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Peters GJ Adema AD Bijnsdorp IV Sandvold ML 《Nucleosides, nucleotides & nucleic acids》2011,30(12):1168-1180
Many drugs that are currently used for the treatment of cancer have limitations, such as induction of resistance and/or poor biological half-life, which reduce their clinical efficacy. To overcome these limitations, several strategies have been explored. Chemical modification by the attachment of lipophilic moieties to (deoxy)nucleoside analogs should enhance the plasma half-life, change the biodistribution, and improve cellular uptake of the drug. Attachment of a lipophilic moiety to a phosphorylated (deoxy)nucleoside analog will improve the activity of the drugs by circumventing the rate-limiting activation step of (deoxy)nucleoside analogs. Encapsulating drugs in nanoparticles or liposomes protects the drug against enzymatic breakdown in the plasma and makes it possible to get lipophilic compounds to the tumor site. In this review, we discuss the considerable progress that has been made in increasing the efficacy of classic (deoxy)nucleoside and fluoropyrimidine compounds by chemical modifications and alternative delivery systems. 相似文献
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Rocha CM Carrola J Barros AS Gil AM Goodfellow BJ Carreira IM Bernardo J Gomes A Sousa V Carvalho L Duarte IF 《Journal of proteome research》2011,10(9):4314-4324
In this work, the variations in the metabolic profile of blood plasma from lung cancer patients and healthy controls were investigated through NMR-based metabonomics, to assess the potential of this approach for lung cancer screening and diagnosis. PLS-DA modeling of CPMG spectra from plasma, subjected to Monte Carlo Cross Validation, allowed cancer patients to be discriminated from controls with sensitivity and specificity levels of about 90%. Relatively lower HDL and higher VLDL + LDL in the patients' plasma, together with increased lactate and pyruvate and decreased levels of glucose, citrate, formate, acetate, several amino acids (alanine, glutamine, histidine, tyrosine, valine), and methanol, could be detected. These changes were found to be present at initial disease stages and could be related to known cancer biochemical hallmarks, such as enhanced glycolysis, glutaminolysis, and gluconeogenesis, together with suppressed Krebs cycle and reduced lipid catabolism, thus supporting the hypothesis of a systemic metabolic signature for lung cancer. Despite the possible confounding influence of age, smoking habits, and other uncontrolled factors, these results indicate that NMR-based metabonomics of blood plasma can be useful as a screening tool to identify suspicious cases for subsequent, more specific radiological tests, thus contributing to improved disease management. 相似文献
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Larsen HS Aure MH Peters SB Larsen M Messelt EB Kanli Galtung H 《Journal of molecular histology》2011,42(1):71-81
Aquaporin 5 (AQP5) is known to be central for salivary fluid secretion. A study of the temporal-spatial distribution of AQP5
during submandibular gland (SMG) development and in adult tissues might offer further clues to its unknown role during development.
In the present work, SMGs from embryonic day (E) 14.5–18.5 and postnatal days (P) 0, 2, 5, 25, and 60 were immunostained for
AQP5 and analyzed using light microscopy. Additional confocal and transmission electron microscopy were performed on P60 glands.
Our results show that AQP5 expression first occurs in a scattered pattern in the late canalicular stage and becomes more prominent
and organized in the terminal tubuli/pro-acinar cells towards birth. Additional apical membrane staining in the entire intralobular
duct is found just prior to birth. During postnatal development, AQP5 is expressed in both the luminal and lateral membrane
of pro-acinar/acinar cells. AQP5 is also detected in the basal membrane of acinar cells at P25 and P60. In the intercalated
ducts at P60, the male glands show apical staining in the entire segment, while only the proximal region is positive in the
female glands. These results demonstrate an evolving distribution of AQP5 during pre- and postnatal development in the mouse
SMGs. 相似文献
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Biological systems are characterized by a high number of interacting components. Determining the role of each component is difficult, addressed here in the context of biological oscillations. Rhythmic behavior can result from the interplay of positive feedback that promotes bistability between high and low activity, and slow negative feedback that switches the system between the high and low activity states. Many biological oscillators include two types of negative feedback processes: divisive (decreases the gain of the positive feedback loop) and subtractive (increases the input threshold) that both contribute to slowly move the system between the high- and low-activity states. Can we determine the relative contribution of each type of negative feedback process to the rhythmic activity? Does one dominate? Do they control the active and silent phase equally? To answer these questions we use a neural network model with excitatory coupling, regulated by synaptic depression (divisive) and cellular adaptation (subtractive feedback). We first attempt to apply standard experimental methodologies: either passive observation to correlate the variations of a variable of interest to system behavior, or deletion of a component to establish whether a component is critical for the system. We find that these two strategies can lead to contradictory conclusions, and at best their interpretive power is limited. We instead develop a computational measure of the contribution of a process, by evaluating the sensitivity of the active (high activity) and silent (low activity) phase durations to the time constant of the process. The measure shows that both processes control the active phase, in proportion to their speed and relative weight. However, only the subtractive process plays a major role in setting the duration of the silent phase. This computational method can be used to analyze the role of negative feedback processes in a wide range of biological rhythms. 相似文献