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Biomedical subjects

D A Frank

Publications and source records attributed to D A Frank.

At least 55 records · Page 3Linked to original sources
PubMed1997

Induction of STAT protein signaling through the CD40 receptor in B lymphocytes: distinct STAT activation following surface Ig and CD40 receptor engagement.

Cross-linking CD40 mediates B lymphocyte growth and differentiation and regulates cell death pathways by an unknown mechanism. Previous reports have suggested that protein tyrosine kinase activity is critical for CD40-mediated biologic responses. We show here that CD40 engagement on murine B cells results in the rapid tyrosine phosphorylation of the STAT6 transcription factor and the transactivation of a reporter gene containing an IFN-regulatory factor-1 STAT-binding site. In earlier studies, surface Ig engagement was found to produce rapid activation of STAT6 accompanied by later induction of STAT1, which is not observed after CD40 ligation. Thus, these results define mitogenic receptor-specific induction of STAT proteins in B cells and identify a novel and direct signal transduction pathway from the cell surface to the nucleus activated in B cells stimulated through CD40 that regulates a gene previously shown to be involved in oncogenesis and programmed cell death.

Animals↗
PubMed1997

Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway.

A mechanism by which members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor cytokine family regulate gliogenesis in the developing mammalian central nervous system was characterized. Activation of the CNTF receptor promoted differentiation of cerebral cortical precursor cells into astrocytes and inhibited differentiation of cortical precursors along a neuronal lineage. Although CNTF stimulated both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Ras-mitogen-activated protein kinase signaling pathways in cortical precursor cells, the JAK-STAT signaling pathway selectively enhanced differentiation of these precursors along a glial lineage. These findings suggest that cytokine activation of the JAK-STAT signaling pathway may be a mechanism by which cell fate is controlled during mammalian development.

Animals↗
PubMed1997

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in normal, self-renewing B-1 cells but only inducibly expressed in conventional B lymphocytes.

Cytokine and growth factor receptor engagement leads to the rapid phosphorylation and activation of latent, cytosolic signal transducers and activators of transcription (STAT) proteins, which then translocate to the nucleus where they regulate transcriptional events from specific promoter sequences. STAT3 expression in particular has been associated with Abl, Src, and HTLV-1 transformation of normal cells. B-1 lymphocytes are self-renewing, CD5+ B cells that display a propensity for malignant transformation and are the normal counterpart to human chronic lymphocytic leukemias. Further, B-1 cells are characterized by aberrant intracellular signaling, including hyperresponsiveness to phorbol ester PKC agonists. Here we demonstrate that B-1 lymphocytes constitutively express nuclear activated STAT3, which is not expressed by unmanipulated conventional (B-2) lymphocytes. In contrast, STAT3 activation is induced in B-2 cells after antigen receptor engagement in a delayed fashion (after 3 h). Induction of STAT3 is inhibited by both the serine/threonine protein kinase inhibitor H-7 and the immunosuppressive drug rapamycin and requires de novo protein synthesis, demonstrating novel coupling between sIg and STAT proteins that differs from the classical paradigm for STAT induction by cytokine receptors. The inability of prolonged stimulation of conventional B-2 cells with anti-Ig, a treatment sufficient to induce CD5 expression, to result in sustained STAT3 activation suggests that STAT3 is a specific nuclear marker for B-1 cells. Thus, STAT3 may play a role in B cell antigen-specific signaling responses, and its constitutive activation is associated with a normal cell population exhibiting intrinsic proliferative behavior.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Onlay patch repair of tracheobronchial rupture.

Two cases are reported of tracheobronchial repair in which a posteriorly based intercostal muscle flap was incorporated into the membranous portion of the airway to increase the diameter of the reconstruction or to relieve tension in the suture lines. This technique permits repair of a small left main bronchus without compromise to the lumen and tension-free repair of the membranous trachea.

Adult↗
PubMed1997

Elevated plasma norepinephrine after in utero exposure to cocaine and marijuana.

OBJECTIVE: To compare plasma catecholamine concentrations between cocaine-exposed and unexposed term newborns and to determine the relationship between plasma catecholamines and newborn behavior. METHODS: Forty-six newborn infants participating in a prospective study of the neonatal and long-term effects of prenatal cocaine exposure were studied. Based on maternal self-report, maternal urine screening, and infant meconium analysis, 24 infants were classified as cocaine-exposed and 22 as unexposed. Between 24 and 72 hours postpartum, plasma samples for norepinephrine (NE), epinephrine, dopamine, and dihydroxyphenylalanine analysis were obtained. The Neonatal Behavioral Assessment Scale was administered at 1 to 3 days of age and at 2 weeks of age by examiners masked to the drug exposure status of the newborns. RESULTS: The cocaine-exposed newborns had increased plasma NE concentrations when compared to the unexposed infants (geometric mean, 923 pg/mL vs 667 pg/mL). There were no significant differences in plasma epinephrine, dopamine, or dihydroxyphenylalanine concentrations. Analysis for the effect of potential confounding variables revealed that maternal marijuana use was also associated with increased plasma NE, although birth weight, gender, and maternal use of alcohol or cigarettes were not. Geometric mean plasma NE was 1164 pg/mL in those infants with in utero exposure to both cocaine and marijuana compared to 812 pg/mL in those exposed to only cocaine and 667 pg/mL in those exposed to neither. Among the cocaine-exposed infants, plasma NE concentration correlated with an increased score for the depressed cluster (r = .53) and a decreased score for the orientation cluster (r = -.43) of the Neonatal Behavioral Assessment Scale administered at 1 to 3 days of age. Adjusting for marijuana exposure had no effect on these relationships between plasma NE and the depressed and orientation clusters. CONCLUSION: Plasma NE is increased in newborns exposed to cocaine and marijuana. Increased plasma NE is associated with selected neurobehavioral disturbances among cocaine exposed infants at 1 to 3 days of life but not at 2 weeks.

Cannabis↗
PubMed1996

Delayed tyrosine phosphorylation and nuclear expression of STAT1 following antigen receptor stimulation of B lymphocytes.

The regulation of the STAT1 alpha transcription factor was assessed during B cell activation induced by cross-linking the surface IgM Ag receptor. Surface Ig ligation or pharmacologic stimulation with PMA and ionomycin resulted in the delayed (2-3 h after stimulation) nuclear appearance of tyrosine-phosphorylated STAT1 alpha, in contrast to the rapid induction that follows cytokine treatment. Nuclear expression of phosphorylated STAT1 alpha was abrogated by co-incubation of anti-Ig-treated B cells with the protein synthesis inhibitor cycloheximide (CHX), with the protein kinase inhibitor H-7, or with the immunosuppressive drug rapamycin. Tyrosine-phosphorylated STAT1 alpha was found to be recruited to the STAT binding site of the IFN regulatory factor-1 (IRF-1) gene promoter only after 2 to 3 h, and this association was also inhibitable by CHX and rapamycin. The arrival of STAT1 alpha coincided with attenuation of anti-Ig-induced STAT-binding activity specific for the IRF-1 promoter site, and both rapamycin and CHX treatment counteracted the loss of this activity. Furthermore, basal transcription of the endogenous IRF-1 gene was decreased as a result of anti-Ig treatment, and this effect of anti-Ig was blocked by co-incubation with rapamycin. Thus, STAT1 alpha plays a dynamic role in the composition of IRF-1 promoter-specific DNA binding complexes stimulated by B cell Ag receptor ligation, and nuclear expression of phosphorylated STAT1 alpha is regulated in a unique fashion by Ag receptor engagement. In addition, surface Ig cross-linking imparts negative regulatory control of IRF-1 gene expression, possibly through activation of STAT1 alpha.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

Antigen-receptor engagement in B cells induces nuclear expression of STAT5 and STAT6 proteins that bind and transactivate an IFN-gamma activation site.

The signal transducer and activator of transcription (STAT) family of transcription factors is triggered by cytokine and growth factor receptors in a number of cell types, and binds to a consensus sequence defined in part by the IFN-gamma activation site (GAS). It is not known whether these transcription factors respond to other kinds of growth stimuli, and, with particular relevance to lymphocytes, it is not known whether STAT proteins participate in Ag-specific responses. To determine the role of STAT proteins, coupling between Ag-receptor cross-linking and nuclear expression of DNA-binding protein complexes that recognize GAS sequences was evaluated. Ag-receptor triggering in primary B lymphocytes stimulated nuclear expression of a complex that specifically binds the IFN response factor-1 (IRF-1) GAS sequence, and is distinguished by electrophoretic mobility and GAS preference from IRF-1 GAS-binding complexes induced by IFN-gamma. Activation of nuclear IRF-1 GAS-binding activity by sIg was inhibited by the tyrosine kinase inhibitor, herbimycin A, and binding activity was eliminated by tyrosine phosphatase treatment. Activation of IRF-1 GAS-binding activity was blocked by depletion of protein kinase C. The IRF-1 GAS-binding activity induced by sIg engagement in B cells was transcriptionally active, and was found to consist of immunoreactive STAT5 and STAT6 proteins. This work demonstrates that the STAT signaling pathway previously associated with cytokine signaling is triggered in B lymphocytes through Ag-receptor engagement in a protein kinase C-dependent fashion. This heretofore described cytokine signaling pathway may play a role in bringing about Ag-specific proliferative and differentiative responses.

Animals↗
PubMed1996

Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl.

Bcr/Abl is a chimeric oncogene that can cause both acute and chronic human leukemias. Bcr/Abl-encoded proteins exhibit elevated kinase activity compared to c-Abl, but the mechanisms of transformation are largely unknown. Some of the biological effects of Bcr/Abl overlap with those of hematopoietic cytokines, particularly interleukin 3 (IL-3). Such effects include mitogenesis, enhanced survival, and enhanced basophilic differentiation. Therefore, it has been suggested that p210Bcr/Abl and the IL-3 receptor may activate some common signal transduction pathways. An important pathway for IL-3 signaling involves activation of the Janus family kinases (JAKs) and subsequent tyrosyl phosphorylation of STAT proteins (signal transducers and activators of transcription). This pathway directly links growth factor receptors to gene transcription. We analyzed JAK activation, STAT protein phosphorylation, and the formation of specific DNA-binding complexes containing STAT proteins, in a series of leukemia cell lines transformed by Bcr/Abl or other oncogenes. We also examined these events in cell lines transformed by a temperature sensitive (ts) mutant of Bcr/Abl, where the kinase activity of Abl could be regulated. STAT1 and STAT5 were found to be constitutively phosphorylated in 32D, Ba/F3, and TF-1 cells transformed by Bcr/Abl, but not in the untransformed parental cell lines in the absence of IL-3. Phosphorylation of STAT1 and STAT5 was also observed in the human leukemia cell lines K562 and BV173, which express the Bcr/Abl oncogene, but not in several Bcr/Abl-negative leukemia cell lines. Phosphorylation of STAT1 and STAT5 was directly due to the tyrosine kinase activity of Bcr/Abl since it could be activated or deactivated by temperature shifting of cells expressing the Bcr/Abl ts mutant. DNA-STAT complexes were detected in all Bcr/Abl-transformed cell lines and they were supershifted by antibodies against STAT1 and STAT5. DNA-STAT complexes in 32Dp210Bcr/Abl cells were similar, but not identical, to those formed after IL-3 stimulation. It is interesting to note that JAK kinases (JAK1, JAK2, JAK3, and Tyk2) were not consistently activated in Bcr/Abl-positive cells. These data suggest that STATs can be activated directly by Bcr/Abl, possibly bypassing JAK family kinase activation. Overall, our results suggest a novel mechanism that could contribute to some of the major biological effects of Bcr/Abl transformation.

Base Sequence↗
PubMed1996

Infants and young children in orphanages: one view from pediatrics and child psychiatry.

A large body of medical knowledge exists that can inform the public policy debate as to whether the current needs and future life prospects of poor children could better be served in orphanages than by continuing safety net programs, such as Aid to Families with Dependent Children, Medicaid, and Supplemental Social Security Income, which maintain children in families. This special article explores a century of pediatric and child psychiatry research covering five areas of potential biologic and social risk to infants and young children in orphanage care: (1) infectious morbidity, (2) nutrition and growth, (3) cognitive development, (4) socioaffective development, and (5) physical and sexual abuse. These data demonstrate that infants and young children are uniquely vulnerable to the medical and psychosocial hazards of institutional care, negative effects that cannot be reduced to a tolerable level even with massive expenditure. Scientific experience consistently shows that, in the short term, orphanage placement puts young children at increased risk of serious infectious illness and delayed language development. In the long term, institutionalization in early childhood increases the likelihood that impoverished children will grow into psychiatrically impaired and economically unproductive adults.

Child↗
PubMed1996

Late dose-response effects of prenatal cocaine exposure on newborn neurobehavioral performance.

OBJECTIVE: To determine in a representative sample of full-term urban newborns of English-speaking mothers whether an immediate or late dose-response effect could be demonstrated between prenatal cocaine exposure and newborn neurobehavioral performance, controlling for confounding factors. METHODS: The Neonatal Behavioral Assessment Scale (NBAS) was administered by masked examiners to a total sample of 251 clinically healthy, full-term infants at 2 days and/or 17 days. Three in utero cocaine exposure groups were defined: heavily exposed (n = 44, > 75th percentile self-reported days of use during pregnancy and/or > 75th percentile of meconium benzoylecognine concentration); lightly exposed (n = 79, less than both 75th percentiles); and unexposed (n = 101, no positive biological or self-report marker). At the 3-week examination there were 38 heavily exposed, 73 lightly exposed, and 94 unexposed infants. Controlling for infant birth weight, gestational age, infant age at the time of examination, mothers' age, perinatal risk, obstetric medication, and alcohol, marijuana, and cigarette use, a regression analysis evaluated the effects of levels of cocaine exposure on NBAS performance. RESULTS: No neurobehavioral effects of exposure on the newborn NBAS cluster scores or on the qualifier scores were found when confounders were controlled for at 2 to 3 days of age. At 3 weeks, after controlling for covariates, a significant dose effect was observed, with heavily exposed infants showing poorer state regulation and greater excitability. CONCLUSIONS: These findings demonstrate specific dose-related effects of cocaine on 3-week neurobehavioral performance, particularly for the regulation of arousal, which was not observed in the first few days of life.

Cannabis↗
PubMed1996

BCR/abl leads to the constitutive activation of Stat proteins, and shares an epitope with tyrosine phosphorylated Stats.

The mechanism by which BCR/abl leads to the transformation of hematopoietic cells is not understood. The introduction of BCR/abl into BaF3 cells, an IL-3-dependent pro-lymphocytic cell line, abrogates the requirement of IL-3 for growth. Given that IL-3 leads to the phosphorylation of Stat proteins, we tested the hypothesis that BCR/abl transformation of hematopoietic cells induces the phosphorylation of Stats. We found that BaF3 cells transformed by either the p190 or p210 forms of BCR/abl possess constitutively phosphorylated Stat1 and Stat5. Phosphorylation of Stat proteins was greater in cells transformed by p190 BCR/abl than in cells transformed by p210 BCR/abl, suggesting that the magnitude of phosphorylation of Stat proteins may play a role in the biological effects of BCR/abl. Expression of BCR/abl containing a mutation (Y177F) that prevents its interaction with GRB2 led to a decrease in the phosphorylation of Stat1 and Stat5. This suggested that GRB2, or its binding site on BCR/abl, may participate in the phosphorylation of Stat proteins. We also observed that the anti-phospho-Stat antibody directly recognized both the p190 and p210 forms of BCR/abl. This indicated that a tyrosine residue that becomes phosphorylated in BCR/abl may share homology with the tyrosine phosphorylation site of Stat1 and Stat5. These findings may have implications for the mechanisms by which BCR/abl interacts with signaling pathways to confer growth factor independence and induce transformation of hematopoietic cells.

Animals↗
PubMed1996

Signal transduction pathways activated by ciliary neurotrophic factor and related cytokines.

Neuropoietic cytokines such as ciliary neurotrophic factor, leukemia inhibitory factor, and interleukin-6 are known to be responsible for a wide variety of effects on cells of the immune and nervous systems. The mechanisms by which such diverse effects are regulated and coordinated within cells is of central importance to the understanding of how these molecules function during development. This review discusses the receptor complexes through which neuropoietic cytokines signal and the mechanisms by which activation of specific enzymes such as the Jak family of kinases are transduced into changes of gene expression through molecules such as the Stat proteins. This review also discusses how this JAK-Stat signaling pathway is thought to interact with other known cascades, such as the mitogen-activated protein kinase pathway.

Animals↗
PubMed1995

Identification of a viability domain in the granulocyte/macrophage colony-stimulating factor receptor beta-chain involving tyrosine-750.

The granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor (GMR) is a heterodimeric receptor expressed by myeloid lineage cells. In this study we have investigated domains of the GMR beta-chain (GMR beta) involved in maintaining cellular viability. Using a series of nested GMR beta deletion mutants, we demonstrate that there are at least two domains of GMR beta that contribute to viability signals. Deletion of amino acid residues 626-763 causes a viability defect that can be rescued with fetal calf serum (FCS). Deletion of residues 518-626, in contrast, causes a further decrement in viability that can be only partially compensated by the addition of FCS. GMR beta truncated proximal to amino acid 517 will not support long-term growth under any conditions. Site-directed mutagenesis of tyrosine-750 (Y750), which is contained within the distal viability domain, to phenylalanine eliminates all demonstrable tyrosine phosphorylation of GMR beta. Cell lines transfected with mutant GMR beta (Y750-->F) have a viability disadvantage when compared to cell lines containing wild-type GMR that is partially rescued by the addition of FCS. We studied signal transduction in mutant cell lines in an effort to identify pathways that might participate in the viability signal. Although tyrosine phosphorylation of JAK2, SHPTP2, and Vav is intact in Y750-->F mutant cell lines, Shc tyrosine phosphorylation is reduced. This suggests a potential role for Y750 and potentially Shc in a GM-CSF-induced signaling pathway that helps maintain cellular viability.

Animals↗
PubMed1995

Interleukin 2 signaling involves the phosphorylation of Stat proteins.

One of the most important cytokines involved in immune response regulation is interleukin 2 (IL-2), a potent activator of the proliferation and function of T lymphocytes and natural killer cells. The mechanisms by which the effects of IL-2 are propagated within cells are not understood. While the binding of IL-2 to its receptor was recently shown to lead to the activation of two kinases, Jak-1 and Jak-3, subsequent steps in the signaling pathway to the nucleus that lead to the activation of specific genes had not been characterized. Since many cytokines that activate Jak kinases also lead to the tyrosine phosphorylation and activation of members of the Stat family of transcription factors, the ability of IL-2 to trigger Stat phosphorylation was examined. Exposure of activated human T lymphocytes or of a natural killer cell line (NKL) to IL-2 leads to the phosphorylation of Stat1 alpha, Stat1 beta, and Stat3, as well as of two Stat-related proteins, p94 and p95. p94 and p95 share homology with Stat1 at the phosphorylation site and in the Src homology 2 (SH2) domain, but otherwise are immunologically distinct from Stat1. These Stat proteins were found to translocate to the nucleus and to bind to a specific DNA sequence. These findings suggest a mechanism by which IL-2 binding to its receptor may activate specific genes involved in immune cell function.

Blotting, Western↗
PubMed1995

Housing subsidies and pediatric undernutrition.

OBJECTIVE: To test the hypothesis that receipt of housing subsidies by poor families is associated with improved nutritional status of their children. DESIGN: Cross-sectional study. SETTING: Pediatric emergency department of an urban municipal hospital. PATIENTS: Convenience sample of 203 children younger than 3 years and their families who were being seen during one of twenty-seven 24-hour periods. MAIN OUTCOME MEASURES: Anthropometric indicators (z scores of weight for age, weight-for-height, and height-for-age), and the proportion of children with low growth indicator (weight-for-height below the 10th percentile or height-for-age below the fifth percentile, or both, of the reference population). RESULTS: Multivariate analysis controlling for demographics and program participation showed that receipt of housing assistance contributed significantly to z scores for weight-for-age (P = .03) and weight-for-height (P = .04). The risk of a child's having low growth indicators was 21.6% for children whose families were on the waiting list for housing assistance compared with 3.3% for those whose families received subsidies (adjusted odds ratio = 8.2, 95% confidence interval = 2.2 to 30.4, P = .002) CONCLUSION: Receiving a housing subsidy is associated with increased growth in children from low-income families, an effect that is consistent with a protective effect of housing subsidies against childhood undernutrition.

Child Nutrition Disorders↗
PubMed1995

Relation between meconium concentration of the cocaine metabolite benzoylecgonine and fetal growth.

Among 95 term infants with benzoylecgonine, the cocaine metabolite, detectable in their meconium, there was an inverse relation between the concentration of benzoylecgonine and birth weight, length, and head circumference. Multiple regression analysis confirmed these relations after controlling for gestational age and maternal use of marijuana, cigarettes, and alcohol. These data suggest a dose-response relation between the magnitude of prenatal cocaine exposure and impaired fetal growth.

Birth Weight↗