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Biomedical subjects

R E Gallagher

Publications and source records attributed to R E Gallagher.

At least 37 records · Page 2Linked to original sources
PubMed1995

Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.

All-trans-retinoic acid induces acute promyelocytic leukemia cell differentiation in vitro, and it produces greater than 90% complete remissions in patients with acute promyelocytic leukemia. Despite the high response rate, the majority of patients relapse with continued trans-retinoic acid therapy, and disease progression has been observed to be accompanied by an increase in the metabolism of trans-retinoic acid in the patients. In this study, the pharmacokinetic disposition of trans-retinoic acid was determined by HPLC in patients with acute promyelocytic leukemia before and after concurrent therapy with the triazole antimycotic agent fluconazole. Treatment with trans-retinoic acid for 1 week reduced the area under the plasma trans-retinoic acid concentration vs time curve in one patient by 67%, from 277 to 91 ng/mL/hr. Trans-retinoic acid pharmacokinetics were repeated after the second dose of fluconazole, administered 1 hour prior to the retinoid, and the AUC was found to be 401 ng/mL/hr, a greater than 4-fold increase from the pre-fluconazole level. A similar, though more modest, effect of fluconazole was seen in a second acute promyelocytic leukemia patient. The effect of fluconazole on trans-retinoic acid metabolism was examined in vitro using isolated human hepatic microsomes. Fluconazole inhibited the NADPH-dependent cytochrome P450-mediated catabolism of trans-retinoic acid in a concentration-dependent manner. Although fluconazole was approximately one-half as potent an inhibitor when compared with ketoconazole, a related antifungal drug, 60-90% inhibition was observed at the concentrations of fluconazole measured in the acute promyelocytic leukemia patients. Neither fluconazole nor ketoconazole inhibited lipid hydroperoxide-mediated metabolism of trans-retinoic acid. Since fluconazole is a well-tolerated agent frequently administered to leukemia patients, its use in combination with trans-retinoic acid merits further consideration.

Adult↗
PubMed1995

Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid.

Of 113 acute promyelocytic leukemia cases documented to have diagnostic PML-RAR alpha hybrid mRNA, 10 cases (8.8%) had fusion sites in PML gene exon 6 (V-forms) rather than in the two common hybrid mRNA configurations resulting from breaksites in either PML gene intron 6 (L-forms) or intron 3 (S-forms). In 4 V-form cases, a common break/fusion site was discovered at PML gene nucleotide (nt) 1685, abutting a 3' cryptic splice donor sequence. The fusion site was proximal to the common site in 1 case and more distal in 5 cases. The open reading frame encoding a PML-RAR alpha gene was consistently preserved, either by an in-frame fusion site or by the insertion of 3 to 127 unidentified nts. In 2 V-form cases, hybridization analysis of the reverse transcriptase-polymerase chain reaction products with a PML-RAR alpha juction probe was required for discrimination from L-form cases. Two V-form subgroups were defined by in vitro sensitivity to all-trans retinoic acid (tRA)-induced differentiation: 4 of 4 cases tested with fusion sites at or 5' to nt 1685 (subgroup E6S) had reduced sensitivity (EC50 > or = 10(-7) mol/L), whereas 4 of 4 cases with fusion sites at or 3' to nt 1709 (subgroup E6L) had high sensitivity (EC50 < 10(-8) mol/L) indistinguishable from that of L-form and S-form cases. These results provide the first link between PML-RAR alpha configuration and tRA sensitivity in vitro and support the importance of subclassifying APL cases according to PML-RAR alpha transcript type.

Adult↗
PubMed1995

Estimating cancer screening indicators in the primary care setting.

The software "Profile: A Cancer Risk Profile of Your Patient Practice" was used to estimate cancer screening activities in a primary care practice. "Profile" is a public health tool that does not track the screening histories of individual patients, but rather, using a sampling strategy, provides estimates for the entire practice of the age and sex specific number of screening eligible patients, the number screened, and the number that should have been screened, based on National Cancer Institute/American Cancer Society (NCI/A CS) guidelines. This report describes "Profile," and the results it generated from a sample of medical records. Primary care providers who seek to integrate primary and secondary cancer prevention activities into their routine practices will find it useful to have an objective estimate of their current level of such activities.

Adult↗
PubMed1995

A comprehensive cognitive-behavioral/educational program for schizophrenic patients.

Modern treatment of schizophrenia emphasizes pharmacology and nonspecific rehabilitative strategies, but there is renewed interest in psychologically oriented treatments as well. Borrowing from dynamic, cognitive-behavioral, and psychoeducational traditions, the authors describe a program aimed at teaching patients with schizophrenia about their illness and at addressing key cognitive, social, and emotional areas of difficulty from which they generally suffer. The authors document the enthusiasm of the patients for such an approach and provide a case example.

Adult↗
PubMed1994

Retinoic acid-resistant HL-60 cells exclusively contain mutant retinoic acid receptor-alpha.

Sequence analysis of the retinoic acid receptor-alpha (RAR alpha) gene from a subline of HL-60 cells (RA-res) stably resistant to all-trans retinoic acid (RA) disclosed a single-base change in codon number 411, the same C to T transition previously reported in an independently selected HL-60 RA resistant clone by Robertson et al (Blood 80:1885, 1992). This mutation eliminates a FokI restriction endonuclease site. Using primers framing this mutation in exon 9 of the RAR alpha gene, we showed that polymerase chain reaction products amplified from either mRNA or genomic DNA templates from the RA-res subline were completely resistant to FokI digestion whereas those from wild-type (wt) HL-60 cells could be digested to completion. The lack of a normal allele in the RA-res cells was confirmed by mixing experiments and hybridization analyses. Southern blot analysis of DNA from the RA-res and wt cells versus control placental DNA indicated that the RAR alpha gene is not haploid. The independent isolation of the same RAR alpha mutation in different laboratories suggests either that the mutation exits in a small subpopulation in the wt line or that this is a mutational "hot spot." Furthermore, the results indicate that if a dominant negative mode of resistance is involved in the RA-res subline, this must involve interference with the function of heterologous receptor proteins such as the retinoid X receptors. The lack of any normal RAR alpha in this subline may facilitate studies of the mode of action of retinoids.

Alleles↗
PubMed1994

Effect of retinoic acid and interferon alpha on granulocyte-macrophage colony forming cells in chronic myeloid leukemia: increased inhibition by all-trans- and 13-cis-retinoic acids in advanced stage disease.

Granulocyte-macrophage colony forming units (CFU-GM) from patients with advanced stage chronic myelogenous leukemia (CML), i.e. in blastic crisis (BC) or accelerated phase (AP), were inhibited by all-trans-retinoic acid (tRA) approximately 1000-fold more potently than those from chronic phase (CP) CML patients (median IC50 = 10(-9) M tRA for six CML-AP/BC cases vs > 10(-6) M tRA for seven CML-CP cases). A similar activity pattern was observed for the stereoisomer 13-cis-RA (cRA). There was no apparent correlation of CFU-GM retinoid sensitivity with cloning efficiency or other colony characteristics. Interferon alpha-2a (INF alpha) alone strongly inhibited CFU-GM growth in all four CML-AP/BC cases (IC50 < or = 250 IU/ml) and three out of seven CML-CP cases (IC50 < or = 500 IU/ml), but there was little or no interactive effect between various concentrations of tRA and INF alpha (50 IU/ml) on CFU-GM from either CML-AP/BC or CML-CP cases. These results suggest that CML-AP/BC CFU-GM have some intrinsic molecular alteration(s) which markedly enhances their responsiveness to tRA and cRA, which may be clinically exploitable.

Adult↗
PubMed1994

Stages of group psychotherapy supervision: a model for supervising beginning trainees of dynamic group therapy.

This article presents a model for supervising beginning therapists of dynamic group psychotherapy. It is geared to their experience with the challenging patients most often seen in training clinics. The model presupposes no particular metapsychology but, to meet trainees' needs, advocates a hierarchically organized set of operational goals. The supervision is conceptualized as ideally occurring in three sequential stages: (a) The "Technical" phase conveys the fundamentals of technique, the "craft." (b) The "Enrichment" stage emphasizes appreciation of group phenomena, including formal group dynamic theory. (c) The final phase highlights the more "Personal" side of becoming a skilled group psychotherapist, including countertransferential issues and the termination process. The model, not intended to be applied in a Procrustean manner, also serves, nevertheless, as a description of how a satisfactory supervision for beginners generally proceeds.

Curriculum↗
PubMed1994

Pediatric oncologists' assessment of oncology education in U.S. medical schools: Cancer Education Survey II.

The status of cancer education in U.S. medical schools was reassessed in the Cancer Education Survey II, which was initiated in 1989. One thousand and thirty-five cancer educators from 126 of the country's 128 medical schools participated, including 65 pediatric oncologists and 36 family physicians. All agreed that the most important aspects of cancer to teach medical students are early detection and cancer prevention; they considered less important electives in basic science, radiation therapy, and surgical oncology. The 101 pediatric oncologists and family physicians believed that more curriculum time should be devoted to cancer epidemiology, psychosocial aspects, and palliative care. Approximately one third of these 101 physicians also expressed the desire to have more teaching materials available in five general areas: patient education about pediatric cancer, nutrition, epidemiology, palliative care, and continuing care. Lay-language information about pediatric cancer, participation in clinical trials, and current cancer research is still needed.

Curriculum↗
PubMed1992

Survey design and observations relating to cancer education funding. Cancer Education Survey II: cancer education in United States medical schools (conducted by The American Association for Cancer Education with the support of the American Cancer Society).

A survey has been conducted of cancer education programs for medical students in United States medical schools by the American Association for Cancer Education with grant support from the Department of Detection and Treatment of the American Cancer Society (formerly the Professional Education Department). Two questionnaires were used, an Educational Resources Questionnaire (ERQ), which 126 of the 128 medical schools completed and returned, and a Faculty and Curriculum Questionnaire (FCQ), which was completed and returned by 1,035 faculty members who had been named as active in undergraduate medical student cancer education by respondents in each school who had been designated by the Dean's Office to complete the ERQ. Overall conclusions included: (1) increased coordination of cancer education activities is a major need in many schools; (2) there is widespread interest in the further development of cancer education objectives; (3) development of a national cancer education curriculum is needed; (4) there is interest in the development of improved instructional materials and methods; (5) development of evaluation methods is needed for cancer education programs; and (6) an ongoing funding process is needed to provide support for interdepartmental coordination of cancer education activities. Cancer prevention and detection topics were ranked above cancer treatment in plans for future curriculum emphasis. More detailed conclusions and recommendations are provided in this publication and three subsequent articles in this issue of the Journal of Cancer Education.

American Cancer Society↗
PubMed1992

Instructional methods and the use of teaching resources in cancer education curricula. Cancer Education Survey II: cancer education in United States medical schools.

The findings on cancer teaching methodology presented in this abstract come from an American Association for Cancer Education (AACE)/American Cancer Society-sponsored survey of American allopathic medical schools in 1989 and 1990 to determine how and how well cancer is presented in the medical school curriculum. Responses were received from 126 institutional and approximately 1,000 faculty respondents. Approximately one-third (368) of faculty respondents indicated the use of specific learning objectives; utilization does vary across disciplines. The lecture remains the dominant form of instructional method. Computers were reported as an instructional modality by only 16% of the faculty respondents. Prepared audiovisual instructional materials appeared to be widely utilized. Use varied from 86% for 35mm slides to 11% for video discs. Faculty favored the development of new teaching materials for ten topic areas ranging from approximately 40% for early detection and prevention to a low of approximately 25% for rehabilitation and continuing care. The survey identified an underutilization of existing outpatient facilities and tumor registries for cancer teaching purposes. The findings give rise to questions concerning the appropriateness of the match between specific instructional goals and the teaching methods employed. Eight recommendations designed to strengthen cancer training are made.

Computer-Assisted Instruction↗
PubMed1992

Cancer prevention education in United States medical schools. Cancer Education Survey II: cancer education in United States medical schools.

The Cancer Education Survey collected data from 126 of 128 US Medical Schools on the current status of cancer-related educational activities for undergraduate medical students. The study was conducted by a Supervisory Committee of the American Association for Cancer Education, with funding from the American Cancer Society. The survey obtained data concerning institutional characteristics in support of undergraduate medical student cancer education, ie, administrative structures, current cancer-related curricula, sources of financial support, and anticipated changes in these characteristics. Institutions were also queried on specific topics of cancer prevention, detection, and diagnosis that might be taught as identifiable areas of instruction for medical students. Three-fourths of the institutions had a lecture on the principles of cancer screening, and, among those, nearly three-fourths classified it as a part of a required course or rotation. Detection of common cancers is taught in virtually all institutions. The least likely cancer prevention lecture topics are related to prevention and cessation of smoking, a well-verified cancer risk. Also, no consistent pattern emerges that might indicate that association with a cancer center imparts to a medical school a greater emphasis on delivery of cancer prevention topics.

American Cancer Society↗
PubMed1992

Changing the cancer curriculum: a curriculum committee's response to the results of the AACE Cancer Education Survey II. Cancer Education Survey II: cancer education in United States medical schools.

The AACE Cancer Education Survey-II offers an unusual opportunity based on data from 125 medical schools and 1,035 experienced cancer educators to effect constructive change with regard to cancer education. The changes suggested include more coordination; integration; and a shift of emphasis to include more on topics of prevention, early diagnosis, tumor biology, rehabilitation, palliative care, and psychosocial issues. Ample opportunities, especially in the ambulatory care arena, exist at most medical schools, and there is a great deal of interest in improving the situation. This article reviews the factors contributing to resistance to change, the data on adult learning, and the major movements and dilemmas facing medical education today. It also discusses some of the external forces like the Liaison Committee on Medical Education (LCME) and foundation support, which are being harnessed to effect change. Given these barriers, forces, and opportunities, the article ends with a possible action plan for an individual, an institution, and national bodies interested in cancer education. The knowledge, skills, values, and attitudes must be defined, taught effectively, and evaluated. It is an opportune time, armed with this useful data, to bring about change in how cancer subjects are taught. The ultimate goal is more knowledgeable and effective practitioners and scientists who can decrease the morbidity and mortality from cancer.

Curriculum↗
PubMed1991

Expression of aberrant O-glycans attached to leukosialin in differentiation-deficient HL-60 cells.

Promyelocytic leukemia HL-60 cells can be induced to differentiate into granulocytic cells by various agents including retinoic acid (RA), dimethyl sulfoxide, and 6-thioguanine (6-TG). Although the induced cells are no longer capable of proliferation, a few cells continue to divide in the presence of inducers, and these cells are resistant to terminal differentiation by these inducers (R. E. Gallagher, D. A. Giangiulio, C-S. Chang, C. J. Glover, and R. L. Felsted, Blood, 68: 1402-1406, 1986). The present study examined the structures of O-glycans attached to leukosialin, a major sialoglycoprotein in HL-60 cells, and the activities of glycosyltransferases involved in O-glycan synthesis. Leukosialin from RA-resistant and 6-TG-resistant HL-60 sublines migrated much more slowly than those from wild-type HL-60 cells when applied to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The dimethyl sulfoxide-resistant HL-60 subline, on the other hand, expressed leukosialin with a molecular weight similar to wild-type HL-60 cells. RA-resistant and 6-TG-resistant HL-60 cells were found to express a significant amount of tetrasaccharides that contain no sialic acid residue, while wild-type HL-60 cells expressed mainly disialosyl hexasaccharides and contained no detectable amount of asialo-oligosaccharides. Furthermore, wild-type HL-60 cells treated with the inducers for 4 days were found to express the same saccharides present in untreated wild-type HL-60 cells, indicating that the altered O-glycans present in RA and 6-TG sublines were not caused by a direct effect of these agents but rather are intrinsically unique to these sublines. To better understand the mechanisms underlying the differences in O-glycans, the activities of four sialyltransferases were measured: Gal beta 1----3GalNAc alpha 2----3sialyltransferase, Gal beta 1----4(3) GlcNAc alpha 2----3sialyltransferase, Gal beta 1----4GlcNAc alpha 2----6sialyltransferase, and GalNAc alpha 2----6sialyltransferase. Among them, Gal beta 1----3GalNAc alpha 2----3sialyltransferase and Gal beta 1----4(3)GlcNAc alpha 2----3sialyltransferase were much lower in the RA- or 6-TG-resistant HL-60 subline than in wild-type HL-60 cells. These findings indicate that the differences in O-glycans are due to the differences in alpha 2----3sialyltransferase activities. These results strongly suggest that O-glycans associated with leukosialin may play some role in HL-60 cell differentiation.

Antigens, CD↗
PubMed1991

Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid.

Two recent reports have described major clinical benefits from all-trans-retinoic acid (tRA) therapy of patients with promyelocytic leukemia (APL). This paper describes the first patient with a blast crisis of chronic myelogenous leukemia (CML-BC) who responded to oral tRA therapy. In vitro marrow studies, including clonogenic assays, immunopheno-typing, cytogenetics and premature chromosome condensation together with chromosome painting provided evidence for the in vivo differentiation and maturation of the malignant cells. The patient achieved a partial remission with reversal of all clinical features of disease, including normalization of peripheral blood counts, complete resolution of fever, fatigue and splenomegaly, and marked maturation of the bone marrow. This response to tRA in CML-BC is unique, and broadens the spectrum of diseases which may respond to retinoids.

Antineoplastic Agents↗