZnCdS was dispersed from the land based sites, but significant soil contamination occurred only in limited areas, which were and have remained uninhabited. Of the four personnel involved in the dispersion procedures (who were probably exposed to much higher concentrations of Cd than people on the ground), none are suspected of having related illnesses. Conclusion: Exposure to Cd from dissemination of ZnCdS during the “cold war” should not have resulted in adverse health effects in the United Kingdom population.