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Nicotinamide adenine dinucleotide (NAD) exists in an oxidized form (NAD+) and a reduced form (NADH). NAD+ plays crucial roles in cancer metabolism, including in cellular signaling, energy production and redox regulation. However, it remains unclear whether NAD(H) pool size (NAD+ and NADH) could be used as biomarker for colon cancer progression. Here, we showed that the NAD(H) pool size and NAD+/NADH ratio both increased during colorectal cancer (CRC) progression due to activation of the NAD+ salvage pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT). The NAMPT expression was upregulated in adenoma and adenocarcinoma tissues from CRC patients. The NADH fluorescence intensity measured by two‐photon excitation fluorescence (TPEF) microscopy was consistently increased in CRC cell lines, azoxymethane/dextran sodium sulfate (AOM/DSS)‐induced CRC tissues and tumor tissues from CRC patients. The increases in the NAD(H) pool inhibited the accumulation of excessive reactive oxygen species (ROS) levels and FK866, a specific inhibitor of NAMPT, treatment decreased the CRC nodule size by increasing ROS levels in AOM/DSS mice. Collectively, our results suggest that NAMPT‐mediated upregulation of the NAD(H) pool protects cancer cells against detrimental oxidative stress and that detecting NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression. NAD(H) pool size increased during colorectal cancer (CRC) progression due to activation of the enzymes in the salvage pathway of NAD+ synthesis, especially NAMPT. The increases in the NAD(H) pool promoted colon cancer progression by decreasing excessive ROS levels. Detection of NADH fluorescence by TPEF microscopy could be a potential method for monitoring CRC progression. [ABSTRACT FROM AUTHOR]

What is known and objective Treatment adherence is an essential component in ensuring best outcomes in the management of paediatric cancers. Compared to the adult population, treatment adherence in the paediatric population is a more complex subject which involves unique dimensions. In this study, we aimed to systematically review the literature to identify factors associated with treatment adherence in the paediatric oncology population. Methods A literature search was carried out using related keywords on electronic databases. Results and discussion A total of 1036 articles were reviewed, and 39 articles were found to be relevant. A comprehensive review of these articles identified 17 factors that influence adherence. These factors were classified into five major categories: patient-/caregiver-related factors; therapy-related factors; condition-related factors; health system-related factors; and social/economic factors. A baby bear model was proposed to better visualize these five categories that affect treatment adherence, and a framework of questions was designed to help clinicians identify those at risk of non-adherence for early intervention. What is new and conclusion Seventeen factors reviewed were categorized into five main categories, namely patient-/caregiver-related factors, therapy-related factors, condition-related factors, health system factors and social/economic factors, as causes for poor medication adherence in the paediatric oncology population. Clinicians need to be aware that these factors can interact to influence treatment adherence and that some factors may be more relevant in specific contexts (e.g. third world countries, minority groups). The baby bear model is presented to help understand the issues affecting adherence in the paediatric oncology population, and a framework of questions is proposed to help clinicians identify patients at risk of non-adherence. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a metabolic disorder affecting a large number of people worldwide. Numerous studies have demonstrated that DM can cause damage to multiple systems, leading to complications such as heart disease, cancer, and cerebrovascular disorders. Numerous epidemiological studies have shown that DM is closely associated with dementia and cognition dysfunction, with recent research focusing on the role of DM-mediated cerebrovascular damage in dementia. Despite the therapeutic benefits of antidiabetic agents for the treatment of DM-mediated cognitive dysfunction, most of these pharmaceutical agents are associated with various undesirable side-effects and their long-term benefits are therefore in doubt. Early evidence exists to support the use of traditional Chinese medicine (TCM) interventions, which tend to have minimal toxicity and side-effects. More importantly, these TCM interventions appear to offer significant effects in reducing DM-related complications beyond blood glucose control. However, more research is needed to further validate these claims and to explore their relevant mechanisms of action. The aims of this paper are (1) to provide an updated overview on the association between DM and cognitive dysfunction and (2) to review the scientific evidence underpinning the use of TCM interventions for the treatment and prevention of DM-induced cognitive dysfunction and dementia. [ABSTRACT FROM AUTHOR]

The article presents a study examining the promoter methylation of the dickkopf homolog 3 gene (Dkk-3) and its significant role in digestive cancers. The study primarily investigates the prognostic implication of Dkk-3 methylation in patients with gastric cancer and colorectal cancer, evaluating as well the growth of the cancer cells. Details of the study are cited, indicating the common presence on the epigenetic silencing of the DKK-3 gene by promoter methylation in these cancer patients.

Autologous stem cell transplantation (ASCT) has a well-established role in the treatment of haematological malignancies. Stem cells are commonly collected following salvage chemotherapy although there may be advantages in collecting earlier in the disease course. A ’rainy day’ harvest (RDH) refers to the collection of autologous haemopoietic stem cells for long-term storage. Although there are few data to support RDH, there is increasing evidence that such harvests are being carried out, creating storage pressures in stem cell laboratories across New South Wales. The Bone Marrow Transplant Network New South Wales conducted a three-staged exercise to develop consensus-based RDH guidelines. Using available evidence, guidelines were developed supporting RDH for specific patients with acute and chronic myeloid leukaemias, follicular and other lymphomas, and multiple myeloma. Physician agreement with these disease-specific guidelines ranged between 58 and 100%. These consensus guidelines will improve equity of access to appropriate RDH and assist the planning of future storage requirements in New South Wales. [ABSTRACT FROM AUTHOR]

Background and Purpose:Statins (3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors) have been demonstrated to reduce cardiovascular mortality. It is unclear how the expression level of HMG CoA reductase in cardiovascular tissues compares with that in cells derived from the liver. We hypothesized that this enzyme exists in different cardiovascular tissues, and simvastatin modulates the vascular iberiotoxin-sensitive Ca2+-activated K+ (BKCa) channels.Experimental Approaches:Expression of HMG CoA reductase in different cardiovascular preparations was measured. Effects of simvastatin on BKCa channel gatings of porcine coronary artery smooth muscle cells were evaluated.Key Results:Western immunoblots revealed the biochemical existence of HMG CoA reductase in human cardiovascular tissues and porcine coronary artery. In porcine coronary artery smooth muscle cells, extracellular simvastatin (1, 3 and 10 μM) (hydrophobic), but not simvastatin Na+ (hydrophilic), inhibited the BKCa channels with a minimal recovery upon washout. Isopimaric acid (10 μM)-mediated enhancement of the BKCa amplitude was reversed by external simvastatin. Simvastatin Na+ (10 μM, applied internally), markedly attenuated isopimaric acid (10 μM)-induced enhancement of the BKCa amplitude. Reduced glutathione (5 mM; in the pipette solution) abolished simvastatin -elicited inhibition. Mevalonolactone (500 μM) and geranylgeranyl pyrophosphate (20 μM) only prevented simvastatin (1 and 3 μM)-induced responses. simvastatin (10 μM) caused a rottlerin (1 μM)-sensitive (cycloheximide (10 μM)-insensitive) increase of PKC-δ protein expression.Conclusions and Implications:Our results demonstrated the biochemical presence of HMG CoA reductase in different cardiovascular tissues, and that simvastatin inhibited the BKCa channels of the arterial smooth muscle cells through multiple intracellular pathways.British Journal of Pharmacology (2007) 151, 987–997; doi:10.1038/sj.bjp.0707327; published online 11 June 2007 [ABSTRACT FROM AUTHOR]

The boundary immobilization method (BIM) is extended to the cases of outward spherical and cylindrical solidifications, which involves the development of starting solutions. When applying the method to time-dependent problems, good agreement is achieved when comparing the positions of the moving boundary and the temperature distribution with those obtained by the perturbation method. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A structural motif called the small exterior hydrophobic cluster (SEHC) has been proposed to explain the stabilizing effect mediated by solvent-exposed hydrophobic residues; however, little is known about its biological roles. Unusually, inΔ5-3-ketosteroid isomerase from Pseudomonas putida biotype B (KSI-PI) Trp92 is exposed to solvent on the protein surface, forming a SEHC with the side-chains of Leu125 and Val127. In order to identify the role of the SEHC in KSI-PI, mutants of those amino acids associated with the SEHC were prepared. The W92A, L125A/V127A, and W92A/L125A/V127A mutations largely decreased the conformational stability, while the L125F/V127F mutation slightly increased the stability, indicating that hydrophobic packing by the SEHC is important in maintaining stability. The crystal structure of W92A revealed that the decreased stability caused by the removal of the bulky side-chain of Trp92 could be attributed to the destabilization of the surface hydrophobic layer consisting of a solvent-exposedβ-sheet. Consistent with the structural data, the binding affinities for three different steroids showed that the surface hydrophobic layer stabilized by SEHC is required for KSI-PI to efficiently recognize hydrophobic steroids. Unfolding kinetics based on analysis of theΦU value also indicated that the SEHC in the native state was resistant to the unfolding process, despite its solvent-exposed site. Taken together, our results demonstrate that the SEHC plays a key role in the structural integrity that is needed for KSI-PI to stabilize the hydrophobic surface conformation and thereby contributes both to the overall conformational stability and to the binding of hydrophobic steroids in water solution. [ABSTRACT FROM AUTHOR]

This paper describes and compares several effective methods for the numerical solution of one-dimensional Stefan problems. It is not intended to be an exhaustive review but is restricted to a range of problems and geometries including melting in the half-plane, outward cylindrical solidification and outward spherical solidification. From the limited comparison of numerical results obtained, some helpful comments can be made which may prove valuable in the future use of these methods. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

One of the major problems encountered in antiviral therapy against AIDS is the emergence of viral variants that exhibit drug resistance. The sequences of proteases (PRs) from related retroviruses sometimes include, at structurally equivalent positions, amino acids identical to those found in drug-resistant forms of HIV-1 PR. The statine-based inhibitor LP-130 was found to be a universal, nanomolar-range inhibitor against all tested retroviral PRs. We solved the crystal structures of LP-130 in complex with retroviral PRs from HIV-1, feline immunodeficiency virus, and equine infectious anemia virus and compared the structures to determine the differences in the interactions between the inhibitor and the active-site residues of the enzymes. This comparison shows an extraordinary similarity in the binding modes of the inhibitor molecules. The only exceptions are the different conformations of naphthylalanine side chains at the P3/P3′ positions, which might be responsible for the variation in the Ki values. These findings indicate that successful inhibition of different retroviral PRs by LP-130 is achieved because this compound can be accommodated without serious conformational differences, despite the variations in the type of residues forming the active-site region. Although strong, specific interactions between the ligand and the enzyme might improve the potency of the inhibitor, the absence of such interactions seems to favor the universality of the compound. Hence, the ability of potential anti-AIDS drugs to inhibit multiple retroviral PRs might indicate their likelihood of not eliciting drug resistance. These studies may also contribute to the development of a small-animal model for preclinical testing of antiviral compounds. [ABSTRACT FROM AUTHOR]