N-acetyltransferase polymorphisms and colorectal cancer: a HuGE review

The two expressed genes coding for N-acetyltransferase (NAT) activity, NAT1 and NAT2, are located on chromosome 8 at 8p21.3-23.1 and are polymorphic. Both enzymes are capable of N-acetylation, O-acetylation, and N,O-acetylation and are implicated in the activation and detoxification of known carcinogens. Single base-pair substitutions in NAT2 tend to occur in combination with other substitutions within the gene. As yet, less work has been done to characterize NAT1 allelic variants. Various methods for the detection of the reported polymorphisms exist. It is important to select a method that is appropriate to the population being studied. The functional significance of many NAT allelic variants has not been determined. Geographic and ethnic variation in the frequency of NAT2 genotypes associated with fast or intermediate acetylation has been observed. Insufficient data for NAT1 genotypes are available to reveal a clear geographic pattern. No consistent association has been found between acetylator phenotype or genotype and colorectal cancer. The lack of consistency can in part be accounted for by methodological factors, including limited statistical power. Possible interactions between the NAT genes and either environmental exposures or other polymorphic genes encoding xenobiotic metabolizing enzymes have been investigated in only a minority of these studies, and these studies have lacked statistical power to detect interactions.     

beta-hydroxy-beta-methylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors

The leucine metabolite, beta-hydroxy-beta-methylbutyrate (HMB) enhances the effects of exercise on muscle size and strength. Although several reports in animals and humans indicate that HMB is safe, quantitative safety data in humans have not been reported definitively. The objective of this work was to summarize safety data collected in nine studies in which humans were fed 3 g HMB/d. The studies were from 3 to 8 wk in duration, included both males and females, young and old, exercising or nonexercising. Organ and tissue function was assessed by blood chemistry and hematology; subtle effects on emotional perception were measured with an emotional profile test (Circumplex), and tolerance of HMB was assessed with a battery of 32 health-related questions. HMB did not adversely affect any surrogate marker of tissue health and function. The Circumplex emotion profile indicated that HMB significantly decreased (improved) one indicator of negative mood (Unactivated Unpleasant Affect category, P < 0.05). No untoward effects of HMB were indicated. Compared with the placebo, HMB supplementation resulted in a net decrease in total cholesterol (5.8%, P < 0.03), a decrease in LDL cholesterol (7.3%, P < 0.01) and a decrease in systolic blood pressure (4.4 mm Hg, P < 0.05). These effects of HMB on surrogate markers of cardiovascular health could result in a decrease in the risk of heart attack and stroke. In conclusion, the objective data collected across nine experiments indicate that HMB can be taken safely as an ergogenic aid for exercise and that objective measures of health and perception of well-being are generally enhanced.     

Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines.

The level of expression of the multidrug resistance-associated protein (MRP1) in a panel of human ovarian carcinoma cell lines and their variants with acquired cisplatin resistance was determined using Western blotting. No overexpression of MRP1 was detected in any of the cell lines. In addition, we have transfected the MRP1 gene into an intrinsically cisplatin-resistant cell line SKOV3, previously shown to have elevated levels of glutathione (GSH). The MRP1-transfected line SKOV3-S2 was shown to be cross-resistant to doxorubicin, vincristine and etoposide but not to paclitaxel, vinblastine and platinum agents, such as cisplatin, JM216 [bis-acetato-ammine-dichloro-cyclohexylamine platinum (IV)] and AMD473 [cis-ammine dichloro (2-methyl-pyridine) platinum (II)]. No cross-resistance to any of the platinum agents was observed in a MRP1-overexpressing human lung cancer cell line with acquired doxorubicin resistance. Reduction of GSH levels (80-90%) by buthionine sulphoximine (BSO) produced significant potentiation in cisplatin sensitivity in the parental SKOV3, the vector-alone control SKOV3-puro and the MRP1-transfected line SKOV3-S2. The degree of sensitization was similar in all cell lines (1.6-fold). However, selective sensitization by BSO to vincristine was observed in the MRP1-transfected line (4.1-fold) but not in the vector control. No significant differences were observed in cisplatin accumulation in the SKOV3-puro and the SKOV3-S2 cells, although both these transfected lines accumulated significantly more than the parental line. Our results suggest that MRP1 does not play a significant role in platinum resistance in the human tumour cell lines investigated in this study.     

Cerulenin, an inhibitor of protein acylation, selectively attenuates nutrient stimulation of insulin release: a study in rat pancreatic islets

Nutrients such as glucose stimulate insulin release from pancreatic beta-cells through both ATP-sensitive K+ channel-independent and -dependent mechanisms, which are most likely interrelated. Although little is known of the molecular basis of ATP-sensitive K+ channel-independent insulinotropic nutrient actions, mediation by cytosolic long-chain acyl-CoA has been implicated. Because protein acylation might be a sequel of cytosolic long-chain acyl-CoA accumulation, we examined if this reaction is engaged in nutrient stimulation of insulin release, using cerulenin, an inhibitor of protein acylation. In isolated rat pancreatic islets, cerulenin inhibited the glucose augmentation of Ca2+-stimulated insulin release evoked by a depolarizing concentration of K+ in the presence of diazoxide and Ca2+-independent insulin release triggered by a combination of forskolin and phorbol ester under stringent Ca2+-free conditions. Cerulenin inhibition of glucose effects was concentration dependent, with a 50% inhibitory concentration (IC50) of 5 microg/ml and complete inhibition at 100 microg/ml. Cerulenin also inhibited augmentation of insulin release by alpha-ketoisocaproate, a mitochondrial fuel. Furthermore, cerulenin abolished augmentation of both Ca2+-stimulated and Ca2+-independent insulin release by 10 micromol/l palmitate, which causes palmitoylation of cellular proteins. In contrast, cerulenin did not attenuate insulin release elicited by nonnutrient secretagogues, such as a depolarizing concentration of K+, activators of protein kinases A and C, and mastoparan. Glucose oxidation, ATP content in islets, and palmitate oxidation were not affected by cerulenin. In conclusion, cerulenin inhibits nutrient augmentation of insulin release with a high selectivity. The finding is consistent with a prominent role of protein acylation in the process of beta-cell nutrient sensing.     

Pre and postnatal diagnosis of fetus‐in‐fetu

Differentiation of abdominal masses detected on prenatal ultrasound is difficult and requires careful characterization of the mass and precise localization. Differentiation is required in order to distinguish benign from potentially malignant conditions. We describe a case of fetus‐in‐fetu with pre and postnatal imaging.     

Corrosion Resistance of 3D Printed Ti6Al4V Gyroid Lattices with Varying Porosity

Corrosion of medical implants is a possible failure mode via induced local inflammatory effects, systemic deposition and corrosion related mechanical failure. Cyclic potentiodynamic polarisation (CPP) testing was utilized to evaluate the effect of increased porosity (60% and 80%) and decreased wall thickness in gyroid lattice structures on the electrochemical behaviour of LPBF Ti6Al4V structures. The use of CPP allowed for the landmarks of breakdown potential, resting potential and vertex potential to be analysed, as well as facilitating the construction of Tafel plots and qualitative Goldberg analysis. The results indicated that 60% gyroid samples were most susceptible to the onset of pitting corrosion when compared to 80% gyroid and solid samples. This was shown through decreased breakdown and vertex potentials and were found to correlate to increased lattice surface area to void volume ratio. Tafel plots indicated that despite the earlier onset of pitting corrosion, both gyroid test groups displayed lower rates of corrosion per year, indicating a lower severity of corrosion. This study highlighted inherent tradeoffs between lattice optimisation and corrosion behaviour with a potential parabolic link between void volume, surface area and corrosion being identified. This potential link is supported by 60% gyroid samples having the lowest breakdown potentials, but investigation into other porosity ranges is suggested to support the hypothesis. All 3D printed materials studied here showed breakdown potentials higher than ASTM F2129′s suggestion of 800 mV for evaluation within the physiological environment, indicating that under static conditions pitting and crevice corrosion should not initiate within the body.