Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors.

BACKGROUND: Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies, although the frequency and severity varies among the different agents. Inhibitors targeting vascular endothelial growth factor receptor (VEGFR) often inhibit other kinases, which may contribute to their adverse-event profiles. METHODS: Kinase selectivity of pazopanib, sorafenib, and sunitinib was evaluated in a panel of 242 kinases. Cellular potency was measured using autophosphorylation assays. Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity. RESULTS: Sunitinib inhibited more kinases than pazopanib and sorafenib, at potencies within 10-fold of VEGFR-2. All three compounds potently inhibited VEGFR-2, platelet-derived growth factor receptor-beta and c-Kit, However, pazopanib was less active against Flt-3 in both kinase and cellular assays. The inhibitory properties of pazopanib, sorafenib, and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation. Addition of stem cell factor and/or Flt-3 ligand with granulocyte-macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib. CONCLUSION: Activity against c-kit and Flt-3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients.

Fragrance chemistry and pollinator affinities in Nyctaginaceae.

We present results of dynamic head-space collections and GC-MS analyses of floral and vegetative fragrances for 20 species in three genera of Nyctaginaceae: Acleisanthes, Mirabilis and Selinocarpus. Most of the species included in this study are either hawkmoth or noctuid moth-pollinated. A wide variety of compounds were observed, including mono- and sesquiterpenoids, aromatics (both benzenoids and phenylpropanoids), aliphatic compounds, lactones, and nitrogen-bearing compounds. Intraspecific variation in fragrance profiles was significantly lower than interspecific variation. Each species had a unique blend of volatiles, and the fragrance of many species contained species-specific compounds. The fragrance profiles presented here are generally consistent with previous studies of fragrance in a variety of moth-pollinated angiosperms.

Limiting resuscitation: emerging policy in the emergency medical system.

Patients, families, and physicians frequently decide that a hospitalized patient will forgo cardiopulmonary resuscitation and document this decision with a do-not-resuscitate (DNR) order. In community settings (home, nursing home, hospice), these orders may conflict with paramedics' standing orders to provide cardiopulmonary resuscitation whenever it is medically indicated. We did a nationwide telephone survey of state offices for coordination of emergency medical services (EMS) to see how the states deal with this potential conflict. We identified eight states that have specific policies enabling EMS personnel to accept DNR orders for patients being transported by ambulance. State officials identified administrative complexities and legal concerns as the primary barriers to enacting prehospitalization DNR policies. We also identified 21 local EMS systems that have developed policies for accepting orders to withhold life-sustaining treatment. Four types of policy models, characterized according to procedure for validating DNR orders and telephone accessing the EMS system, show that regulatory reform can address policy barriers in the absence of enabling legislation.

Importance of "significant others" in predicting cooperation with diabetic regimen.

Patients' cooperation with their medical regimen is of prime importance in the treatment of a chronic illness such as diabetes. A psychosocial model of behavioral prediction developed by Fishbein was used to examine compliance intentions among diabetic patients. Patients' beliefs about the consequences of following their diet were identified. Surprisingly, how important following the regimen was to "significant others" in a patient's life was a stronger predictor of behavioral intention than were the patient's own beliefs.

Handcuff neuropathy: two unusual cases.

Handcuff applications may result in compression of peripheral nerves at the wrist, and most reported cases involve only the superficial radial nerve. In this report, two cases of bilateral handcuff neuropathy involving multiple nerves were confirmed by electrodiagnostic findings of membrane instability, prolonged latencies and/or conduction block. In addition to the superficial radial nerves, one case involved the median nerves, and a second case the ulnar nerves. It was postulated that injury might occur to any nerve at the wrist as a result of pressure and edema from handcuffs, with the radial nerve most frequently involved due to its superficial location. Radial nerve injury has been described as functionally insignificant; however for the two cases presented, in which the median or ulnar nerves were involved, significant disability resulted, and a rehabilitation program was indicated.

Conjugation in Agrobacterium tumefaciens in the absence of plant tissue.

A general, reliable conjugation system for Agrobacterium tumefaciens in the absence of plant tissue is described in which A. tumefaciens can serve either as the donor or recipient of plasmid deoxyribonucleic acid with reasonable efficiency. Plasmid RP4 was transferred from Escherichia coli to A. tumefaciens and from strain of A. tumefaciens. Both RP4 and the A. tumefaciens virulence-associated plasmids were detected by alkaline sucrose gradients in A. tumefaciens strains A6 and C58 after mating with E. coli J53(RP4). The pathogenicity (tumor foramtion) of strains A6 and C58 and the sensitivity of strain C58 to bacteriocin 84 were unaffected by the acquistion of RP4 by the Agrobacterium strains. Plasmid R1drd-19 was not transferred to A. tumefaciens. Transformation experiments with plasmid deoxyribonucleic acid were unsuccessful, even though, in the case of RP4, conjugation studies showed taht the deoxyribonucleic acid was compatible with that of the recipient strains.

Effect of some inhibitors derived from nitrite on marcomolecular synthesis in Bacillus cereus.

The effect of several inhibitors derived from nitrite on incorporation of [14C]uracil into ribonucleic acid of Bacillus cereus during outgrowth and vegetative growth has been determined. A heat-induced inhibitor presumably of the Perigo type was compared with the nitrosothiols of thioglycolate and beta-mercaptoethanol. All were found to effectively inhibit uracil incorporation at all stages tested. Phase-contrast microscopy revealed that inhibition of morphological events occurred either before germination or during early outgrowth, depending on inhibitor concentration. It was also found that a precursor to the heat-induced inhibitor could be isolated from dialyzable tryptone (a pancreatic digest of casein), which chromatographed as a single species on diethylaminoethyl-cellulose and Sephadex G-25, with an apparent molecular weight of about 2,000.

Effect of cultural conditions on the fatty acid composition of Thiobacillus novellus.

The fatty acid content of Thiobacillus novellus was determined under various cultural conditions. Four fatty acids, C(16:0), C(18:0), C(18:1), and a C(19) cyclopropane acid (C(19:cyc)), generally accounted for 90 to 99% of the total acids. Phosphate concentration, temperature, culture agitation, and the presence of branch-chain precursors had no significant effect on cellular fatty acids. Autotrophically grown cells contained more saturated C(16) and C(18) acids than did heterotrophic ones, and the sum of the percentages of the C(18:1) and the C(19:cyc) acids was consistently higher in the heterotrophs. When the inorganic medium was supplemented with biotin, autotrophic cells produced more C(19:cyc) and much less C(18:1) than did autotrophs in unsupplemented medium. Heterotrophic cells grown with biotin also showed a marked reduction of the unsaturated acid and an increase in the cyclopropane acid, except when glutamatecitrate medium was employed, in which case the opposite effect was noted. Two different biotin-supplemented media yielded cells with 75 to 77% of the total fatty acids being the C(19) cyclopropane acid, one of the highest reported values for this class of acid.

Fatty acids of Thiobacillus thiooxidans.

Fatty acid spectra were made on Thiobacillus thiooxidans cultures both in the presence and absence of organic compounds. Small additions of glucose or acetate had no significant effect either on growth or fatty acid content. The addition of biotin had no stimulatory effect but did result in slight quantitative changes in the fatty acid spectrum. The predominant fatty acid was a C(19) cyclopropane acid.