Platinum complexes with anticancer potential and their evaluation by a colorimetric lambda prophage induction assay

A simple biochemical phage induction assay (BIA) showed significant activity with 90% of the antitumor platinum compounds tested and lack of activity for all Pd(II) compounds and Pt(II) cationic complexes, compounds that are expected to be inactive. Structure-activity relationships for a large number of chemicals can be studied simultaneously by this simple, rapid, inexpensive and quantitative biochemical assay. Fifty-three platinum complexes were tested, including a number of ethylenediamines synthesized for this work. The magnitude of inducing activity varied over a 25-fold range; differences among analogs reflected structural differences in a chemically consistent manner. Seven platinum complexes showed greater activity than that of cis-diamminedichloroplatinum(II) (cisplatin, cis-DDP), while other compounds appeared to be substantially less toxic. The assay was predictive for most compounds with very high or very low activity in vivo against L1210. For compounds with intermediate levels of activity, no correlation between inducing and antitumor activity was observed.     

Role of angiotensin II in oral contraceptive hypertension in anesthetized rats

Rats fed a diet containing an oral contraceptive estrogen-progestogen mixture (Enovid) for 26 weeks developed a significant (P<0.01) elevation in mean arterial pressure (145 ± 6 mm Hg) when compared to a control group of rats fed the same diet without oral contraceptive steroids (mean arterial pressure averaged 117 ± 6 mm Hg). Infusion of [Sar¹, Ala⁸] angiotensin II, a competitive antagonist of angiotensin II, reduced the mean arterial pressure (P<0.01) in the oral contraceptive-treated rats to 117 ± 9 mm Hg, while infusion of this angiotensin II analogue into the control rats did not lower the arterial pressure. These studies provided evidence that angiotensin II may be involved in the hypertension produced by Enovid treatment in rats.     

Johnson-McMillin syndrome: report of a new case with novel features

BACKGROUND: Johnson-McMillin syndrome (JMS) is a rare neuroectodermal disorder characterized by alopecia, ear malformations, conductive hearing loss, anosmia/hyposmia, and hypogonadotropic hypogonadism. It is inherited in an autosomal dominant manner; however, the causative gene has not yet been identified. CASE: Herein we report a patient with this condition who exhibits many of the features previously described, including alopecia, malformed auricles, conductive hearing loss, facial asymmetry, and developmental delays. Interestingly, she also has features that have not yet been reported, such as preauricular pits and tags, broad depressions at the lateral aspects of the eyes, and an abnormal left lower eyelid. CONCLUSIONS: In addition to demonstrating a pattern of anomalies consistent with JMS, this patient has several unique features. This phenotype supports the involvement of the branchial arches in the embryologic basis of this condition.     

Potential bias and mitigations when using stable isotope labeled parent drug as internal standard for LC-MS/MS quantitation of metabolites

In recent years, increasing emphasis has been placed on quantitative characterization of drug metabolites for better insight into the correlation between metabolite exposure and toxicological observations or pharmacological efficacy. One common strategy for metabolite quantitation is to adopt the stable isotope labeled (STIL) parent drug as the internal standard in an isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. In the current work, we demonstrate this strategy could have a potential pitfall resulting in quantitation bias if the internal standard is subject to ion suppression from the co-eluting parent drug in the incurred samples. Propranolol and its metabolite 4-hydroxypropranolol were used as model compounds to demonstrate this phenomenon and to systematically evaluate different approaches to mitigate the issue, including atmospheric pressure chemical ionization (APCI) mode of ionization, increased internal standard concentration, quantitation without internal standard, the use of a structural analog as internal standard, and dilution of the samples. Case studies of metabolite quantitation in nonclinical and clinical studies in drug development were also included to demonstrate the importance of using an appropriate bioanalytical strategy for metabolite quantitation in the real world. We present that bias of metabolite concentrations could pose a potential for poor estimation of safety risk. A strategy for quantitation of metabolites in support of drug safety assessment is proposed.     

Indoor Air Inhalation Risk Assessment for Volatiles Emanating from Light Nonaqueous Phase Liquids

The indoor air inhalation pathway for volatile contaminants in soil and groundwater has received much attention recently. The risk of exposure may be higher when volatile organic compounds (VOCs) reside as constituents of a free product plume below residential or commercial structures than when dissolved in groundwater or adsorbed on soil. A methodology was developed for assessing the potential for vapor phase migration—and associated risk of indoor air inhalation—of volatile constituents from a light nonaqueous phase liquid (LNAPL) plume on top of the water table. The potential risk from inhalation of VOCs in indoor air emanating from a subsurface Jet Fuel 4 (JP-4) plume by hypothetical residential receptors was assessed at a site. Chemicals of concern (COCs) were identified and evaluated using data from the composition of JP-4 mixtures and published chemical, physical, and toxicological data. The method estimates the equilibrium vapor concentrations of JP-4 constituents using Raoult's Law for partial vapor pressure of mixtures based on assumptions about the mixture composition of JP-4. The maximum allowable vapor concentration at the source (immediately above the LNAPL) corresponding to an indoor air target concentration based on acceptable risk levels are calculated using the Johnson and Ettinger model. The model calculates the attenuation factor caused by the migration of the vapor phase VOCs through the soil column above the JP-4 plume and through subsurface foundation slabs. Finally, the maximum allowable soil gas concentrations above the LNAPL for individual constituents were calculated using this methodology and compared to the calculated equilibrium vapor concentrations of each COC to assess the likelihood of potential risk from the indoor air inhalation pathway.     

Virus-like particles as vaccines and vessels for the delivery of small molecules

Virus-like particles (VLPs) structurally mimic the viral capsid and have therefore been extensively, and quite successfully, used as vaccine and viral serology reagents. The ability of VLPs to include nucleic acids and small molecules has also made them novel vessels for gene and drug delivery. The regular, repetitive surface of VLPs has been exploited as a template for nanoscale synthesis. Recent progress has been made in the development of several virus models.     

Stevens Johnson Syndrome in a patient undergoing gynaecological brachytherapy: An association or an incident?

Background

Stevens Johnson Syndrome and Erythema Multiforme are hypersensitivity skin reactions generally arising in the context of multiple causes. Radiation therapy is considered to be one of these causes, although most reports are hindered by concomitant medications.

Aim

The aim of this paper was to present a case of Stevens Johnson Syndrome arising in a patient undergoing gynaecological brachytherapy with an unusual presentation.

Case

We describe a case of a 56-year-old woman with endometrial cancer undergoing adjuvant gynaecological radiotherapy. While undergoing a gynaecological brachytherapy boost, she developed bilateral conjunctivitis that progressed to oral mucositis and pruritic erythema with sloughing of the skin on her arms and legs but not the torso or irradiated fields (namely the vaginal mucosa).

Conclusion

This case illustrates the association of RT/SJS; however, it also raises the question of patients undergoing RT being more susceptible to SJS as opposed to a direct cause of the disease.     

Naturalism, evidence and creationism: The case of Phillip Johnson

Phillip Johnson claims that Creationism is a better explanation of the existence and characteristics of biological species than is evolutionary theory. He argues that the only reason biologists do not recognize that Creationist's negative arguments against Darwinism have proven this is that they are wedded to a biased ideological philosophy —Naturalism — which dogmatically denies the possibility of an intervening creative god. However, Johnson fails to distinguish Ontological Naturalism from Methodological Naturalism. Science makes use of the latter and I show how it is not dogmatic but follows from sound requirements for empirical evidential testing. Furthermore, Johnson has no serious alternative type of positive evidence to offer for Creationism, and purely negative argumentation, despite his attempt to legitimate it, will not suffice.     

Association of cone thermogenesis and volatiles with pollinator specificity in Macrozamia cycads

Cone traits (volatile components and thermogenesis) of three cycad species in the genus Macrozamia were examined for differences related to their specific insect pollinators, the weevil, Tranes spp., or the thrips, Cycadothrips chadwicki. Linalool (>80% of emissions) dominated cone volatile components of M. machinii (Tranes-pollinated) and beta-myrcene was a minor component (<9% of emissions). Volatiles of M. lucida and M. macleayi cones (Cycadothrips-pollinated) were dominated by beta-myrcene (up to 97% of emissions), but no linalool was detected. Pollinator movement into and out of cones coincided with cone thermogenesis and peak odor emission: around sunset for Tranes, and at mid-day for Cycadothrips. Female cone traits were similar to those of their conspecific male cones. Differences in cone traits between Macrozamia species may thus be responsible for conferring pollinator specificity in areas of sympatry.