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PubMed1986

Mechanism of resistance to tiazofurin in hepatoma 3924A.

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC-286193) has shown potent cytotoxic and antitumor activity against hepatoma 3924A carried in the rat [Lui et al. J. biol. Chem. 259, 5078 (1984)]. However, eventually the tumor emerged, proliferated and killed the host. To throw light on the factors that play a role in the resistance to this drug, a tiazofurin-induced resistant hepatoma 3924A line in culture was produced, and its biochemical and pharmacological pattern was examined. Resistance in hepatoma cells was expressed by a reprogramming of gene expression that entailed the display of a program of multiple biochemical alterations. In the resistant cells the activity of IMP dehydrogenase, the target enzyme of tiazofurin, was increased 2- to 3-fold. The steady-state guanylate pools were elevated 3-fold, and there was a decrease in the de novo synthesis of guanylate. There was an expansion of guanylate salvage, which could circumvent inhibition of de novo guanylate synthesis by tiazofurin. For the first time in studies on the resistance of different cell lines to tiazofurin, reduced tiazofurin transport (to 50%) in resistant hepatoma cells was identified which might account for the decreased concentration (50%) of the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), in these cells. NAD pyrophosphorylase activity also decreased to 53% of that of the sensitive line, which was responsible, in part at least, for the decreased TAD concentration of the resistant cells. When resistant cells were cultured in the absence of tiazofurin, resistance to the drug gradually decreased, and by 50 passages sensitivity returned. Resistance to tiazofurin in hepatoma cells appears to be a drug-induced metabolic adaptation which involves alterations in the activity of the target enzyme, in the transport and concentration of the drug and the active metabolite, and an increase of guanylate concentration and guanine salvage capacity.

Adenosine Monophosphate↗

PubMed1985

Cell proliferation changes during pattern regulation in imaginal leg discs of Drosophila melanogaster.

Upon fragmentation of a leg imaginal disc, cells near parts of the wounded surface are reprogrammed and form a blastema. This occurs without a change in fate and without the direct contact of the two wounded surfaces (G. H. Karpen and G. Schubiger, Nature (London) 294, 744-747, 1981). Two phases of the cell cycle have now been analyzed for several areas of disc fragments prior to and during wound healing. A mitotic index was used to compare the location of cell division, and autoradiography was used to reveal patterns of DNA synthesis. In contrast to the uniform division pattern in noncultured fragments, more dividing cells were observed near the two wound surfaces after 1 day of in vivo culture. During the second day, wound healing began and mitotic activity increased dramatically near both wound areas, and decreased in distant areas. Three and a half days of culture led to more complete wound closure and only cells on one site continued to show the highest frequency of labeled cells. It is concluded that changes in patterns of DNA synthesis and an increase in cell division begin prior to wound closure. This proliferation is consistent with the morphological changes and regulative behavior observed. In addition, the role of compartmental identity during regulation was tested. After wound closure began an increase in mitotic activity near wounds in the anterior compartment was observed whereas such an increase in division level was not seen in posterior cells near a wound.

Animals↗

PubMed1986

Major transitions in histone gene expression do not occur during development in Xenopus laevis.

In light of the parallels that exist in the structure of histone genes in sea urchins and in the frog, Xenopus laevis, and in the early development of these animals, it has been thought that Xenopus histone gene expression might be subject to the type of developmental regulation observed in sea urchins. We have examined the patterns of histone mRNA accumulation in Xenopus oocytes and embryos by primer extension and S1 nuclease protection techniques. The data demonstrate that histone genes which are active in Xenopus oocytes, and which contribute to large pools of histone mRNA in the absence of DNA replication, are also transcriptionally active in late embryos and in cultured cells. These results suggest that, rather than activating distinct sets of histone genes at different developmental stages, the developing frog embryo reprograms the expression of histone genes active in nondividing oocytes so that their expression becomes coupled to DNA replication subsequently during embryogenesis.

Animals↗

PubMed1987

The zygotic segmentation mutant tailless alters the blastoderm fate map of the Drosophila embryo.

The well-characterized spatial distributions of the transcripts from several Drosophila segmentation genes provide molecular markers which can be used to examine the determination of the segment pattern in early embryos. Tailless (tll) is a zygotic lethal mutation, the phenotype of which is observed by 9 hr of embryogenesis and includes the absence of segments A8, A9, and A10 and a decrease in the procephalic lobe (Strecker et al., Dev. Biol. 113, 64-76, 1986). To establish whether this effect of the tll mutation is due, as proposed previously by Strecker et al., to a reprogramming of the blastoderm fate map, we hybridized probes for the segmentation genes fushi tarazu (ftz) and hairy (h) to whole embryos. The transcripts of these genes show an altered distribution in tll embryos as early as nuclear cycle 14, indicating that the tll gene acts on cellular determination at the blastoderm stage, and is required for normal expression of the ftz and h genes. We obtained more precise information about the alterations in the blastoderm fate map by measuring the position of ftz protein stripes in wild-type and tll embryos. From the results reported here and previously, we conclude that the tll mutation results in a deletion of anterior and posterior ectodermal positional values, concomitant with an expansion of the remaining fate map.

Alleles↗

PubMed1992

Developmental profiles of epidermal mRNAs during the pupal-adult molt of Tenebrio molitor and isolation of a cDNA clone encoding an adult cuticular protein: effects of a juvenile hormone analogue.

Changes in translatable mRNAs from the wing epidermis of the Coleoptera Tenebrio molitor have been investigated during metamorphosis by analysis of in vitro translated products. Striking differences between the patterns obtained from mRNAs extracted during pupal and adult cuticle secretion indicated that a drastic change in gene expression occurs during the pupal-adult transition. In addition to these stage-specific modifications, the mRNA patterns changed within each cuticular synthesis program (pupal or adult), especially at ecdysis. After tritiated leucine incorporation, some of the major radiolabeled cuticular proteins showed similar changes suggesting that the sequential appearance of mRNAs corresponds to sequential deposition of cuticular proteins. In supernumerary pupae obtained after juvenile hormone analogue (JHA) application on newly ecdysed pupae, translatable mRNA were very similar to those of pharate pupae. The JHA seemed, therefore, to prevent the expression of the adult program. By immunoblotting in vitro translated products with a monoclonal antibody recognizing an adult-specific cuticular protein, the developmental profile of the corresponding mRNA was studied. This mRNA was detected in anterior wing epidermis during the first 80 hr of the pharate adult stage. Using the same antibody, a cDNA clone was isolated from epidermal mRNA. The hybrid selected mRNA coded for only one protein with an apparent MW of 22 kDa which was, furthermore, recognized by the antibody. The Northern blot analysis performed with the clone confirmed the Western blot analysis of the in vitro translation products. JHA application at the beginning of the pupal-adult reprograming prevented the appearance of this mRNA; however, this transcript was present during the following molting cycle. This reversibility of the JHA action was confirmed by immunogold labeling of the cuticles formed in treated animals.

Animals↗

PubMed1988

Regulation of collagen synthesis in fibroblasts within a three-dimensional collagen gel.

Fibroblasts cultivated within a three-dimensional collagen gel display an elongated, spindle-like morphology, reduce their proliferation rate, contact the gel to a very dense tissue, and modify their metabolic activity as compared to monolayer cultures. Collagen synthesis measured as protein-bound hydroxyproline is reduced to 5% of the values found in monolayer culture. The reduction involving type I and type III collagen is due to decreased de novo synthesis and not to enhanced degradation. Dot blot hybridization, Northern blot analysis, and in situ hybridization using collagen I- and III-specific cDNA probes demonstrate that reduced biosynthesis rates are reflected by a marked reduction of pro alpha 1 (I), pro alpha 2 (I), and pro alpha 1 (III) collagen mRNA indicating pretranslational regulation. A similar reduction was observed for actin mRNA whereas levels of tubulin mRNA were similar for fibroblasts in monolayer culture or cultivated within the three-dimensional collagen gels. The data suggest a specific reprogramming of various cellular activities in response to contact with the reconstituted extracellular matrix.

Blotting, Northern↗

PubMed1986

Effect of stretch combined with electrical stimulation on the type of sarcomeres produced at the ends of muscle fibers.

Stretching a muscle results in a rapid addition of sarcomeres at the ends of the muscle fibers. The effect of a pattern of electrical stimulation resembling that of a slow motoneuron on the newly formed muscle tissue in a stretched, fast-contracting muscle was investigated. We found that after a period as short as 4 days, the type of sarcomeres which were added on to the ends of the existing myofibrils differed from those in the middle regions of the experimental muscles: there was a much higher proportion of type I and type IIA sarcomeres in the stretch-stimulated ends. This study showed that reprogramming of the synthesis of fiber type-specific contractile proteins can be achieved and detected within a very short time by using electrical stimulation combined with stretch.

Animals↗

PubMed1993

Downregulation of collagen synthesis in fibroblasts within three-dimensional collagen lattices involves transcriptional and posttranscriptional mechanisms.

Culturing human fibroblasts in a three-dimensional collagen matrix leads to a reduction of collagen I by more than 90%, both on the level of mRNA steady-state as well as protein. In order to differentiate changes in de novo transcription and posttranscriptional control, nuclear run on assays and pulse/chase experiments determining mRNA stability were used. Our results indicate that de novo transcription of the COL1A1 gene and pro-alpha 1 (I)collagen mRNA half-life are both decreased by 50% in fibroblasts grown in three-dimensional collagen lattices as compared to monolayer cultures. The extracellular matrix therefore elicits signals which are transduced from the cell surface to the inside of fibroblasts resulting in a specific reprogramming of transcriptional as well as posttranscriptional processes.

Cells, Cultured↗

PubMed1987

20 (OH) ecdysone-induced transition from intermolt to premolt protein biosynthesis patterns in the hypodermis of the crayfish, Astacus leptodactylus, in vitro.

20 (OH) Ecdysone-induced alteration of protein biosynthesis and secretion by the hypodermis of the crayfish Astacus leptodactylus was studied using isolated tissues in vitro. Characteristic quantitative and qualitative changes of late intermolt tissues are governed by the hormone in a dose- and time-dependent manner. The greatest response to the hormone was observed in tissues which were exposed for 48 hr to 10(-8) M 20 (OH) ecdysone, followed by 1 day of hormone withdrawal. The observed differences correspond to the reprogramming in protein biosynthesis after transition from intermolt to the premolt stage.

Animals↗

PubMed1990

Dynamics of pathological motion: applied to the anterior cruciate deficient knee.

The analysis of the dynamics of pathological motion can provide new and meaningful knowledge about musculoskeletal disorders. The application of the study of pathological ambulation to the analyses of clinical problems is analyzed and discussed. The importance of the selection of appropriate measurement protocols and variable selection is illustrated using an example of the evaluation of patients with an anterior cruciate deficient knee. In particular, the importance of the joint moment as a measure of normal and pathological ambulation is described. An example is provided from a study based on the analysis of 16 patients with unilateral anterior cruciate deficiency. Patients were studied during walking, jogging and ascending and descending stairs. The results are used to demonstrate the importance of testing activities of the knee (e.g. walking, jogging, stair-climbing) that stress the knees during different ranges of motion in order to differentiate functional adaptation associated with the anterior cruciate deficient knee. Results demonstrate that functional abnormalities occur during low stress activities such as level walking. Further, it appears that the functional adaptation occurring during these activities is associated with the anterior force generated on the tibia when the quadriceps contract and the knee is near full extension. It appears that locomotion patterns are reprogrammed to produce an adaptive gait in the majority of patients with anterior cruciate deficient knees.

Anterior Cruciate Ligament↗

PubMed1977

Posterior unilateral condylar displacement: its diagnosis and treatment.

The treatment procedure for posterior unilateral condylar displacement has been described. An acrylic resin repositioning prosthesis may be used to decrease trismus. Occlusal adjustment permits lateral freedom for mandibular movement to the opposite side which provides a dual, or a therapeutic, centric occlusion as well as the existing dysfunctional centric relation. This permits the patient's physiologic adaptive mechanism to choose between the existing dysfunctional centric relation, which resulted in unilateral condylar retrusion and pain, or a therapeutic centric occlusion which is aimed at anterior unilateral condylar repositioning. Over long period of time, muscle reprogramming produces maximum intercuspation of teeth in the planned therapeutic centric occlusion rather than in the original dysfunctional position. No explanation has been established for this phenomenon. It is important, however, to provide a technique that permits physiologic adaptability over a period of time. It should be emphasized that this is not TMJ "remodeling" but a functional change in the position of the jaw. The treatment objectives of bilateral and unilateral posterior condylar displacement are similar, but the clinical techniques are completely different. In either instance, TMJ radiographs are necessary to establish the diagnosis and treatment, as well as to document the postoperative results.

Acrylic Resins↗

PubMed1976

Alteration of the maximal activity of the gluconeogenetic enzyme fructose-1,6-diphosphatase of skeletal muscle by cross-reinnervation. A histochemical and biochemical investigation of fatiguability-related aspects.

Fatiguability is a determining characteristic of different muscle fibre types. An important aspect, indirectly related to fatiguability, gluconeogenesis, was investigated by observing fructose-1,6-diphosphatase (FDP) activity in experimental models prepared in rabbits by cross-reinnervation of the fatigue-resistant m.soleus (postural muscle) and the highly fatiguable m.flexor digitorum longus (fast muscle -- m.fdl). The resultant reprogramming of the m. soleus was associated with greatly intensified FDP activity. Changes in the m.fdl 6-9 months after cross-reinnervation indicated a shift in the opposite direction. The study adds some data on the much neglected state of fatiguability to the otherwise much explored field of alien reinnervation.

Animals↗

PubMed1993

Time for reorienting of attention: a premotor hypothesis of the underlying mechanism.

The paradigm of the covert orienting of attention (COA) has shown that the displacement of visual attention may be assessed even in the absence of eye movement. Stimuli correctly cued before their presentation are usually detected faster than uncued stimuli. However, miscued stimuli induce an increased detection time, which has been attributed to the time required for the reorientation of attention from the incorrect to the correct spatial location. Currently, the mechanism of such a displacement of visual attention remains unknown. Rizzolatti et al. Neuropsychologia 25, 31-40 (1987) have suggested a premotor hypothesis which suggests that an oculomotor disprogramming and reprogramming is necessary to reorient visual attention, even if the eye movement is inhibited. Since shifting of auditory attention from one ear to the other does not require any motor control, we further investigated the model of COA in 20 normal subjects who performed two tasks requiring a reorienting of auditory attention: (1) a choice RT task that requires a response readjustment during the auditory reorienting; (2) a simple RT task that does not require a response readjustment during the auditory reorienting; (2) a simple RT task that does not require a response readjustment during the auditory reorienting. Results indicate that correctly cued stimuli significantly reduce the RT in both tasks and that this reduction is greater in the choice than in the simple RT task. This suggests that a correct cue may produce a pre-programming of the response, in addition to the pre-engagement of the perceptual attention.(ABSTRACT TRUNCATED AT 250 WORDS)

Acoustic Stimulation↗

PubMed1976

A dental radiologic health laboratory teaching method.

The School of Dental Medicine at Tufts University has given new direction to the understanding of radiologic health through a program in which all students participate in some laboratory activities directly related to the problems of radiologic health in dental practice. This article presents an explanation of the background of this program and the experiments performed and discusses the interest in the program and its effect on the dental students. The laboratory program described is held for 3 1/2 hours on Wednesday afternoons at the Dental School, since this is a period of minimum patient load in the Radiology Department. The course is presented for third-year dental students who already have takin a lecture course in the fundamentals and techniques of radiology and have received training in the proper procedures for taking radiographs. The program is designed as a series of experiments dealing with machine output, filtration, collimation, exposure factors, scatter radiation, film density, patient protection, and shielding. The students are introduced to various radiation-detection instruments and given the opportunity to use these instruments to measure output and scatter-radiation levels under varying conditions. The laboratory teaching method presented can also be reprogrammed for different group sizes and time schedules.

Boston↗

PubMed1976

Epidermal cell development during the pupal-adult metamorphosis of Hyalophora cecropia.

To establish a base for studying the hormonal control of insect epidermal cell activity, the ultrastructure of abdominal epidermis was analyzed during the normal pupal-adult development of Hyalophora cecropia. Adjacent epidermal cells could be distinguished on the basis of organelle content and staining intensity, suggesting that this monolayer is not composed of a homogenous cell population. At the onset of adult development the form of the epidermal cell is transformed from that typical of a quiescent cell with free ribosomes and few mitochondria to one which is metabolically active and possesses numerous apical membrane microvilli, rough endoplasmic reticulum and numerous mitochondria. On about day 5 of pharate adult development the apical plasma membrane is no longer folded but becomes folded again several days later when cuticulin and endocuticle are deposited. On about day 7, giant autophagic vacuoles are discerned that may be important in cellular reprogramming. After adult ecdysis, the epidermal cells continue to deposit endocuticle.

Animals↗

PubMed1985

Biochemical mechanisms of resistance to tiazofurin.

The purpose of this investigation was to examine factors which regulate the reprogramming of gene expression in tumors responsible for resistance to tiazofurin. To study the resistance phenomenon drug-induced tumor lines were selected and examined for the mechanism of resistance. A comparison of the biochemical expression of resistance to tiazofurin in drug-induced resistant lines of hepatoma 3924A, leukemias L1210 and P388 revealed that the 3 lines expressed similar genetic alterations related to reduced TAD content, decreased NAD pyrophosphorylase activity and increased synthesis of guanylates from salvaging preformed guanine indicating that these 3 factors play an important role in the resistance to tiazofurin. Resistance was stable in the leukemia lines and did not require drug to maintain resistance. Hepatoma 3924A resistant line reverted to sensitive state in the absence of drug selection pressure. NAD pyrophosphorylase activity was substantially deleted in the tiazofurin resistant leukemia lines, but was only significantly decreased in the hepatoma resistant line. Extensive biochemical alterations including enhanced activity of IMP dehydrogenase, increased inosinate and guanylate pools, and reduced uptake of tiazofurin were found in the hepatoma line resistant to tiazofurin. To examine the applicability of these results to naturally sensitive and spontaneously resistant tumors, murine tumors were examined. In murine tumors, TAD accumulation, ratios of enzyme activities responsible for the synthesis and degradation of TAD, and the ratios of perturbation of inosinate and guanylate pools following tiazofurin challenge demonstrated significant correlation with the sensitive or resistant nature of the tumors. To extrapolate these observations to human tumor systems, cytotoxicity of tiazofurin and its metabolic effects were compared in 6 human lung cancer cell lines derived from cancer patients with small cell lung cancer (4 lines) and lung adenocarcinoma (2 lines). Cell lines exhibiting greater sensitivity to tiazofurin accumulated significantly larger amounts of TAD and showed significant reduction of guanylate pools following tiazofurin incubation. The activity of the enzyme responsible for the formation of TAD, NAD pyrophosphorylase, did not correlate with responsiveness to tiazofurin but the enzyme which hydrolyzes TAD, TADase, correlated positively with the status of resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenine Nucleotides↗

PubMed1978

Activation of teratocarcinoma-derived hemoglobin genes in teratocarcinoma-Friend cell hybrids.

Hybrid cells formed by the fusion of murine teratocarcinoma and Friend erythroleukemia cells synthesize hemoglobin in the presence of chemical inducers such as dimethylsulfoxide (DMSO). By making use of the fact that the parental teratocarcinoma and Friend cells carried different alleles at the locus coding for the alpha chain of hemoglobin, it was possible to demonstrate that the teratocarcinoma-derived genes for the globin alpha chains are genetically active in hemoglobin-synthesizing hybrid cells. In addition, evidence is presented suggesting that the teratocarcinoma-derived genes for the beta-globin chains may also be expressed in the hybrids. Apparently the teratocarcinoma-derived genome has become reprogrammed to express erythroid functions following fusion of the teratocarcinoma cell to the Friend cell.

Alleles↗

PubMed1983

Cytoplasmic activation of human nuclear genes in stable heterocaryons.

We have induced the stable expression of muscle-specific genes in human nonmuscle cells. Normal diploid human amniocytes were fused with differentiated mouse muscle cells by using polyethylene glycol. The fusion product, a stable heterocaryon in which the parental cell nuclei remained distinct, did not undergo division and retained a full complement of chromosomes. This is in contrast with typical interspecific hybrids (syncaryons), in which the parental nuclei are combined and chromosomes are progressively lost during cell division. The human muscle proteins, myosin light chains 1 and 2, MB and MM creatine kinase and a functional mouse-human hybrid MM enzyme molecule were detected in the heterocaryons. Synthesis of these proteins was evident 24 hr after fusion and increased in a time-dependent manner thereafter. Our results indicate that differentiated mouse muscle nuclei can activate human muscle genes in the nuclei of a cell type in which they are not normally expressed, and that this activation occurs via the cytoplasm. The activators are still present in cells which have already initiated differentiation, are recognized by nuclei of another species, and do not diffuse between unfused cells. The reprogrammed amniocyte nuclei of stable heterocaryons provide a unique system in which to study the mechanisms regulating gene expression during cell specialization.

Amniotic Fluid↗