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T Bowman

Publications and source records attributed to T Bowman.

18 recordsLinked to original sources
PubMed2001

Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis.

Signal transducer and activator of transcription (STAT) proteins perform key roles in mediating signaling by cytokines and growth factors, including platelet-derived growth factor (PDGF). In addition, Src family kinases activate STAT signaling and are required for PDGF-induced mitogenesis in normal cells. One STAT family member, Stat3, has been shown to have an essential role in cell transformation by the Src oncoprotein. However, the mechanisms by which STAT-signaling pathways contribute to mitogenesis and transformation are not fully defined. We show here that disruption of Stat3 signaling by using dominant-negative Stat3beta protein in NIH 3T3 fibroblasts suppresses c-Myc expression concomitant with inhibition of v-Src-induced transformation. Ectopic expression of c-Myc is able to partially reverse this inhibition, suggesting that c-Myc is a downstream effector of Stat3 signaling in v-Src transformation. Furthermore, c-myc gene knockout fibroblasts are refractory to transformation by v-Src, consistent with a requirement for c-Myc protein in v-Src transformation. In normal NIH 3T3 cells, disruption of Stat3 signaling with dominant-negative Stat3beta protein inhibits PDGF-induced mitogenesis in a manner that is reversed by ectopic c-Myc expression. Moreover, inhibition of Src family kinases with the pharmacologic agent, SU6656, blocks Stat3 activation by PDGF. These findings, combined together, delineate the signaling pathway, PDGF --> Src --> Stat3 --> Myc, that is important in normal PDGF-induced mitogenesis and subverted in Src transformation.

3T3 Cells↗
PubMed2000

Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling.

While the activated viral Src oncoprotein, v-Src, induces uncontrolled cell growth, the mechanisms underlying cell cycle deregulation by v-Src have not been fully defined. Previous studies demonstrated that v-Src induces constitutively active STAT3 signaling that is required for cell transformation and recent data have implicated STAT3 in the transcriptional control of critical cell cycle regulators. Here we show in mouse fibroblasts stably transformed by v-Src that mRNA and protein levels of p21 (WAF1/CIP1), cyclin D1, and cyclin E are elevated. Using reporter constructs in transient-transfection assays, the cyclin D1 and p21 promoters were both found to be transcriptionaly induced by v-Src in a STAT3-dependent manner. The kinase activities of cyclin D/CDK4, 6 and cyclin E/CDK2 complexes were only slightly elevated, consistent with the findings that coordinate increases in p21, cyclin D1 and cyclin E resulted in an increase in cyclin/CDK/p21 complexes. Similar results were obtained in NIH3T3 and BALB/c 3T3 cells stably transformed by v-Src, indicating that these regulatory events associated with STAT3 signaling represent common mechanisms independent of cell line or clonal variation. These findings suggest that STAT3 has an essential role in the regulation of critical cell cycle components in v-Src transformed mouse fibroblasts.

3T3 Cells↗
PubMed2000

STATs in oncogenesis.

Since their discovery as key mediators of cytokine signaling, considerable progress has been made in defining the structure-function relationships of Signal Transducers and Activators of Transcription (STATs). In addition to their central roles in normal cell signaling, recent studies have demonstrated that diverse oncoproteins can activate specific STATs (particularly Stat3 and Stat5) and that constitutively-activated STAT signaling directly contributes to oncogenesis. Furthermore, extensive surveys of primary tumors and cell lines derived from tumors indicate that inappropriate activation of specific STATs occurs with surprisingly high frequency in a wide variety of human cancers. Together, these findings provide compelling evidence that aberrant STAT activation associated with oncogenesis is not merely adventitious but instead contributes to the process of malignant transformation. These studies are beginning to reveal the molecular mechanisms leading to STAT activation in the context of oncogenesis, and candidate genes regulated by STATs that may contribute to oncogenesis are being identified. Recent studies suggest that activated STAT signaling participates in oncogenesis by stimulating cell proliferation and preventing apoptosis. This review presents the evidence for critical roles of STATs in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT signaling. Oncogene (2000).

Animals↗
PubMed2000

Modulation of cholesterol concentration in Caco-2 cells by incubation with different n-6 fatty acids.

Incorporation of exogenous cholesterol was compared in human adenocarcinoma colon cells (Caco-2) after incubation with 100 microM of either linoleic acid (LA, 18:2n-6), gamma-linolenic acid (GLA, 18:3n-6), arachidonic acid (AA, 20:4n-6) or adrenic acid (or n-6 docosatetraenoic acid, DTA, 22:4n-6). In both cells 7 days after seeding and 14 days after confluency, incubation with LA significantly raised the proportion of 18:2n-6 but not its long-chain metabolites in cellular phospholipid. Incubation with GLA increased the levels of 18:3n-6, 20:3n-6, and 20:4n-6. Incubation with AA increased the levels of 20:4n-6 and 22:4n-6, and incubation with DTA increased the levels of 22:4n-6 as well as its retro-conversion metabolite, 20:4n-6. A subsequent addition of cholesterol (180 microM) to the medium significantly raised the cellular cholesterol level but less so in the cells 7 days after seeding incubated with GLA. The increase in cellular cholesterol level was generally greater in the cells of 7 days after seeding, particularly those incubated with long-chain highly unsaturated n-6 fatty acids, than in those of 14 days after confluency. These findings suggest that the cell growth and the extent of unsaturation in cell membrane phospholipid fatty acids modulate the incorporation of the exogenous cholesterol into the Caco-2 cells.

Caco-2 Cells↗
PubMed1999

Literary resources for bereavement.

The bereavement process can be aided by multiple resources. Hospice counselors and related therapeutic professionals turn most easily to their own disciplines and training. In this article, complementary or ancillary resources from literature have been offered. If healing includes the "storying" and "restorying" of lives, then literature can enrich and facilitate the mourning process. Suggestions of resources and some of their connections to hospice care have been offered.

Adaptation, Psychological↗
PubMed1999

Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein.

Signal transducers and activators of transcription (STATs) are transcription factors that mediate normal biologic responses to cytokines and growth factors. However, abnormal activation of certain STAT family members, including Stat3, is increasingly associated with oncogenesis. In fibroblasts expressing the Src oncoprotein, activation of Stat3 induces specific gene expression and is required for cell transformation. Although the Src tyrosine kinase induces constitutive Stat3 phosphorylation on tyrosine, activation of Stat3-mediated gene regulation requires both tyrosine and serine phosphorylation of Stat3. We investigated the signaling pathways underlying the constitutive Stat3 activation in Src oncogenesis. Expression of Ras or Rac1 dominant negative protein blocks Stat3-mediated gene regulation induced by Src in a manner consistent with dependence on p38 and c-Jun N-terminal kinase (JNK). Both of these serine/threonine kinases and Stat3 serine phosphorylation are constitutively induced in Src-transformed fibroblasts. Furthermore, inhibition of p38 and JNK activities suppresses constitutive Stat3 serine phosphorylation and Stat3-mediated gene regulation. In vitro kinase assays with purified full-length Stat3 as the substrate show that both JNK and p38 can phosphorylate Stat3 on serine. Moreover, inhibition of p38 activity and thus of Stat3 serine phosphorylation results in suppression of transformation by v-Src but not v-Ras, consistent with a requirement for Stat3 serine phosphorylation in Src transformation. Our results demonstrate that Ras- and Rac1-mediated p38 and JNK signals are required for Stat3 transcriptional activity induced by the Src oncoprotein. These findings delineate a network of tyrosine and serine/threonine kinase signaling pathways that converge on Stat3 in the context of oncogenesis.

3T3 Cells↗
PubMed1999

Quality of life in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure--a prospective study.

BACKGROUND: Obstructive sleep apnea (OSA) is a common condition and is associated with excessive daytime sleepiness and neuropsychological dysfunction. There is limited evidence on the effect of OSA on the quality of life and its response to nasal continuous positive airway pressure (nCPAP) treatment. STUDY OBJECTIVE: To determine the effect of nCPAP on the quality of life in patients with OSA. DESIGN: Prospective determination of nCPAP effect in a case-series analysis. PATIENTS: We studied 29 patients (23 were male and 6 were female) with a mean (+/-SE) age of 4.4+/-2.3 years, a body mass index 36.3+/-2.0 kg/height (m)2, and a diagnosis of OSA with respiratory disturbance index (RDI; apnea/hypopnea) of 77+/-9 events/h. MEASUREMENTS AND RESULTS: The quality of life was assessed by administering a Medical Outcomes Study Short Form-36 questionnaire before and after 8 weeks of nCPAP therapy in polysomnographically documented OSA. All dimensions of the quality of life were significantly impaired when compared with an age- and gender-matched population, expressed as a percentage of normative data: physical functioning, 75%; vitality, 41%; role functioning (physical, 54%; emotional, 61%; social, 66%); general health, 88%; and mental health, 76%. nCPAP therapy significantly improved the sleep-disordered breathing and sleep fragmentation. The nCPAP level for the group was 9.4+/-0.7 cm H2O. Eight weeks of nCPAP therapy improved vitality (75%), social functioning (90%), and mental health (96%). The magnitude of improvement was related to the degree of quality of life impairment prior to treatment, rather than to the severity of disease as measured by the RDI and arousal indices. CONCLUSIONS: All aspects of the quality of life, from physical and emotional health to social functioning, are markedly impaired by OSA. nCPAP therapy improved those aspects related to vitality, social functioning, and mental health.

Adaptation, Psychological↗
PubMed1999

Signal Transducers and Activators of Transcription: Novel Targets for Anticancer Therapeutics.

BACKGROUND: Through specific activation of gene expression, the family of proteins known as signal transducers and activators of transcription (STATs) converts extracellular stimuli into diverse biological responses. Beyond the normal signaling functions of STATs, recent evidence indicates that aberrant activation of STATs contributes to neoplastic transformation. METHODS: Current literature pertaining to the role of STAT proteins in oncogenesis is presented. Also, the rationale for developing novel approaches to disrupt STAT signaling is discussed, and the potential of STATs as anticancer targets in treating human cancer is reviewed. RESULTS: The discovery that certain oncoproteins constitutively activate specific STATs, coupled with observations that elevated STAT activity occurs frequently in a spectrum of human tumors, establishes a direct link between STAT activation and neoplastic transformation. Significantly, abrogation of STAT signaling blocks oncogenesis in model in vitro and in vivo systems. These results make STATs attractive targets for rational design of small molecule inhibitors and gene therapy approaches to disrupt STAT signaling. CONCLUSIONS: As a result of genetic, biochemical, and crystallographic analyses, the functional domains of STAT proteins have been well characterized. Based on these data, selective inhibitors of STAT function can be designed. Because disrupting STAT signaling has proven effective in blocking neoplastic transformation, it is proposed that STAT proteins represent promising targets for development of novel molecular therapeutics to treat human cancer.

Journal Article↗
PubMed1999

Adenosine rinse in human orthotopic liver transplantation: results of a randomized, double-blind trial.

OBJECTIVE: The study was aimed at determining whether the vasodilator, adenosine, shown to produce dramatic improvement in liver graft and animal acute and long-term survival, would be beneficial in human liver transplantation. METHODS: A prospective, randomized, double-blind trial of an adenosine rinse preservation solution in human orthotopic liver transplantation (OLTX) was conducted in 43 consecutive transplants. Intraoperative and postoperative care was performed by a single transplant team utilizing a quadruple drug immunosuppressive protocol, with complete 5-year patient follow-up. At implantation all allografts were flushed with a 4 degrees C (pH 7.4) Normosol solution, with 0.12 mM adenosine or without adenosine. RESULTS: Recipient characteristics were similar in the treated and control groups including age, pre-OLTX diagnosis, and United Network for Organ Sharing (UNOS) status. Donor variables were equivalent in the two groups including age, weight, prothrombin time, and serum chemistries. Operative variables showed no differences except a significant (p = 0.006) reduction of veno-venous bypass time in the adenosine treated group. Liver allograft function improved in the adenosine rinse groups as measured by both postoperative bile production (218 +/- 156cc/24h adenosine vs. 116 +/- 78 cc/24 h without adenosine, p = 0.03) and Factor 7 production at day 3 (64 +/- 26% adenosine vs. 51 +/- 20% without adenosine, p = 0.08). The adenosine treated group had an insignificant 10% patient and graft improvement in survival at 6 months to 60 months compared to the control group. CONCLUSIONS: These results suggest that adenosine added to the intraoperative flush solution during human liver transplantation is safe, does not reduce cardiac stability at reperfusion, improves early liver allograft function, but has an insignificant short- and long-term affect on allograft survival.

Adenosine↗
PubMed1998

Stat3 activation by Src induces specific gene regulation and is required for cell transformation.

While signal transducers and activators of transcription (STATs) were originally discovered as intracellular effectors of normal signaling by cytokines, increasing evidence also points to a role for STAT transcription factors in oncogenesis. Previous studies have demonstrated that one STAT family member, Stat3, possesses constitutively elevated tyrosine phosphorylation and DNA-binding activity in fibroblasts stably transformed by the Src oncoprotein. To determine if this Stat3 activation by Src could induce Stat3-mediated gene expression, luciferase reporter constructs based on synthetic and authentic promoters were transfected into NIH 3T3 cells. Activation of endogenous cellular Stat3 by the Src oncoprotein induced gene expression through a Stat3-specific binding element (TTCCCGAA) of the C-reactive protein gene promoter. A naturally occurring splice variant of human Stat3 protein, Stat3beta, with a deletion in the C-terminal transactivation domain abolished this gene induction in a dominant negative manner. Expression of Stat3beta did not have any effect on a reporter construct based on the c-fos serum response element, which is not dependent on Stat3 signaling, indicating that Stat3beta does not nonspecifically inhibit other signaling pathways or Src function. Transfection of vectors expressing Stat3beta together with Src blocked cell transformation by Src as measured in a quantitative focus formation assay using NIH 3T3 cells. By contrast, Stat3beta had a much less pronounced effect on focus formation induced by the Ras oncoprotein, which does not activate Stat3 signaling. In addition, three independent clones of NIH 3T3 cells stably overexpressing Stat3beta were generated and characterized, demonstrating that Stat3beta overexpression does not have a toxic effect on cell viability. These Stat3beta-overexpressing clones were shown to be deficient in Stat3-mediated signaling and refractory to Src-induced cell transformation. We conclude that Stat3 activation by the Src oncoprotein leads to specific gene regulation and that Stat3 is one of the critical signaling pathways involved in Src oncogenesis. Our findings provide evidence that oncogenesis-associated activation of Stat3 signaling is part of the process of malignant transformation.

3T3 Cells↗
PubMed1997

Use of the GnRH analogue, deslorelin acetate, in a slow-release implant to accelerate ovulation in oestrous mares.

In two separate controlled clinical trials, the efficacy and safety of 2.2 mg of the GnRH analogue deslorelin, administered subcutaneously as a short-term implant to normally cycling mares in oestrus with a dominant ovarian follicle more than 30 mm in diameter, were evaluated, using a placebo as a negative control. The oestrous cycle of each mare was followed by teasing, palpation per rectum and transrectal ultrasonography. Follicles were monitored every 24 hours by ultrasonography until ovulation occurred. The mares were either mated naturally or inseminated artificially. In trial 1, 174 mares were treated at six locations in Canada, and in trial 2, 98 mares were treated at three locations in the USA. In trial 1, the treatment with deslorelin reduced the mean (sd) time to ovulation from 84.2 (48.4) hours to 50.2 (19.6) hours (P < 0.001) and in trial 2 it reduced it from 88.8 (40.3) hours to 54.1 (26.5) hours (P < 0.001). In trial 1, the percentage of mares ovulating within 48 hours increased from 37.7 per cent in control mares to 86.1 per cent in treated mares (P < 0.001) and in trial 2 the percentage increased from 26.5 to 80.9 per cent (P < 0.001). In trial 2, the duration of oestrus in the deslorelin-treated mares was reduced from 6.1 days to 4.3 days and the number of matings or artificial inseminations was reduced from 2.5 to 1.7 (P < 0.001). In trial 1, days 12 to 20 pregnancy rates for matings at the treatment oestrus were not different for deslorelin-treated (75.6 per cent) and placebo-treated (66.1 per cent) mares. In trial 2, days 12 to 20 pregnancy rates from matings at the treatment oestrus were lower for deslorelin-treated (58.7 per cent) than for placebo-treated (83.3 per cent) mares (P < 0.05), although pregnancy rates were similar for deslorelin-treated (97.1 per cent) and placebo-treated (95.0 per cent) mares after mating at the second oestrus. In both trials, pregnancy losses due to early or late abortions were within the normally expected range and similar for deslorelin-treated (3.6 and 3.7 per cent, respectively) and placebo-treated (13.4 and 7.5 per cent) mares. The treatments did not cause systemic side effects and local reactions at the implantation sites were slight and of short duration.

Animals↗
PubMed1997

Peer resource consulting: redesigning a new future.

The current case describes a young woman with diabetes mellitus who developed end-stage renal disease (ESRD) and many other devastating complications related to her primary illness. Her experience illustrates many ways in which complicated illness can interrupt life's plans, dashing any dreams that she or her family might have for the future. Yet her story also illustrates the important role that a trained Peer Resource Consultant (PRC) can play in helping to better understand chronic illness, face and grieve losses, and even design new plans and create new dreams for the future. The discussion that follows includes several perspectives that offer poignant insight into the difficult situations characterized by the young diabetic with ESRD.

Adult↗
PubMed1997

Psychological distress of parents of infants with Down syndrome.

The distress level of parents who had infants with Down syndrome (study parents) was compared to that of control parents of infants without disability (infants were all less than 2 years of age). Data were collected in two independent surveys. We matched subjects case-by-case on socioeconomic status. Analysis of pooled data indicated significantly greater depression for the study parents. However, effect sizes were small, and the prevalence of clinical depression was 5.56% (n = 108) among matched study parents and 4.26% (n = 188) among unmatched study parents. Parenting an infant with Down syndrome may cause less distress than previously thought.

Adult↗
PubMed1996

Tissue-specific inactivation of p53 tumor suppression in the mouse.

The p53 gene is the most frequent target of structural and functional genetic mutations in human cancer. Thus, considerable effort has been devoted to mapping the functional domains of p53 with regard to their impact on tumorigenesis in vivo. Studies have shown that the carboxy-terminal domain of p53 is sufficient for transformation in vitro. To determine whether a transdominant-negative p53 protein could be used to elicit a tissue-specific p53-null effect in vivo, we tested whether a carboxy-terminal p53 fragment (amino acids 302-390) could abolish p53-dependent apoptosis in an established tumor progression model. We showed previously that loss of p53-dependent apoptosis accelerates brain tumorigenesis in a transgenic mouse model. Here, we show that the same effect can be elicited by expressing a dominant-negative p53 protein tissue specifically in the presence of wild-type p53. Transgenic mice in which pRb function has been disrupted and that coexpress a p53 carboxy-terminal dominant-negative fragment (p53DD) develop aggressive brain tumors mimicking genetic loss of p53 in this model. Inactivation of endogenous p53, which we show to be complexed with p53DD, results in a reduction in apoptosis and acceleration of tumorigenesis. These studies establish a mechanism for tissue-specific knock out of p53 function in vivo.

Animals↗
PubMed1992

Dietary practices, physical activity, and body-mass index in a selected population of Down syndrome children and their siblings.

Thirty sibling pairs, each with one Down syndrome child between the ages of 2 and 14, were selected from families who had participated in an infant-stimulation program. The maternal and paternal educational levels were 14.9 and 16.9 years, respectively. The Down syndrome patients and their siblings were compared in terms of body-mass index, that is, weight/stature2 (w/s2); activity as measured on a questionnaire; and weekly caloric intake. There were no significant differences between the Down syndrome children and their siblings in terms of w/s2. The Down syndrome patients were less active than their siblings and spent significantly more time indoors, showing a preference for indoor activities. Caloric intake calculated as percentage of recommended allowance for height was somewhat less in the Down syndrome children--88.7%, compared with 95% in the siblings--but not significantly so. It is postulated that even though Down syndrome patients have been shown to be at risk for obesity, familial and other environmental factors, such as dietary control and involvement in physical activity, have an influence.

Adolescent↗
PubMed1987

A controlled study of progabide in partial seizures: methodology and results.

The results of a multicenter, double-blind, placebo-controlled clinical trial of the efficacy and safety of progabide (PGB) in the treatment of partial seizures are presented. This study was performed with a number of rigorous controls not usually present in clinical trials. These included uniform co-medication in which all patients received only phenytoin and carbamazepine; concentrations of these two drugs were maintained within narrow, predefined concentration ranges. There was no statistically significant difference between PGB and placebo in seizure frequency and seizure duration for most of the analyses performed. One patient was withdrawn from the study because of hepatotoxicity. PGB was associated with a significant inhibition of phenytoin but not carbamazepine clearance. The results of this study indicate that PGB was not a potent antiepileptic drug in this population of persons with intractable epilepsy.

Adolescent↗