An extensive bile ductular cell hyperplasia with the formation of well-differentiated bile ductules is the most prominent feature of rat liver at 6 to 15 weeks after bile duct ligation. We have improved our previous cell isolation procedure and are now routinely able to obtain from such livers high yields of viable bile ductular epithelial cells. These cells were characterized with respect to their specific activities of gamma-glutamyl transpeptidase and beta-glucuronidase and of select Phase I and Phase II enzymes of biotransformation. At the time of their isolation, only a very small number of the bile ductular epithelial cells were observed to be in DNA synthesis. In addition, in histological sections prepared from intact hyperplastic bile ductular tissue isolates, only the bile ductular epithelial cells exhibited histochemical staining for gamma-glutamyl transpeptidase activity. Typically, greater than 95% of the cells isolated from this tissue were also found to be histochemically positive for gamma-glutamyl transpeptidase activity, and no hepatocytes were seen contaminating this cell population. Biochemically, the isolated bile ductular cells exhibited a gamma-glutamyl transpeptidase specific activity that was 100 times higher than that of hepatocytes isolated at the same time from the bile duct-ligated rats and more than 300 times higher than the specific activity of the enzyme of freshly isolated normal rat hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

The CLcr-based fludarabine dose adjustments used in this study provided reasonably equivalent F-ara-A exposure with acceptable safety in patients with varying degrees of renal function.

No abstract

Acute myeloid leukemia (AML) is a life-threatening malignancy that is more prevalent in the elderly. Because the patient population is heterogenous and advanced in age, choosing the optimal therapy can be challenging. There is strong evidence supporting antileukemic therapy, including standard intensive induction chemotherapy (IC) and non-intensive chemotherapy (NIC), for older patients with AML, and guidelines recommend treatment selection based on a patient’s individual and disease characteristics as opposed to age alone. Nonetheless, historic evidence indicates that a high proportion of patients who may be candidates for NIC receive no active antileukemic treatment (NAAT), instead receiving only best supportive care (BSC). We conducted a focused literature review to assess current real-world patterns of undertreatment in AML. From a total of 25 identified studies reporting the proportion of patients with AML receiving NAAT, the proportion of patients treated with NAAT varied widely, ranging from 10 to 61.4% in the US and 24.1 to 35% in Europe. Characteristics associated with receipt of NAAT included clinical factors such as age, poor performance status, comorbidities, and uncontrolled concomitant conditions, as well as sociodemographic factors such as female sex, unmarried status, and lower income. Survival was diminished among patients receiving NAAT, with reported median overall survival values ranging from 1.2 to 4.8 months compared to 5 to 14.4 months with NIC. These findings suggest a proportion of patients who are candidates for NIC receive NAAT, potentially forfeiting the survival benefit of active antileukemic treatment.

Pseudomonas fluorescens N3 is able to grow on naphthalene as the sole carbon and energy source. The mutant TTC1, blocked at the dihydrodiol dehydrogenase level, which can transform the hydrocarbon into the corresponding dihydrodiol, has been used to produce bioconversion products. To rationalize the different grades of conversion obtained with different substrates, a study was performed using non-naphthalene derivatives, including benzenes, conjugated benzenes, and polycyclic aromatic hydrocarbons. The corresponding diols obtained by bioconversion have been isolated and characterized. A theoretical model that considers both energy and geometry factors has been proposed to rationalize the experimental data. Good agreement has been found between the calculated values and the experimental results.Pseudomonas dioxygenases are a family of closely related enzymes that can add an oxygen molecule to a substrate double bond (1). Their ability to make such a transformation on aromatic compounds, often the first step in the biodegradation of such compounds (2), is particularly interesting. The high stability of aromatic compounds requires an unusually high redox potential that, in most cases, is made available by two or three component enzymes (3). The active site is believed to belong to the class of Rieske-type iron-sulfur proteins, in which the iron, coordinated by two histidine nitrogens and two cysteine sulfurs, is, at the same time, the end point of a long redox chain transporting the necessary electrons from NADH (or NADPH) and the coordination site of molecular oxygen (3). In the general framework of this type of dioxygenase, the specificity of recognition could be related to the geometric and functional characteristics of the active site. As a consequence, there are well-known oxygenases that transform monocyclic compounds (benzene (4) or toluene (5)), naphthalenes (6), or polycyclic aromatic hydrocarbons (7).Since 1992, our research group has been interested in exploiting the power of the dioxygenase of P. fluorescens N3 that we isolated from the activated sludge of a wastewater treatment plant (8). The wild type is able to completely degrade naphthalene and some of its derivatives and to transform many other naphthalenes into the corresponding salicylic acids (8).We later isolated a mutant strain (TTC1) blocked at the dihydrodiol dehydrogenase level (9), and then we cloned the naphthalene dioxygenase gene in Escherichia coli JM109 (10). Thus, we could efficiently produce dihydrodiols from many naphthalenes carrying substituents in both position 1 and position 2. The yield seemed to be correlated to two aspects, the electronic characteristics of the substituents and their position, and was higher for electron releasing groups in position 2. However, the yield trend was not readily understandable, so we decided to extend our investigation to assess the specificity of N3 dioxygenase.Two strongly correlated actions were considered: the experimental verification of substrate specificity (by testing diverse aromatic s...