Treatment of adrenocortical carcinoma: a case report and review of the literature

A case report of adrenocortical carcinoma is presented, and its natural history and treatment are discussed. Adrenocortical carcinoma is a rare malignant disease. The mean survival time for untreated patients is less than three months. The tumor is classified as functioning or nonfunctioning depending on biochemical and clinical evidence of steroid overproduction. Surgical resection of the tumor is the primary treatment. Chemotherapy is indicated for antitumor and antihormonal effects. Mitotane is a direct adrenolytic, and is the only drug currently available that has extended survival in patients with this disease. Its clinical usefulness is limited by its gastrointestinal and neurological toxicity. Aminoglutethimide inhibits steroid synthesis by blocking the conversion of cholesterol to pregnenolone. It has no antitumor effect in adrenocortical carcinoma, but is effective in relieving the signs and symptoms of excessive hormone production in functioning tumors. Both mitotane and aminoglutethimide have complex mechanisms of action. Their combined use in the treatment of adrenocortical carcinoma requires a complete understanding of their individual actions and awareness of the potential for additive effects, both therapeutic and toxic.     

Influence of polymer architecture on the structure of complexes formed by PEG-tertiary amine methacrylate copolymers and phosphorothioate oligonucleotide.

The influence of polymer structure on the characteristics of complexes of a phosphorothioate antisense oligonucleotide (ISIS 5132) was studied, using well-defined cationic copolymers based on 2-(dimethylamino) ethyl methacrylate (DMAEMA) and poly(ethylene glycol) (PEG). The three related copolymer structures were: DMAEMA-PEG (a diblock copolymer) DMAEMA-OEGMA 7 (a brush-type copolymer), DMAEMA-stat-PEGMA (a comb-type copolymer); each of these were examined together with DMAEMA homopolymer, which served as a control. The results revealed that all the polymers exhibited good binding ability with the oligonucleotide (ON). Interestingly, the comb-type polymer DMAEMA-stat-PEGMA demonstrated the highest binding ability and DMAEMA homopolymer the lowest, as judged by a dye displacement assay. DMAEMA homopolymer produced large agglomerates of smaller individual complexes as observed by optical density, photon correlation spectroscopy and transmission electron microscopy studies. In contrast, two PEG-block copolymers, DMAEMA-PEG and DMAEMA-OEGMA 7, formed compact complexes of 80-150 nm which had good long-term colloidal stability. This is attributed to the steric stabilisation effect of the PEG chains on the ON-copolymer complexes. These two copolymers are believed to form complexes with ON that have a micellar structure. Comb-type DMAEMA-stat-PEGMA copolymer formed highly soluble complexes with the ON that did not phase separate from the buffer solution. This study clearly demonstrates that varying the copolymer architecture allows access to a range of ON complexes. In vitro cytotoxicity experiments on HepG2 cells showed that all of the tertiary amine methacrylate copolymers displayed lower cytotoxicity than the control poly(L-lysine).     

Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires

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Patterns of Self-reported Behaviour Change Associated with Receiving Voluntary Counselling and Testing in a Longitudinal Study from Manicaland, Zimbabwe

Voluntary counselling and testing (VCT) is promoted as a potential HIV prevention measure. We describe trends in uptake of VCT for HIV, and patterns of subsequent behaviour change associated with receiving VCT in a population-based open cohort in Manicaland, Zimbabwe. The relationship between receipt of VCT and subsequent reported behaviour was analysed using generalized linear models with random effects. At the third survey, 8.6% of participants (1,079/12,533), had previously received VCT. Women who received VCT, both those positive and negative, reduced their reported number of new partners. Among those testing positive, this risk reduction was enhanced with time since testing. Among men, no behavioural risk reduction associated with VCT was observed. Significant increases in consistent condom use, with regular or non-regular partners, following VCT, were not observed. This study suggests that, among women, particularly those who are infected, behavioural risk reduction does occur following VCT.     

Absorption-promoting effects of chitosan in airway and intestinal cell lines: a comparative study

This work explored the interaction of chitosan with Calu-3 and Caco-2 cell lines, as models of the airway and intestinal epithelium, respectively. The toxicity, tight junction opening and mucoadhesive effects of chitosan were compared in the two cell lines. Additionally, the role of mucus in the absorption-promoting activity of chitosan was studied systematically. Notably, chitosan exhibited a different degree of toxicity on the Calu-3 and Caco-2 cells. Chitosan's tight junction-opening effect, observed in terms of reduction of transepithelial electrical resistance and permeability enhancement, was apparent in both cell lines, though somewhat lower in Caco-2 compared to Calu-3 cell layers (though overall permeability was higher in the former). Tight junction opening and association of chitosan with the epithelial cell layers were more prominent in mucus-containing than in mucus-depleted Calu-3 cells and non mucus-excreting Caco-2 monolayers. Overall, the work suggests that chitosan exhibits a different level of toxicity in airway, as compared to intestinal cells and although absorption enhancement is apparent in both cell lines, enabling its potential use as an absorption-promoting excipient in both pulmonary and oral macromolecular delivery, the magnitude and the duration of the effect are dependent on the level of mucus present on the epithelial surfaces.     

Critique of early models of the demographic impact of HIV/AIDS in sub-Saharan Africa based on contemporary empirical data from Zimbabwe

Early mathematical models varied in their predictions of the impact of HIV/AIDS on population growth from minimal impact to reductions in growth, in pessimistic scenarios, from positive to negative values over a period of 25 years. Models predicting negative rates of natural increase forecast little effect on the dependency ratio. Twenty years later, HIV prevalence in small towns, estates, and rural villages in eastern Zimbabwe, has peaked within the intermediate range predicted by the early models, but the demographic impact has been more acute than was predicted. Despite concurrent declines in fertility, fueled in part by HIV infections (total fertility is now 8% lower than expected without an epidemic), and a doubling of the crude death rate because of HIV/AIDS, the rate of natural population increase between 1998 and 2005 remained positive in each socioeconomic stratum. In the worst-affected areas (towns with HIV prevalence of 33%), HIV/AIDS reduced growth by two-thirds from 2.9% to 1.0%. The dependency ratio fell from 1.21 at the onset of the HIV epidemic to 0.78, the impact of HIV-associated adult mortality being outweighed by fertility decline. With the benefit of hindsight, the more pessimistic early models overestimated the demographic impact of HIV epidemics by overextrapolating initial HIV growth rates or not allowing for heterogeneity in key parameters such as transmissibility and sexual risk behavior. Data collected since the late 1980s show that there was a mismatch between the observed growth in the HIV epidemic and assumptions made about viral transmission.     

A mitotic function for the high-mobility group protein HMG20b regulated by its interaction with the BRC repeats of the BRCA2 tumor suppressor

The inactivation of BRCA2, a suppressor of breast, ovarian and other epithelial cancers, triggers instability in chromosome structure and number, which are thought to arise from defects in DNA recombination and mitotic cell division, respectively. Human BRCA2 controls DNA recombination via eight BRC repeats, evolutionarily conserved motifs of ～35 residues, that interact directly with the recombinase RAD51. How BRCA2 controls mitotic cell division is debated. Several studies by different groups report that BRCA2 deficiency affects cytokinesis. Moreover, its interaction with HMG20b, a protein of uncertain function containing a promiscuous DNA-binding domain and kinesin-like coiled coils, has been implicated in the G2-M transition. We show here that HMG20b depletion by RNA interference disturbs the completion of cell division, suggesting a novel function for HMG20b. In vitro, HMG20b binds directly to the BRC repeats of BRCA2, and exhibits the highest affinity for BRC5, a motif that binds poorly to RAD51. Conversely, the BRC4 repeat binds strongly to RAD51, but not to HMG20b. In vivo, BRC5 overexpression inhibits the BRCA2-HMG20b interaction, recapitulating defects in the completion of cell division provoked by HMG20b depletion. In contrast, BRC4 inhibits the BRCA2-RAD51 interaction and the assembly of RAD51 at sites of DNA damage, but not the completion of cell division. Our findings suggest that a novel function for HMG20b in cytokinesis is regulated by its interaction with the BRC repeats of BRCA2, and separate this unexpected function for the BRC repeats from their known activity in DNA recombination. We propose that divergent tumor-suppressive pathways regulating chromosome segregation as well as chromosome structure may be governed by the conserved BRC motifs in BRCA2.