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Biomedical subjects

R Morgan

Publications and source records attributed to R Morgan.

At least 37 records · Page 2Linked to original sources
PubMed1991

Reversal of multidrug resistance in HL-60 cells by verapamil and liposome-encapsulated doxorubicin.

The means of circumventing multidrug resistance was investigated in HL-60 and HL-60R (a drug resistance variant) cell lines. The HL-60R cell line was developed from the parent line by serial exposure to increasing concentrations of doxorubicin over a 4-month period. This drug resistant cell line expressed P-glycoprotein in its cell surface and is 80-fold more resistant than the parent cell line. Multidrug resistance, as evaluated by a cell cytotoxicity assay using doxorubicin, can be overcome by use of verapamil. Multidrug resistance can also be circumvented when doxorubicin is encapsulated in liposomes. The combination of verapamil and doxorubicin-encapsulated liposomes does enhance circumvention of multidrug resistance beyond the effect of each agent alone, implying a synergistic effect. The lipid composition of the liposomes does affect the rate of drug uptake but not the overall cytotoxic effect of doxorubicin. The synergistic reversal of multidrug resistance by doxorubicin-encapsulated liposomes and verapamil suggests a multifactorial basis for drug resistance in this cell line.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Lymphocytes as cellular vehicles for gene therapy in mouse and man.

The application of bone marrow gene therapy has been stalled by the inability to achieve stable high-level gene transfer and expression in the totipotent stem cells. We show that retroviral vectors can stably introduce genes into antigen-specific murine and human T lymphocytes in culture. Murine helper T cells were transduced with the retroviral vector SAX to express both neomycin-resistance and human adenosine deaminase genes. These cells were expanded in culture and selected for expression of neomycin resistance with G418. The gene insertion, selection, and culture expansion did not alter antigen specificity or growth characteristics of the T cells in vitro. To determine if cultured T cells might be used for gene therapy, their persistence and continued expression of the introduced genes was evaluated in nude mice transplanted with the SAX-transduced T cells. G418-resistant cells could be readily recovered from the spleens of recipients of transduced T cells for several months. In addition, recovered cells continued to produce human adenosine deaminase. Based on these observations, we studied cultured human tumor-infiltrating lymphocytes as a candidate cell for a trial of gene transfer in man. Exponential cultures of interleukin-2-stimulated tumor-infiltrating lymphocytes were efficiently transduced with the neomycin-resistance gene using the retroviral vector N2. Gene insertion and subsequent G418 selection did not substantially alter the growth characteristics, interleukin 2 dependence, membrane phenotype, or cytotoxicity profile of the transduced T cells. These studies provided a portion of the experimental evidence supporting the feasibility of the presently ongoing clinical trials of lymphocyte gene therapy in cancer as well as in patients with adenosine deaminase deficiency.

Animals↗
PubMed1991

Phase II study of 4'-deoxydoxorubicin (esorubicin) in advanced or metastatic adenocarcinoma of the stomach.

4'-deoxydoxorubicin (DxDx) was administered to 17 patients with locally advanced or metastatic gastric adenocarcinoma. Treatment cycles were repeated every 21 days. 15 eligible patients with a Karnofsky performance status of 50% or better (median: 70%) received at least one course of treatment; a median of 2 courses of DxDx was delivered (range 1 to 13). The median dose per treatment course was 26 mg/m2 (range 8.5 mg/m2 to 53 mg/m2). 69% of patients required dose reduction following the first course of therapy due to grade 3 or 4 myelosuppression, primarily neutropenia. The principal side effects included anemia, mild gastrointestinal toxicities, and alopecia; one patient experienced a 10% decrease in cardiac ejection fraction without clinical cardiac toxicity. Of the 15 patients assessable for response and toxicities, 1 patient had a partial response lasting 2.5 months. The median survival from the time of the first treatment was 3.3 months. We conclude that DxDx has only limited activity in the treatment of advanced gastric adenocarcinoma.

Adenocarcinoma↗
PubMed1991

Cytogenetic findings in typical and atypical meningioma.

Comparative pathological and karyotypic findings of a typical and an atypical meningioma in two different patients are presented. The chromosomal abnormalities observed appeared unique for the histopathological subtype of the tumor. Cytogenetic analysis of atypical meningioma has not previously been reported.

Adult↗
PubMed1991

t(16;21)(p11.2;q22): a recurrent primary rearrangement in ANLL.

We have identified three patients with acute nonlymphocytic leukemia (ANLL), subtypes M2, M4, and M7, who had a t(16;21)(p11.2;q22) in the affected cells. There are six previously reported cases of ANLL with the same t(16;21). The t(6;21) should therefore be included as another primary rearrangement in ANLL. Follow-up of these cases, though still limited, suggests a poor prognosis, as most patients have achieved a clinical remission but only for a short duration.

Adult↗
PubMed1991

Translocation (3;21) characterizes crises in myeloid stem cell disorders.

Three patients, one with Philadelphia (Ph) chromosome positive chronic myelocytic leukemia (CML) and two with primary acquired myelodysplastic syndromes (MDS), have been identified to have a t(3;21)(q26;q22). In the patient with CML, the t(3;21) was detected only in the blast phase. The t(3;21) as the sole abnormality appeared at presentation of MDS [refractory anemia with excess blasts (RAEB)] in one patient and remained as such when progression to RAEB in transformation (RAEB-t) occurred. The other patient with MDS had the t(3;21), in addition to other changes, during the progression of the disease. Thus, t(3;21) may characterize myeloid crises of clonal hematopoietic stem cell disorders (HSCD) and indicates a poor prognosis. As a primary cytogenetic event it may be also involved in the genesis of myelodysplasia with subsequent leukemic transformation.

Aged↗
PubMed1991

Nonradioactive in situ hybridization. A rapid approach for the identification of marker chromosomes: study of a case of acute leukemia with a Yq specific DNA probe.

Nonradioactive in situ hybridization provides a rapid method for detecting specific nucleic acid sequences. In this study of a patient with acute leukemia, we applied in situ hybridization for identification of a marker chromosome and determination of the number of copies of this marker in interphase nuclei using a biotinylated Yq-specific DNA probe (pY3.4). We show that nonradioactive interphase in situ hybridization can be a useful method for karyotypic analysis in addition to routine cytogenetic techniques in neoplastic disorders.

Acute Disease↗
PubMed1991

Expression of the multidrug resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype.

Previous studies have indicated relative resistance to chemotherapy in the myelodysplastic syndromes (MDS) and associated acute leukaemia. To determine if multidrug resistance may contribute to chemoresistance in these disorders, we studied bone marrow specimens for P-glycoprotein expression (P-GP) by immunocytochemical staining with monoclonal antibodies reactive with cytoplasmic (C219) or surface epitopes (MRK16) of P-GP. Forty-five case specimens from 43 patients were studied, including 32 cases of primary MDS, seven cases of acute myeloid leukaemia (AML) following MDS, and six therapy-related haematological disorders. Cytogenetic analysis was available on 36 specimens. Two staining patterns were detected: (1) cytoplasm and plasma membrane, and (2) staining restricted primarily to the nuclear-cytoplasmic junction. P-GP was detected in seven (22%) cases of primary MDS, four (57%) cases of AML evolving from MDS, and five (83%) cases of therapy-related haematological disorders. Expression of P-GP was restricted to blasts and leukaemic monocytes, and was otherwise absent from terminally differentiated blood cells. Analysis of the relation between P-GP expression and reactivity with the human progenitor cell antigen CD34, revealed a highly significant association (P = 0.001). P-GP reactivity was distributed equally among normal and abnormal karyotypes and did not correlate with specific cytogenetic abnormalities. These findings indicate that multidrug resistance in MDS and karyotypically-related haematological disorders is closely linked to a stem cell phenotype and may contribute to chemoresistance in these disorders.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects.

We investigated the prevalence of mutations in the gene encoding the major insulin-responsive facilitative glucose transporter (GLUT4) in patients with non-insulin-dependent diabetes mellitus (NIDDM). All 11 exons of the GLUT4 gene from 30 British white subjects with NIDDM were amplified using the polymerase chain reaction and screened for nucleotide sequence variation using the single-stranded conformation polymorphism (SSCP) method. No variation between the study subjects was detected in exons 1-3, 4b-8, and 10. Variant SSCP patterns were detected in exons 4a and 9. SSCP variation in exon 4a was revealed by direct nucleotide sequencing to be due to a common silent polymorphism (AAC----AAT at Asn130). One NIDDM patient demonstrated a variant SSCP pattern in exon 9. This was caused by a point mutation (GTC----ATC) at codon 383, which leads to the conservative substitution of isoleucine for valine in the putative fifth extracellular loop of the transporter. Allele-specific oligonucleotide hybridization was used to examine the frequency of this mutation in 240 Welsh white subjects (160 with NIDDM and 80 controls). The Val----Ile383 mutation was found in the heterozygous state in two diabetic subjects and no control subjects. We conclude that mutations of the GLUT4 coding sequence are very uncommon in this population of subjects with typical NIDDM. Determining whether the Ile383 GLUT4 variant present in 3 diabetic subjects contributes in any way to their disease will require further study.

Alleles↗
PubMed1991

Association of vitamin B6 status with parameters of immune function in early HIV-1 infection.

Nutritional deficiencies have been documented to affect immune function. The present study indicates that vitamin B6 deficiency is prevalent in CDC stage III HIV-1-infected subjects, despite adequate dietary vitamin B6 intake. As vitamin B6 deficiency has been previously shown to affect immune function, these relatively asymptomatic HIV-1-infected patients were examined for evidence of a relationship between vitamin B6 deficiency and immune dysregulation. Vitamin B6 status in HIV-1-infected subjects was significantly associated with functional parameters of immunity [multivariate F(3,36) = 3.70, p less than or equal to 0.02]. Additional analyses indicated that overtly deficient participants exhibited significantly decreased lymphocyte responsiveness to the mitogens phytohemagglutinin and pokeweed, and reduced natural killer cell cytotoxicity, compared to subjects with clearly adequate vitamin B6 status (chi 2 = 8.78, df = 3, p less than 0.04). Vitamin B6 status was not related to immune cell subpopulations, e.g., CD4, CD8 cell number, or level of serum immunoglobulins. The results of this study indicate that while vitamin B6 status is not a primary etiological factor in HIV-1-related immunological dysregulation, it appears to be an important cofactor of immune function.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Norepinephrine response in early HIV infection.

Norepinephrine response to a cold pressor test was investigated in 95 homosexual men in a longitudinal study of human immunodeficiency virus (HIV) infection. The baseline data obtained from 76 HIV+ and 19 HIV- subjects are included in this report. After the insertion of a venicatheter and following a 30 min rest, subjects immersed one of their hands in ice water for 2 min, and serial blood samples were obtained for the determination of catecholamine levels. The results show that the norepinephrine response in HIV+ subjects compared to that of HIV- subjects was blunted. Examination of the responses using linear and quadratic orthogonal polynomials suggested that these differences between the two groups were primarily a function of their rate of increase in norepinephrine levels. It was observed also that in HIV+ subjects, norepinephrine level peaked earlier than that in HIV- subjects. The data suggest that autonomic dysfunction is present in the early stages of HIV infection.

Autonomic Nervous System↗
PubMed1990

Structural alterations at the putative retinoblastoma locus in some human leukemias and preleukemia.

Homozygous loss of alleles of the retinoblastoma susceptibility locus (RB1) has been implicated in the onset of many different solid tumors. Heterozygous deletions of chromosome 13q14, the region containing the RB1 locus, have been observed by us in several subvariants of leukemia and preleukemia. We examined four cases of leukemia and one case of preleukemia for homozygous inactivation of the RB1 locus; in at least one case, evidence supports the concept that homozygous loss of both alleles of RB1 was an important step during leukemogenesis.

Adolescent↗
PubMed1990

Cognition in early human immunodeficiency virus infection.

Relatively little is known about cognitive changes in early human immunodeficiency virus (HIV) infection. This study examined cognitive functioning in 46 HIV-positive gay men relative to an age and education equivalent group of 13 HIV-negative gay men. The HIV-positive men were asymptomatic except for lymphadenopathy or T4 counts less than 700. The cognitive battery measured language, memory, visuospatial, information processing speeds, reasoning, attention, and psychomotor processes. The HIV-positive group was significantly slower in processing information and performed significantly less well than the HIV-negative group on certain verbal memory measures. Deviations of 1 as well as 2 SDs from the norm/control group mean on four or more tests were observed in 43% and 22% of the HIV-positive subjects, respectively, compared with 8% and none of the HIV-negative subjects, respectively. The results suggest that cognitive inefficiency occurs in a subsample of individuals during early HIV infection.

Adult↗
PubMed1990

Apparent duplication of inv(3)(q21q26) in one of five cases with inv (3) in myelodysplastic syndromes and acute leukemia.

Rearrangements affecting the long arm of chromosome 3 have been linked to abnormalities of platelet production and morphology in hematologic disorders. We present five patients with myelodysplastic syndromes or acute leukemia in whom inv(3)(q21q26) was seen. One of the patients showed an inversion of both homologs involving precisely the same breakpoints, suggesting apparent duplication of the abnormal chromosome 3 and loss of the normal homolog. To our knowledge this is the first report detailing such a condition.

Acute Disease↗
PubMed1990

Characterization of the breakpoint of a t(14;14)(q11.2;q32) from the leukemic cells of a patient with T-cell acute lymphoblastic leukemia.

The leukemic cells and derivative cell line from a 74-year-old male with T-cell acute lymphoblastic leukemia showed chromosomal abnormalities including a t(14;14)(q11.2;q32). This translocation is characteristic of a variety of T-cell malignancies, particularly T-cell prolymphocytic leukemia and the clonal proliferations of peripheral T cells in patients with ataxia-telangiectasia. Using DNA probes that spanned the T-cell receptor alpha chain (TCRA) joining (J) locus, the DNA rearrangement caused by the translocation was identified, cloned, and sequenced. The breakpoint shows site-specific juxtaposition of a TCRA joining segment and DNA from a region of 14q32 centromeric to the immunoglobulin heavy chain locus. Comparison of restriction map and nucleotide sequence from this translocation with other related chromosomal breakpoints suggests a dispersion of breakpoints throughout the 14q32 region.

Amino Acid Sequence↗