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PubMed1992

The 3' untranslated region of localized maternal messages contains a conserved motif involved in mRNA localization.

Messenger RNA (mRNA) localization is emerging as a means of regulating gene expression. This process is operational in fly and frog development, where a subset of maternally inherited RNAs are asymmetrically distributed and thought to impart axial polarity to the embryo. Since most maternal mRNAs are uniformly distributed, an apparatus must exist to recognize and specifically transport these rare localized species. Here I report the identification of a nine-nucleotide motif, YUGUUYCUG, common to the 3' untranslated regions of four sequenced messages of this class: Drosophila bicoid and nanos mRNAs and Xenopus An2 and Vg1 mRNAs. To test the role of this nonamer sequence in the localization process, a Drosophila transient assay has been established. The assay reveals that bicoid mRNA specifically lacking this nonamer is partially mislocalized. In contrast, nonamer deletion is inconsequential to message stability. The existence of specific and general mRNA localization signals is proposed and it is suggested that this conserved motif belongs to the latter category.

Animals↗
PubMed2003

Subcellular localization of cyclic nucleotide phosphodiesterase type 10A variants, and alteration of the localization by cAMP-dependent protein kinase-dependent phosphorylation.

Our previous studies have suggested that two phosphodiesterase type 10A (PDE10A) variants, PDE10A1 and PDE10A2 transcripts, are mainly expressed in humans and that PDE10A2 and PDE10A3 transcripts are major variants in rats. In the present study, immunoblot analysis demonstrated that PDE10A proteins, especially PDE10A2, are more abundant in membrane fractions than in cytosolic fractions of rat striatum. Recombinant PDE10A1 and PDE10A3 were produced only in cytosolic fractions of transfected PC12h cells. By contrast, recombinant PDE10A2 was present mainly in membrane fractions. This finding agreed well with the result of subcellular fractionation of PDE10A in rat striatum. Immunocytochemical analysis showed that PDE10A2 was localized in the Golgi apparatus of transfected PC12h cells. PDE10A2 was phosphorylated by cAMP-dependent protein kinase (PKA) at Thr16. Interestingly, recombinant protein of wild-type PDE10A2, but not PDE10A2 mutant with an Ala replacement at Thr16, was distributed to cytosolic fractions by co-transfection with a plasmid encoding the catalytic subunit of PKA. A PDE10A2 mutant with Glu substitution at Thr16, which can be a mimic of phosphorylation, was localized in the cytosolic fractions of transfected PC12h cells. These observations implied that phosphorylation of PDE10A2 at Thr16 by PKA caused alteration of subcellular localization of PDE10A2 from the Golgi apparatus to cytosol. It is hypothesized that cAMP signaling in the Golgi area and the cytosol in neurons is controlled through alteration of subcellular localization of PDE10A brought by activation of PKA in response to intracellular elevations of cAMP.

Alternative Splicing↗
PubMed1999

Characterization of Fus3 localization: active Fus3 localizes in complexes of varying size and specific activity.

The MAP kinase Fus3 regulates many different signal transduction outputs that govern the ability of Saccharomyces cerevisiae haploid cells to mate. Here we characterize Fus3 localization and association with other proteins. By indirect immunofluorescence, Fus3 localizes in punctate spots throughout the cytoplasm and nucleus, with slightly enhanced nuclear localization after pheromone stimulation. This broad distribution is consistent with the critical role Fus3 plays in mating and contrasts that of Kss1, which concentrates in the nucleus and is not required for mating. The majority of Fus3 is soluble and not bound to any one protein; however, a fraction is stably bound to two proteins of approximately 60 and approximately 70 kDa. Based on fractionation and gradient density centrifugation properties, Fus3 exists in a number of complexes, with its activity critically dependent upon association with other proteins. In the presence of alpha factor, nearly all of the active Fus3 localizes in complexes of varying size and specific activity, whereas monomeric Fus3 has little activity. Fus3 has highest specific activity within a 350- to 500-kDa complex previously shown to contain Ste5, Ste11, and Ste7. Ste5 is required for Fus3 to exist in this complex. Upon alpha factor withdrawal, a pool of Fus3 retains activity for more than one cell cycle. Collectively, these results support Ste5's role as a tether and suggest that association of Fus3 in complexes in the presence of pheromone may prevent inactivation in addition to enhancing activation.

Adaptor Proteins, Signal Transducing↗
PubMed1996

The effects of clathrin inactivation on localization of Kex2 protease are independent of the TGN localization signal in the cytosolic tail of Kex2p.

Localization of Kex2 protease (Kex2p) to the yeast trans-Golgi network (TGN) requires a TGN localization signal (TLS) in the Kex2p C-terminal cytosolic tail. Mutation of the TLS accelerates transport of Kex2p to the vacuole by an intracellular (SEC1-independent) pathway. In contrast, inactivation of the clathrin heavy-chain gene CHC1 results in transport of Kex2p and other Golgi membrane proteins to the cell surface. Here, the relationship of the two localization defects was assessed by examining the effects of a temperature-sensitive CHC1 allele on trafficking of wild-type (WT) and TLS mutant forms of Kex2p. Inactivation of clathrin by shifting chc1-ts cells to 37 degrees C caused WT and TLS mutant forms of Kex2p to behave identically. All forms of Kex2p appeared at the plasma membrane within 30-60 min of the temperature shift. TLS mutant forms of Kex2p were stabilized, their half-lives increasing to that of wild-type Kex2p. After inactivation of clathrin heavy chain, vacuolar protease-dependent degradation of all forms of Kex2p was blocked by a sec1 mutation, which is required for secretory vesicle fusion to the plasma membrane, indicating that transport to the cell surface was required for degradation by vacuolar proteolysis. Finally, after clathrin inactivation, all forms of Kex2p were degraded in part by a vacuolar protease-independent pathway. After inactivation of both chc1-ts and sec1-ts, Kex2 was degraded exclusively by this pathway. We conclude that the effects of clathrin inactivation on Kex2p localization are independent of the Kex2p C-terminal cytosolic tail. Although these results neither prove nor rule out a direct interaction between the Kex2 TLS and a clathrin-dependent structure, they do imply that clathrin is required for the intracellular transport of Kex2p TLS mutants to the vacuole.

Biological Transport↗
PubMed2005

The mitotic exit network Mob1p-Dbf2p kinase complex localizes to the nucleus and regulates passenger protein localization.

The Saccharomyces cerevisiae mitotic exit network (MEN) is a conserved signaling network that coordinates CDK inactivation, cytokinesis and G1 gene transcription. The MEN Cdc14p phosphatase is sequestered in the nucleolus and transiently released in early anaphase and telophase. Cdc14p mediates mitotic exit by dephosphorylating Cdk1p substrates and promoting Cdk1p inactivation. Cdc14p also regulates the localization of chromosomal passenger proteins, which redistribute from kinetochores to the mitotic spindle during anaphase. Here we present evidence that the MEN protein kinase complex Mob1p-Dbf2p localizes to mitotic nuclei and partially colocalizes with Cdc14p and kinetochore proteins. Chromatin immunoprecipitation (ChIP) experiments reveal that Mob1p, Dbf2p, and Cdc14p associate with centromere DNA and require the centromere binding protein Ndc10p for this association. We establish that Mob1p is essential for maintaining the localization of Aurora, INCENP, and Survivin chromosomal passenger proteins on anaphase spindles, whereas Cdc14p and the Mob1p-Dbf2p-activating kinase Cdc15p are required for establishing passenger protein localization on the spindle. Moreover, Mob1p, but not Cdc15p, is required for dissociating Aurora from the kinetochore region. These findings reveal kinetochores as sites for MEN signaling and implicate MEN in coordinating chromosome segregation and/or spindle integrity with mitotic exit and cytokinesis via regulation of chromosome passenger proteins.

Cell Cycle↗
PubMed1997

Do local inhabitants want to participate in community injury prevention?: a focus on the significance of local identities for community participation.

During the 1980s the community became the object of new interest and enthusiasm among many health promotion practitioners and researchers, and the principle of community participation was put on the research agenda. However, recent evaluations of major community health promotion programs have questioned the value of community interventions. This paper argues that the community level need not be of less importance in future health promotion initiatives. It is discussed whether the cultural dimension and the significance of local identities, neglected in most community health promotion programs, should receive more attention when local inhabitants are invited to participate in health promotion or disease prevention activities. Results from a study of injury prevention projects in small Norwegian municipalities indicate that the inhabitants' identification with local spatial subarenas might play an important role when they decide to become involved in injury prevention. Contemporary sociological approaches to the community, focusing on developments of local identities in processes of globalization, have formed a theoretical frame of reference in this study.

Attitude to Health↗
PubMed2000

Early results of LH-RH agonist treatment with or without chlormadinone acetate for hormone therapy of naive localized or locally advanced prostate cancer: a prospective and randomized study. The Prostate Cancer Study Group.

BACKGROUND: The majority of patients with localized and some cases of locally advanced prostate cancer undergo radical prostatectomy. However, radical prostatectomy cannot always be selected for those patients. In this situation, primary hormone therapy is an alternative treatment option. We have designed a prospective randomized study of the effects of primary hormone therapy for such patients. METHODS: A total of 151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer who were not scheduled for radical prostatectomy were enrolled into this study. Patients were randomly allocated into two groups; Group I received luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy (leuprorelin acetate depot, 3.75 mg monthly) and Group II received LH-RH agonist in combination with chlormadinone acetate (100 mg/day). Effects on serum prostate-specific antigen level, progression-free survival and survival were observed for 2 years. RESULTS: The reasons why radical prostatectomy was not scheduled were poor risk for surgery (38%), patient's wish (32%) and physician's recommendation (30%). After 12 weeks of treatment, 49% of the patients in both groups showed a complete response (CR). Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I and 52% in Group II improved to CR 1 year later (p<0.05). Group II showed a longer progression-free survival (p <0.05). Progression-free survival rates were 62% (Group I) and 91% (Group II) in T2b patients and 43% (Group I) and 73% (Group II) in T3 patients. Only one patient in each group died from prostate cancer. CONCLUSIONS: Early primary hormone therapy is a reasonable treatment option for localized or locally advanced prostate cancer patients if radical prostatectomy was not scheduled. Chlormadinone acetate showed an additive effect with LH-RH agonist, at least in 2 years' observation.

Aged↗
PubMed2001

Long-term local control and survival after concomitant boost accelerated radiotherapy for locally advanced cervix cancer.

Between 1989 and 1994, a prospective clinical trial tested the safety and efficacy of concomitant boost accelerated superfractionated (CBASF) radiotherapy for patients with locally advanced cervix cancer. CBASF radiotherapy included 45 Gy/25 fractions to the pelvis and a 14.4 Gy/9 fraction concomitant boost to the primary tumor, followed by brachytherapy for a total point A dose of 85 Gy to 90 Gy. The 22 patients of International Federation of Gynecology and Obstetrics stages IIIA-IVA who received CBASF radiotherapy now have a median follow-up time of more than 8 years. The 7-year actuarial rates of local control and overall survival are 81% and 36%, respectively. Serious late toxicity included bowel injury requiring colostomy in eight patients within 2.5 years after treatment, but no other severe toxicity was observed after longer follow-up intervals. The local control and survival rates achieved with CBASF radiotherapy were higher than those observed within a matched contemporaneous cohort of patients treated with standard radiotherapy alone at the same institution (p = 0.1 for local control, 0.09 for survival). The encouraging trend toward improved tumor control, tempered by the complication rate, suggests an opportunity to apply more sophisticated radiotherapy techniques that might sustain the favorable effects of dose intensification while mitigating the normal tissue toxicity.

Adult↗
PubMed1998

Local cerebral blood flow, local cerebral glucose utilization, and flow-metabolism coupling during sevoflurane versus isoflurane anesthesia in rats.

BACKGROUND: Compared to isoflurane, knowledge of local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) during sevoflurane anesthesia is limited. METHODS: LCGU, LCBF, and their overall means were measured in Sprague-Dawley rats (8 groups, n=6 each) during sevoflurane and isoflurane anesthesia, 1 and 2 MAC, and in conscious control animals (2 groups, n=6 each) using the autoradiographic 2-[14C]deoxy-D-glucose and 4-iodo-N-methyl-[14C]antipyrine methods. RESULTS: During anesthesia, mean cerebral glucose utilization was decreased: control, 56+/-5 micronmol x 100 g(-1) x min(-1); 1 MAC isoflurane, 32+/-4 micromol x 100 g(-1) x min(-1) (-43%); 1 MAC sevoflurane, 37+/-5 micromol x 100 g(-1) x min(-1) (-34%); 2 MAC isoflurane, 23+/-3 micromol x 100 g(-1) x min(-1) (-58%); 2 MAC sevoflurane, 23+/-5 micromol x 100 g(-1) x min(-1) (-59%). Local analysis showed a reduction in LCGU in the majority of the 40 brain regions analyzed. Mean cerebral blood flow was increased as follows: control 93+/-8 ml x 100 g(-1) x min(-1); 1 MAC isofurane, 119+/-19 ml x 100 g(-1) x min(-1) (+28%); 1 MAC sevoflurane, 104+/-15 ml x 100 g(-1) x min(-1) (+12%); 2 MAC isoflurane, 149+/-17 ml x 100 g(-1) x min(-1) (+60%); 2 MAC sevoflurane, 118+/-21 ml x 100 g(-1) min(-1) (+27%). LCBF was increased in most brain structures investigated. Correlation coefficients obtained for the relationship between LCGU and LCBF were as follows: control 0.93; 1 MAC isoflurane, 0.89; 2 MAC isoflurane, 0.71; 1 MAC sevoflurane, 0.83; 2 MAC sevoflurane, 0.59). CONCLUSION: Mean and local cerebral blood flows were lower during sevoflurane than during isoflurane anesthesia. This difference cannot be explained by differing changes in glucose utilization because glucose utilization was decreased to the same extent in both groups.

Anesthesia↗
PubMed2004

Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer.

PURPOSE: We evaluated changes in bone mineral density (BMD), fat-free mass (FFM) and serum lipid levels during bicalutamide 150 mg monotherapy compared with medical castration for 2 years. MATERIALS AND METHODS: A total of 103 men with localized or locally advanced prostate cancer (T1-T4, Nx, M0) for whom immediate androgen deprivation was indicated were enrolled in this prospective, multicenter, open-label, parallel group study. Patients were randomized to bicalutamide 150 mg once daily (51) or medical castration with a luteinizing hormone releasing hormone analogue (52) for 96 weeks. Primary end points were mean percent change from baseline in lumbar spine BMD, hip BMD and FFM at 96 weeks. Mean changes in lipid parameters with time were also evaluated. RESULTS: BMD was maintained during bicalutamide 150 mg monotherapy (+2.42% for lumbar spine BMD and +1.13% for hip BMD at week 96), while castration was associated with a progressive loss in BMD (-5.40% and -4.39% at week 96, respectively, both p <0.0001 at week 96). There was no significant difference between bicalutamide 150 mg and castration in mean percent change from baseline in FFM (-1.56% and -3.86%, respectively, at week 96, p = 0.31), although there was a trend for greater progressive loss over time with castration. Mean changes in lipid parameters were small and similar in the 2 groups. CONCLUSIONS: Bicalutamide 150 mg monotherapy may offer an important advantage compared to castration in terms of bone loss and body composition for patients who require long-term androgen deprivation for localized or locally advanced prostate cancer.

Aged↗
PubMed2003

The medial circumflex femoral (gracilis) local perforator flap--a local medial groin perforator flap.

The medial circumflex femoral(GRACILIS) perforator free flap has been previously used to capture the superior medial thigh skin territory. This can also be valuable as a local flap, especially for adjacent groin wounds that are not uncommon after vascular interventions. Uncomplicated healing without vascular compromise was achieved using this as a local flap in 4 recent cases. Because the gracilis muscular branches can be independently dissected from the musculocutaneous perforators, the muscle itself can be separately included to form a combined conjoint flap, where the muscle is specifically only used to wrap around and protect any exposed vascular structures while the cutaneous component simplifies skin wound closure. The axis of rotation of the medial circumflex femoral perforator local flap extends throughout the groin region and potentially to the lateral thigh. This is an ideal local perforator flap because the source pedicle has a consistent location already well known to most plastic surgeons, the boundaries of the potential skin territory are reliable and well defined, and the scar from closure of the donor site within the medial groin can be readily concealed by clothing.

Femoral Artery↗
PubMed2005

Photon localization laser: low-threshold lasing in a random amplifying layered medium via wave localization.

We demonstrate low-threshold lasing in random amplifying layered medium via photon localization. Lasing is facilitated by resonant excitation of localized modes at the pump laser wavelength, which are peaked deep within the sample with greatly enhanced intensity. Emission occurs into long-lived localized modes overlapping the localized gain region. This mechanism overcomes a fundamental barrier to reducing lasing thresholds in diffusive random lasers, in which multiple scattering restricts the excitation region to the proximity of the sample surface.

Journal Article↗
PubMed1980

Skeletal muscle oxygen pressure fields in rats. A study of the normal state and the effects of local anesthetics, local trauma and hemorrhage.

The MDO (Mehrdraht Dortmund Oberfläche) oxygen electrode was used for studies of oxygen pressure fields in rat skeletal muscle. With this multiwire oxygen electrode, the three-dimensional oxygen pressure field was measured and presented as a two-dimensional frequency distribution, i.e., a histogram. Statistical analysis of the histograms was carried out with the two-sample Kolmogorov-Smirnov test. This eliminated the influence of mean values, since these do not always represent the actual biological situation. The oxygen pressure fields in skeletal muscle of anesthetized normal rats breathing air spontaneously were investigated. When the oxygen pressure in the inspired gas was changed (50% and 95%), changes were seen in muscle oxygen pressure curves. The normal oxygen pressure field histograms were compared with those obtained after local anesthesia, after local trauma to the muscle and after hemorrhage. After local anesthesia the histograms were unchanged. Significant changes in the distribution types of the histograms were found after trauma in all rats studied. After hemorrhage significant changes, similar to those seen after trauma, were found in 15 of the 23 rats studied. Local blood flow was also measured with the 133xenon-clearance method in the hemorrhage experiments. No correlation was found between the changes in the mean oxygen tension values and the changes in 133xenon-clearance.

Animals↗
PubMed2006

Efficacy of primary hormonal therapy for patients with localized and locally advanced prostate cancer: a retrospective multicenter study.

AIM: A retrospective review of patients with localized and locally advanced prostate cancer was performed to evaluate the efficacy of primary hormonal therapy and predict long-term prognosis in these patients. METHODS: A total of 628 patients who were diagnosed with stage T1c to T3 prostate cancer were treated with primary hormonal therapy at participating institutions. The patients were classified based on pretreatment prostate-specific antigen (PSA) level, Gleason score, and time to nadir PSA level. Disease-specific and progression-free survival rates were investigated, and compared among the subgroups. RESULTS: The mean age of patients was 74.5 years, and median pretreatment PSA level was 14.0 ng/mL. A total of 399 patients (63.5%) were treated with combined androgen blockade (CAB), and 229 patients (36.5%) were treated with castration monotherapy. The disease-specific survival rate of all 628 patients was 89.1% at 8 years. The group that showed a good response to primary hormonal therapy (Group G, pretreatment PSA level < or =20 ng/mL, Gleason score < or =7, and time to nadir PSA < or =6 months) accounted for approximately one-third of the total number of T1c-T3 patients. Disease-specific and progression-free survival rates at 8 years in Group G were 98.9% and 82.0%, respectively. These rates increased to 100% and 87.3%, respectively, in patients receiving CAB treatment in Group G. CONCLUSIONS: The results indicate the usefulness of primary hormonal therapy, especially CAB treatment, for patients showing a good response to hormonal therapy in long-term control of localized and locally advanced prostate cancer.

Aged↗
PubMed2005

Clinical outcomes of androgen deprivation as the sole therapy for localized and locally advanced prostate cancer.

OBJECTIVE: To characterize the clinical outcomes of androgen deprivation therapy (ADT) as the sole therapy for localized prostate cancer, and to determine independent predictors of disease progression, as recent studies indicate an increasing use of ADT. PATIENTS AND METHODS: The records of all patients with cT1-4NXM0 adenocarcinoma of the prostate treated with ADT as the primary initial therapy at the Portland Veterans Affairs Medical Center between 1993 and 2000 were reviewed. Age, race, Charlson Health Index, family history, prostate-specific antigen (PSA) level, PSA density, digital rectal examination (DRE) findings, Gleason score, and percentage of positive biopsy cores at diagnosis were recorded for 81 patients. Patients had a median (SD, range) age of 73 (5.6, 58-84) years, a PSA level of 14.3 (34.6, 1.4-252) ng/mL and tumours were classified as Gleason score < or = 5 in 9% of patients, 6 in 31%, 7 in 31% and 8-10 in 30%. Outcomes extracted were PSA progression, PSA nadir, bone fractures, local progression, distant progression and overall survival. RESULTS: With a median (range) follow-up of 54 (6-115) months, the incidence of local progression, distant progression, bone fractures, PSA progression, and death were 10%, 7%, 25%, 21% and 41% respectively. The percentage of positive biopsy cores > or = 83%, age < 70 years, Gleason score > or = 7, abnormal DRE, and PSA nadir > or = 0.2 ng/mL were significantly associated with PSA progression by univariate analysis. The multivariate analysis identified age < 70 years (hazard ratio 6.52, 95% confidence interval 2.29-18.55) and Gleason score > or = 6 (4.0, 2.0-12.0) as independent risk factors for PSA progression. CONCLUSIONS: ADT resulted in modest control of localized prostate cancer, but younger patients and those with Gleason > or = 6 cancers were at higher risk of treatment failure. Toxicity, principally in the form of bone fractures, was high.

Adenocarcinoma↗
PubMed1989

Axolinin localization in the nervous tissue of squid revealed by monoclonal antibodies specific for axolinin: cellular and subcellular localization of axolinin in the squid neuron.

Cellular and subcellular distributions of axolinin, the 260-kilodalton (kD) microtubule-associated glycoprotein originally purified from squid axons, in various squid tissues such as optical lobes, bundles of small nerve fibers (fin nerves), giant stellate ganglia, skin, muscle, liver, and gill, were immunologically studied using monoclonal antibodies specifically recognizing the polypeptide chain of axolinin. The following results were obtained: (1) Axolinin is confined to squid neurons and skin; (2) axolinin is localized in the axon whereas another 260-kD microtubule-associated protein, MAP B, is localized in the cell bodies; and (3) axolinin is localized mainly in the peripheral part of the axoplasm of the squid giant axon. The last result has confirmed our previous conclusion obtained using polyclonal antisera against axolinin, which contain antibodies recognizing not only axolinin-specific epitopes but also nonspecific epitopes. The physiological importance of the localization of axolinin in axons and the skin is discussed based on its possible relationship to excitability function.

Animals↗
PubMed1982

Spiking local interneurons mediate local reflexes.

A local spiking interneuron in the locust is excited by particular sensory stimulation of a hind leg and forms an inhibitory connection with one hind leg motor neuron. Its behavioral effect is to mediate a local postural reflex. This interneuron is one of a population of interneurons with similar morphology and physiology that participate in the same local circuits as the better known nonspiking local interneurons.

Animals↗
PubMed1990

Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function.

The human immunodeficiency virus rev gene product regulates the expression of viral structural genes. It was recently shown that Rev regulates the export of viral structural mRNAs from the nucleus to the cytoplasm. Analysis of Rev subcellular localization reveals marked accumulation in the nucleolus, suggesting a role for the nucleolus in this export process. We report here the identification of amino acid residues critical to the nucleolar localization of Rev. Consistent with this finding, a Rev/beta-galactosidase fusion protein, harboring this region of Rev, localized entirely within the nucleolus. Of most significance, mutations that eliminated nucleolar localization markedly diminished Rev function, even though accumulation in the nucleoplasm was retained. These findings support a model whereby Rev-induced export of human immunodeficiency virus structural mRNAs from the nucleus to the cytoplasm is likely to involve nucleolar events.

Amino Acid Sequence↗