Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid

As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.     

A general synthesis of 4-alkyl/aryl substituted saccharins

A new method for the synthesis of 4-alky/aryl substituted saccharins (2) has been developed. The key steps include conjugate addition/acylation of cyclohexenone (3) and reaction of the resulting β-ketoesters 4 with benzyl mercaptan to give the vinyl sulfides 5 and 6. The latter were converted to the saccharins 2 in high yield.     

Life cycle assessment and life cycle cost of repairing surgical scissors

The International Journal of Life Cycle Assessment - The primary objective of this study was to evaluate the environmental impact and financial cost of repairing surgical scissors. We used life...     

SPEED: a molecular-evolution-based database of mammalian orthologous groups

MOTIVATION: The abundance of nucleotide sequence information available has expanded horizons of inquiry for molecular evolution; however, the full potential of whole-genome analysis has not been realized because of inadequate tools. Here, we present one of the first toolkits to aid multidisciplinary high-throughput analysis. SUMMARY: SPEED was created to integrate molecular evolutionary data with existing genetic resources and provide a straightforward user interface to 17,352 orthologous gene groups, containing representatives from eight mammalian species and an avian outgroup. AVAILABILITY: See http://bioinfobase.umkc.edu/speed/ for access.     

pBECKS

A series of binary T-DNA vectors (pBECKS) has been created for use in theAgrobacterium-mediated genetic transformation of plants. The pBECKS series has corrected the undesirable features of the popular pBIN19 vector; the deleterious mutation within the coding sequence ofnptII has been amended and the cloning sites are now adjacent to the right border repeat in order to reduce the possibility of producing truncated sequences of novel genes within transformants. One set of vectors incorporates various combiantions of the marker genesgusA,C1/Lc,nptII,hph, andbar, for pursuit of early and stable transformation events. A set of constructs which contain deleted T-DNA borders in various combinations and display predictably altered efficacies for gene transfer has also been created. A modular set of vectors has been designed to facilitate the insertion and transfer of novel gene sequences by providing anptII-linked plant expression cassette orlacZ-multiple cloning site. A range of antibiotic resistance genes has been incorporated into the non-T-DNA part of the vectors in order to facilitate their selection across the range ofAgrobacterium virulence strains.     

Partial hemi-resurfacing of the hip joint--a new approach to treat local osteochondral defects?

There is currently renewed interest in articular resurfacing for the treatment of damaged hip-joint cartilage. In contrast to these implants, which involve endoprosthetic replacement of both articulating surfaces, we present a new joint-preserving technique that allows treatment of local osteochondral defects of the femoral head by partial hemi-resurfacing. In this study we describe the operative and technical aspects and problems for partial hemi-resurfacing of the hip joint and critically discuss indications for this procedure in one case. To guarantee an adequate view of the situs, we recommend a surgical approach involving trochanter flip osteotomy, followed by surgical dislocation of the hip joint. Besides partial hemi-resurfacing of the osteochondral defect, this approach allows treatment of associated labral tears and cartilage defects of the hip joint at the same time. For adequate implant fixation, good bone quality is required. Furthermore, osteochondral defects of limited extent and excellent patient compliance are essential for clinical success. In particular, prominence of the implant has to be avoided, which can lead to an irregular joint surface and may induce further cartilage destruction. Long-term studies on statistical populations will show if partial articular hemi-resurfacing is a bone-preserving and useful therapeutic alternative to hemi-resurfacing caps in the treatment of osteochondral hip-joint defects, especially in young patients.     

Long-term changes in a population of an invasive bivalve and its effects

Although the ecological and economic effects of non-native species probably often change through time, few studies have documented such effects. The zebra mussel (Dreissena polymorpha) is an important invader that has had large ecological and economic effects on the ecosystems it has invaded in North America and western Europe. Our 20-year study of the Hudson River, New York, showed that the characteristics of a zebra mussel population and its effects on other benthic animals both changed substantially through time. Over the period of study, annual survivorship of adult zebra mussels fell >100-fold, which caused the aggregate filtration rate of the population to fall by 82%. Population size and body size of zebra mussels may also have fallen. In the early years of the invasion, densities of nearly all benthic animals in deepwater sites fell steeply (by 80–99%). After about 8 years of decline, these populations began to recover, and are approaching pre-invasion densities. The littoral zoobenthos showed neither the initial decline nor the subsequent recovery. Although the mechanisms behind these changes are not fully clear, our study shows that the effects of an invader may change considerably over time.     

Risk Stratification of Patients with Peripheral Arterial Disease and Abdominal Aortic Aneurysm Using Aortic Augmentation Index

BackgroundCentral augmentation index (cAIx) is an indicator for vascular stiffness. Obstructive and aneurysmatic vascular disease can affect pulse wave propagation and reflection, causing changes in central aortic pressures.AimTo assess and compare cAIx in patients with peripheral arterial disease (PAD) and / or abdominal aortic aneurysm (AAA).MethodscAIx was assessed by radial applanation tonometry (Sphygmocor) in a total of 184 patients at a tertiary referral centre. Patients were grouped as having PAD only, AAA only, or both AAA and PAD. Differences in cAIx measurements between the three patient groups were tested by non-parametric tests and stepwise multivariate linear regression analysis to investigate associations with obstructive or aneurysmatic patterns of vascular disease.ResultsIn the study sample of 184 patients, 130 had PAD only, 20 had AAA only, and 34 patients had both AAA and PAD. Mean cAIx (%) was 30.5 ± 8.2 across all patients. It was significantly higher in females (35.2 ± 6.1, n = 55) than males (28.4 ± 8.2, n = 129), and significantly higher in patients over 80 years of age (34.4 ± 6.9, n = 22) than in those under 80 years (30.0 ± 8.2, n = 162). Intergroup comparison revealed a significant difference in cAIx between the three patient groups (AAA: 27.3 ± 9.5; PAD: 31.4 ± 7.8; AAA & PAD: 28.8 ± 8.5). cAIx was significantly lower in patients with AAA, higher in patients with both AAA and PAD, and highest in patients with PAD only (beta = 0.21, p = 0.006).ConclusionNon-invasive assessment of arterial stiffness in high-risk patients indicates that cAIx differs according to the pattern of vascular disease. Measurements revealed significantly higher cAIx values for patients with obstructive peripheral arterial disease than for patients with aneurysmatic disease.