Search PubMed⌕ Search

Biomedical subjects

M Carroll

Publications and source records attributed to M Carroll.

At least 73 records · Page 4Linked to original sources
PubMed1997

Receptors that induce erythroid differentiation of Ba/F3 cells: structural requirements and effect on STAT5 binding.

Ectopic expression of the erythropoietin receptor (EpoR) in the interleukin-3 (IL-3)-dependent cell line Ba/F3 results in growth and partial erythroid differentiation in Epo. In contrast, introduction and activation of the interleukin-5 receptor (IL-5R) or of the granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) results in proliferation only. As this effect is specific to the EpoR, the role of its extracellular or cytoplasmic domain in differentiation was tested after construction of two chimeric receptors. One receptor contained the extracellular domain of EpoR fused to the endodomain of IL-3R beta-chain (E/beta), while the other contained the EpoR cytoplasmic region fused to the extracellular domain of GM-CSFR alpha-chain (GMER). Surprisingly, both receptors induced differentiation ruling out a strict specificity of the extracellular or cytoplasmic region of EpoR in this process. Instead the ability to signal differentiation correlated with structural features shared by the EpoR, GMER, and E/beta receptors. Dimerization of all three receptors results in the pairing of two signal transducing chains in the cytoplasm, in contrast to the mitogenic receptors IL-3R, IL-5R, GM-CSFR, which assemble as alphabeta heterodimers. Two new chimeric receptors that fulfilled the structural requirement exemplified by EpoR, but lacked any part of EpoR, were designed to consolidate this model. They consisted of the ectodomains of the GMR-alpha and IL-5R alpha, respectively, fused to the endodomain of IL-3R beta-chain. Both receptors were as effective as EpoR in signaling differentiation in response to their cognate ligand. Another property of receptors fulfilling these structural requirements is that they cause a marked delay in signal transducers and activators of transcription 5 (STAT5) activation on ligand stimulation. Taken together our studies show that structural assembly of receptors dictates their potential to signal erythroid differentiation in Ba/F3 cells, that differentiation can take place in the absence of Epo and that a delay in STAT5 activation is highly predictive of this process.

Base Sequence↗
PubMed1997

Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors.

A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/ m2 per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R2 = 0.71, n = 18, P < 0.0001). The mean +/- SE concentrations were 93 +/- 16, 230 +/- 6 and 302 +/- 27 microM at 1, 2 and 3.2 g/m2 per day, respectively. The mean +/- SE renal and nonrenal clearances of hydroxyurea were 2.14 +/- 0.18 and 3.39 +/- 0.28 l/h per m2 (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean +/- SE half-life of 3.25 +/- 0.18 h (n = 17). The steady-state concentration of hydroxyurea was > 200 microM in all nine patients treated at 2 g/m2 per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents.

Adult↗
PubMed1997

Tradeoff of semantic relatedness and degree of overlearning: differential effects on metamemory and on long-term retention.

We investigated people's recall and recognition of, and Judgments of Learning (JOLs) and Feelings of Knowing (FOKs) about: (a) pairs of related words that were learned to a criterion of two correct recalls (criterion-learned/related) versus (b) pairs of unrelated words that were learned to a criterion of eight correct recalls (overlearned/unrelated). Recall, FOK on unrecalled targets, and recognition were tested at either (between-subjects variable) two or six weeks after learning. In Experiment 1, subjects JOLs were greater in magnitude for criterion-learned/related items than for overlearned/unrelated items, and they predicted that recall would be the same after a 2-week retention interval as after a 6-week retention interval (between-subjects prediction). In contrast, however, subsequent recall was greater on the 2-week retention test than on the 6-week retention test and was greater for the overlearned/unrelated items than for the criterion-learned/related items; also, subjects' FOKs (and recognition performance) were greater in magnitude for the overlearned/unrelated items than for the criterion-learned/related items. Experiment 2 revealed that the overweighting of the importance of relatedness disappears from JOLs when those JOLs occur one day after the acquisition session. These findings imply that the information tracked by metacognitive monitoring judgments is different for JOLs than for FOKs, with the JOLs (relative to FOKs) based more on semantic relatedness and less on the degree of learning during acquisition. Also, subjects' JOLs are not particularly good at accurately forecasting their eventual level of recall on long-term retention tests that occur several weeks after acquisition.

Adult↗
PubMed1997

The effect of context and metamemory judgements on automatic processes in memory.

These experiments examine two aspects of the automatic influences on memory as measured by target responding in the exclusion condition within the process dissociation framework. In Experiment 1, we examine the extent to which congruency between study and test contexts affects automatic processes in memory. In Experiment 2, we investigate qualitative differences in consciously controlled and automatic processing as indexed by metamemory judgements. In both experiments, a process-dissociation procedure was used to separate automatic and consciously controlled uses of memory in a stem completion task. In the study phase of Experiment 1, subjects read a passage from one of two directed perspectives. The subsequent stem completion task, which subjects performed while mindful of the study perspective, contained (a) old words congruent with the directed perspective, (b) old words congruent with a different (non-directed) perspective, and (c) words that had not been presented. Estimates of automatic influences for words congruent with the directed perspective were found to be greater than estimates for words incongruent with the directed perspective. These results provide evidence for the automatic or unconscious influences of meaning on task performance, which is uncontaminated by the influence of consciously controlled recollection which may occur in indirect memory tests. In Experiment 2, judgements of learning made prior to retrieval under inclusion and exclusion instructions were found to be different for consciously controlled and automatic processes, suggesting that memory as measured by the opposition (exclusion) procedure is involuntary and unconscious, with prospective monitoring of performance not sensitive to eventual performance.

Automatism↗
PubMed1997

Auditory context and memory retrieval in young infants.

Three-month-old infants were trained to move an overhead crib mobile while 1 of 2 musical selections was played. Retention was assessed 1 or 7 days later in the presence of either the same music or a different musical selection. In Experiment 1, the musical selections were very different (classical versus jazz); in Experiment 2, they were much more similar (two classical pieces). Infants in both experiments displayed 1 day retention regardless of which music was played during the retention test. At 7 days, retention was seen only when the music played during the retention test matched the training music. These data are consistent with similar findings showing that 3-month-old infants' memory is disrupted at long retention intervals when the context present during retention testing does not match the learning context. As the infant's memory wanes, context appears to function as a necessary cue for the retrieval of acquired expectancies.

Association Learning↗
PubMed1996

The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways.

The TEL/PDGF beta R fusion protein is the product of the t(5;12) translocation in patients with chronic myelomonocytic leukemia. The TEL/PDGF beta R is an unusual fusion of a putative transcription factor, TEL, to a receptor tyrosine kinase. The translocation fuses the amino terminus of TEL, containing the helix-loop-helix (HLH) domain, to the transmembrane and cytoplasmic domain of the PDGF beta R. We hypothesized that TEL/PDGF beta R self-association, mediated by the HLH domain of TEL, would lead to constitutive activation of the PDGF beta R tyrosine kinase domain and cellular transformation. Analysis of in vitro-translated TEL/ PDGF beta R confirmed that the protein self-associated and that self-association was abrogated by deletion of 51 aa within the TEL HLH domain. In vivo, TEL/PDGF beta R was detected as a 100-kDa protein that was constitutively phosphorylated on tyrosine and transformed the murine hematopoietic cell line Ba/F3 to interleukin 3 growth factor independence. Transformation of Ba/F3 cells required the HLH domain of TEL and the kinase activity of the PDGF beta R portion of the fusion protein. Immunoblotting demonstrated that TEL/PDGF beta R associated with multiple signaling molecules known to associate with the activated PDGF beta R, including phospholipase C gamma 1, SHP2, and phosphoinositol-3-kinase. TEL/PDGF beta R is a novel transforming protein that self-associates and activates PDGF beta R-dependent signaling pathways. Oligomerization of TEL/PDGF beta R that is dependent on the TEL HLH domain provides further evidence that the HLH domain, highly conserved among ETS family members, is a self-association motif.

DNA-Binding Proteins↗
PubMed1996

Eosinophil recruitment following allergen challenge is associated with the release of the chemokine RANTES into asthmatic airways.

Eosinophil infiltration of the airways in response to allergen exposure is a characteristic of bronchial asthma. However, the mechanisms by which these cells are recruited are poorly understood. We have investigated the presence of eosinophil chemotactic activity (ECA) in bronchoalveolar lavage fluid obtained from allergic asthmatics (n = 6) 4 h after endobronchial allergen challenge. ECA was purified by sequential heparin affinity chromatography and reverse-phase HPLC. A single peak of ECA was detected; SDS-PAGE and Western blot analysis showed that the peak contained a protein of 8 kDa and corresponded to the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted). Consistent with this, the ECA was neutralized by an Ab to RANTES. Measurement of RANTES by ELISA in 10x concentrated bronchoalveolar lavage fluid showed increased levels of this chemokine at the allergen site (median, 187 pg/ml; range, 46-263 pg/ml) in comparison with a saline challenge control site (median, 32.5 pg/ml; range, 11-94 pg/ml), P < 0.005. Furthermore, there was a significant correlation between concentrations of immunoreactive RANTES and the number of eosinophils at the allergen challenge site (r = 0.8; p < 0.001), but not at the saline site (r = 0.2; p = 0.12). These results suggest that RANTES in involved in the recruitment of eosinophils into the asthmatic airways after allergen challenge.

Adult↗
PubMed1996

DUB-1, a deubiquitinating enzyme with growth-suppressing activity.

Cytokines regulate cell growth by inducing the expression of specific target genes. Using the differential display method, we have cloned a cytokine-inducible immediate early gene, DUB-1 (for deubiquitinating enzyme). DUB-1 is related to members of the UBP superfamily of deubiquitinating enzymes, which includes the oncoprotein Tre-2. A glutathione S-transferase-DUB-1 fusion protein cleaved ubiquitin from a ubiquitin-beta-galactosidase protein. When a conserved cysteine residue of DUB-1, required for ubiquitin-specific thiol protease activity, was mutated to serine (C60S), deubiquitinating activity was abolished. Continuous expression of DUB-1 from a steroid-inducible promoter induced growth arrest in the G1 phase of the cell cycle. Cells arrested by DUB-1 expression remained viable and resumed proliferation upon steroid withdrawal. Our results suggest that DUB-1 regulates cellular growth by modulating either the ubiquitin-dependent proteolysis or the ubiquitination state of an unknown growth regulatory factor(s).

Amino Acid Sequence↗
PubMed1996

Colonic ulceration associated with nonsteroidal anti-inflammatory drugs. Report of three cases.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a variety of gastrointestinal side effects. Effects on the large intestine have been reported with increasing frequency. Recognition of NSAID-induced colonic lesions has been confounded by variable clinical presentations, variable pathologic findings, and unfamiliarity of this entity among clinicians. We have recently seen three cases of NSAID-induced cecal ulcerations in patients undergoing right colectomy. A correct preoperative diagnosis was not made in our patients, one of whom presented with an acute abdomen and two in whom there was an inability to rule out carcinoma. The gross, radiographic, and histologic findings in each case consisted of a characteristic transverse ulceration with thin diaphragm-like scarring. NSAID-induced cecal ulcers can have a variety of presentations to the general surgeon, are likely to be misdiagnosed preoperatively, but may be recognized based on characteristic gross features evident by radiography and colonoscopy, along with a careful history. Review of recent literature suggests that laparotomy can be avoided when diagnosis is considered, but operation is indicated for complications, such as hemorrhage, obstruction, or perforation, and when carcinoma cannot be adequately excluded.

Abdomen, Acute↗
PubMed1996

Inflammatory and T-cell profile of asthmatic airways 6 hours after local allergen provocation.

T cells in the airways are considered to play a key role in orchestrating the inflammatory response of asthma through the elaboration of specific cytokines. Using flow cytometry we have investigated the T-cell response of sensitized asthmatic airways 6 h after local allergen provocation. Twelve subjects with atopic asthma underwent bronchoalveolar lavage (BAL) before and 6 h after local instillation of allergen into the right middle lobe (RML) and saline into the right upper lobe (RUL). Allergen challenge produced a significant 26% fall in FEV1, an increase in eosinophils in BAL at 6 h, and at 24 h an increase in methacholine responsiveness compatible with late-phase airway inflammation. When compared with saline challenge, allergen produced an overall decrease in the number of BAL lymphocytes from 21.3 +/- 2.8% to 16.0 +/- 3.08% of total cells but no change in the proportion of CD4+, CD8+, CD25+, or HLA-DR+ cells. Allergen provocation reduced the proportion of T cells expressing the beta 2 integrin lymphocyte functional antigen-1 (LFA-1) from 72.5 +/- 30 to 43.9 +/- 9.1 mean fluorescent units (p < 0.01) and a similar trend in intercellular adhesion molecule-1 (ICAM-1) (p = 0.08). These results indicate that late-phase inflammatory events 6 h after local allergen provocation involve the selective retention of airway T cells expressing specific cell adhesion molecules.

Adult↗
PubMed1996

Association of cocaine and methamphetamine use with giant gastroduodenal ulcers.

OBJECTIVES: Giant gastric and duodenal ulcers (>2-3 cm in greatest dimension) are reported to have higher rates of complication and mortality and to be associated with increasing age, renal failure, and use of nonsteroidal antiinflammatory drugs (NSAIDs). This study investigated the outcome and associations of gastric and duodenal ulcers >2.5 cm compared to ulcers of lesser size. METHODS: Records from all patients with gastric and duodenal ulcers >0.5 cm diagnosed by upper endoscopy between January 1994 and September 1995 were studied for evidence of concurrent use of aspirin, NSAIDs, methamphetamine, and cocaine, as well as for transfusion requirements, length of hospital stay, mortality, surgery, rebleeding, Helicobacter pylori infection, and malignancy. RESULTS: A logistic regression analysis of the 220 patients identified revealed that recent methamphetamine and/or cocaine use was significantly predictive of giant ulcer formation (p = 0.0002) with an odds ratio of 9.66. Also significant was younger age (p = 0.026) and aspirin or NSAID use (p = 0.046). H. pylori infection was significant only for giant gastric ulcers (p = 0.031). Ulcer size did not predict mortality, rate of rebleeding, requirement for surgery, transfusion requirements, or length of hospital stay. However, giant gastric ulcers were significantly more likely to be malignant (p = 0.002). CONCLUSIONS: Giant gastric and duodenal ulcers were strongly associated with stimulant abuse. They were also associated with younger age and use of aspirin or NSAIDs. Additionally, giant gastric ulcers were associated with malignancy and H. pylori infection. Ulcer size did not predict rate of complications or outcome.

Adolescent↗
PubMed1996

The beta c component of the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3)/IL-5 receptor interacts with a hybrid GM-CSF/erythropoietin receptor to influence proliferation and beta-globin mRNA expression.

BACKGROUND: The interaction of different members of the hematopoietic growth factor receptor family may be relevant to the increased proliferation and the failure of differentiation that characterizes the myeloid leukemias. We recently demonstrated that a chimeric receptor (GMER) that is composed of the extracellular and transmembrane domains of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha-chain (GMR alpha) and the cytoplasmic domain of the murine erythropoietin receptor mEpoR binds hGM-CSF with low affinity (3 nM) and confers both proliferative and differentiation signals to stably transfected murine Ba/F3 cells. MATERIALS AND METHODS: To investigate whether the common beta-subunit of the GM-CSF receptor (beta c) can interact with GMER, either the entire beta-subunit or a mutant, truncated beta-subunit that completely lacks the cytoplasmic domain (beta tr) was introduced into Ba/F3 cells that express GMER, and the binding of GM-CSF as well as proliferation and differentiation responses were measured. RESULTS: Scatchard analysis showed that both GMER + beta c and GMER + beta tr bound hGM-CSF with high affinity (Kd 40 pM to 65 pM). Proliferation assays showed that the maximum growth of cells expressing GMER + beta c was identical to that of cells with GMER alone. However, proliferation of the cells that expressed GMER + beta tr was reduced by 80-95% of GMER. Dose-response curves showed that the concentration of GM-CSF required for half-maximal growth was 0.5-5.0 pM for GMER + beta c and 0.5-5 nM for GMER and GMER + beta tr. The EpoR cytoplasmic domain of GMER also undergoes ligandinducible tyrosine phosphorylation. However, the tyrosine phosphorylation did not correlate with growth in cells expressing beta tr. Coexpression of beta c with GMER in Ba/F3 cells grown in hGM-CSF markedly enhanced beta-globin mRNA expression. CONCLUSIONS: These results indicate that beta c can transduce a unique signal in association with GMER to influence both proliferative and differentiation signal pathways.

Animals↗
PubMed1995

Erythropoietin-induced cellular differentiation requires prolongation of the G1 phase of the cell cycle.

Erythropoietin (EPO), like many other hematopoietic growth factors, can induce either growth or differentiation of hematopoietic cells. Little is known about the molecular basis of this cellular decision, in part because of a paucity of cell lines in which these two phenomena can be dissociated. Ectopic expression of the EPO receptor (EPO-R) in Ba/F3, a murine interleukin 3 (IL-3)-dependent progenitor cell line, confers EPO-dependent cell growth. In these cells (Ba/F3-EPO-R), EPO also induces beta-globin mRNA, a specific marker of erythroid differentiation. Here we show that the induction of erythroid differentiation by EPO requires a delay in cell growth and a prolongation of the (G1) phase of the cell cycle. Interestingly, this effect on G1 prolongation was concentration dependent. At low EPO concentrations (0.05-0.1 unit of EPO per ml; 1 pM EPO = 0.01 unit of EPO per ml), EPO prolonged G1 and induced differentiation; at high concentrations (0.5-10.0 units per ml), EPO shortened G1 and preferentially stimulated growth. IL-3 stimulated Ba/F3 growth but not differentiation at all growth factor concentrations ranging from 0.1 to 500 pM. Moreover, IL-3 suppressed EPO-induced beta-globin induction in a dose-dependent manner. This suppression correlated with the shortening of G1 by IL-3. Taken together, these data demonstrate distinct effects of EPO and IL-3 and a balance between erythroid growth and differentiation that is cell cycle dependent.

Animals↗
PubMed1995

Duodenal leiomyosarcoma.

Two cases of duodenal leiomyosarcoma were encountered, both of which appeared benign by gross and histologic criteria. Both patients suffered recurrences with poor outcomes. We reviewed the literature and found four other such cases and examined the outcomes in the world literature with respect to tumor size and extent of surgical resection. Large size, limited resections, and local recurrence were associated with poor outcomes. A 6% rate of lymphatic metastases was found, and the bearing this has on the extent of resection is discussed.

Adult↗
PubMed1995

The treatment of postanaesthetic shivering: a double blind comparison between alfentanil and pethidine.

It has been postulated that pethidine may mediate its effects on postanaesthetic shivering (PAS) via kappa-opioid receptors. However, clinical evidence indicates that alfentanil, a pure mu-agonist, may also have beneficial effects on PAS. In order to assess whether opioid effects on PAS are effected via kappa receptors, fifty-one patients were randomised to receive alfentanil 250 micrograms (n = 18), pethidine 25 mg (n = 18) or placebo (n = 15) on a double-blind basis for the treatment of established postanaesthesia shivering (PAS). Both drugs proved significantly better in treating PAS than placebo (P < 0.005). Following treatment, blood pressure fell and oxygen saturation increased in patients in the two treatment groups when compared with the control group (P < 0.05). There was a highly significant incidence of reshivering in the alfentanil treated group (P < 0.005). In conclusion, the high incidence of reshivering indicates that alfentanil is unlikely to supercede pethidine in the treatment of PAS, but its initial success rate implies that pethidine's anti-shivering effect is unlikely to be mediated via kappa-opioid receptors.

Adolescent↗
PubMed1995

Phase I trial of carboplatin and infusional cyclosporin in advanced malignancy.

PURPOSE: To determine the maximal-tolerated dose (MTD) of infusional cyclosporine (CSA) with fixed-dose carboplatin (CBDCA). PATIENTS AND METHODS: Clonogenic cytotoxicity assays were performed to assess the effect of CSA on reversal of resistance to CBDCA. The phase I study was performed in three phases. In phases 1 and 2, escalating-dose CSA (5, 7.5, 8.8, or 9.5 mg/kg/d) with fixed-dose CBDCA 300 or 250 mg/m2 were administered. Phase 3 required an initial cycle of CBDCA 250 mg/m2 alone, followed by combination therapy with CBDCA 250 mg/m2 and CSA (8.8, 9.5, or 10.0 mg/kg/d). RESULTS: Preincubation of platinum-resistant A2780 human ovarian cancer cells with CSA 2 micrograms/mL significantly enhanced CBDCA cytotoxicity in clonogenic assays. Fifty-one patients received 130 courses of therapy. The phase 1 MTD was thrombocytopenia (CSA 7.5 mg/kg/d and CBDCA 300 mg/m2) attributable to the effects of CBDCA alone. The phase 2 MTD was reversible nephrotoxicity (serum creatinine elevations to 3.6 and 4.4 mg/dL) and neutropenia (CSA 9.5 mg/kg/d and CBDCA 250 mg/m2). In phase 3, headache was observed in five patients and hypertension in one patient at CSA 10 mg/kg/d. The expected change in platelet count predicted for CBDCA alone was compared with the actual change; no excessive thrombocytopenia was observed with addition of CSA. Steady-state CSA levels of 2 micrograms/mL capable of reversing platinum resistance in vitro were observed. Four objective responses were observed. CONCLUSION: CSA is effective in reversing CBDCA resistance in A2780 ovarian cancer cells. Short-term infusions of CSA < or = 8.8 mg/kg/d in combination with CBDCA are well-tolerated for heavily pretreated patients and result in CSA levels known to reverse CBDCA resistance in vitro.

Adult↗