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Biomedical subjects

M Ray

Publications and source records attributed to M Ray.

At least 91 records · Page 5Linked to original sources

Variant Philadelphia translocations in chronic myeloid leukemia: correlation with cancer breakpoints, fragile sites and oncogenes.

Four cases of variant Philadelphia (Ph1) translocations were found in 72 patients (5.5%) with Ph1-positive chronic myeloid leukemia (CML). One previously unreported case was a simple variant translocation, namely, 46,XY,t(11;17)(q13;p13),t(17;22)(q25;q22); 46,XY,t(1;21)(q32;q11),t(11;17)(q13;p13), t(17;22)(q25;q11). Complex variant translocations were observed in three cases, namely, 46,XY,t(5;9;22)(q31;q34;q11),46,XX,t(8;9;22) (q22;q34;q11) and 46,XX,t(9;15;22) (q34;q15;q11). The chromosomal breakpoints in the cases of variant Ph1 translocations were the following: 1q32, 5q31, 8q22, 11q13, 15q15, 17p13, 17q25 and 21q11. Eight of the eight (100%) breakpoints were located in Giemsa-negative bands. Furthermore, seven of the eight (87%) variant Ph1 breakpoints correspond to the breakpoints present in consistent cancer arrangements. Three of the eight (38%) correspond to fragile sites and four of the eight (50%) correspond to oncogenes.

Genetic Variation

A high affinity Ca2(+)-ATPase on the surface membrane of Leishmania donovani promastigote.

A Ca2(+)-dependent ATP-hydrolytic activity was detected in the crude membrane ghost of the promastigote or vector form of the protozoal parasite Leishmania donovani, the pathogen responsible for kala azar. The Ca2(+)-ATPase was purified to apparent homogeneity after solubilization with deoxycholate. The enzyme consists of two subunits of Mr = 51,000 and 57,000 and has an apparent molecular weight of 215,000 +/- 12,000. The enzyme activity is exclusively dependent on Ca2+, and the pure enzyme can hydrolyze 1.6 mumol of ATP/min/mg of protein. The apparent Km for Ca2+ is 35 nM, which is further reduced to 12 nM in the presence of heterologous calmodulin. The enzyme is sensitive to vanadate, but is insensitive to oligomycin and ouabain. The enzyme is strongly associated with the plasma membrane and has its catalytic site oriented toward the cytoplasmic face. The enzyme spans across the plasma membrane as surface labeling with radioiodine shows considerable radioactivity in the completely purified enzyme. The localization and orientation of this high affinity, calmodulin-sensitive Ca2(+)-ATPase suggest some role of this enzyme in Ca2+ movement in the life cycle of this protozoal parasite.

Adenosine Triphosphate

A case of follicular small cleaved cell lymphoma with t(14;18) and t(8;11).

Follicular small cleaved cell lymphoma is a common B-cell lymphoma exhibiting a t(14;18)(q32;q21) chromosomal translocation, which has been found in most cases studied. In our case of follicular small cleaved cell lymphoma, the chromosome translocation 14;18 was observed. This case also exhibits a second consistent chromosomal translocation, t(8;11)(p21;q13), along with t(14;18).

Adult

Clonal chromosomal changes in chronic lymphocytic leukemia.

Cytogenetic analysis was carried out in 28 B-CLL patients (21 males and 7 females, 38-85 years old, with median age 64 years, disease stage O-IV). Peripheral nominator cells (1 x 10(7)) or isolated B-lymphocytes were incubated in vitro for 5-7 days. The cells were stimulated by pokeweed mitogen (PWM), or phorbol myristate-acetate (PMA), with or without 10% conditioned medium (CM) derived from a T cell leukemia line or 10% B-cell growth factor (BCGF). Twenty-two patients (79%) responded to PWM + CM; 5 out of 5 patients responded to PWM + BCGF. The average mitotic index (+/- S.E.M.) for PWM, PMA, PWM + CM, PMA + CM, PWM + BCGF were 0.13 +/- 0.01, 0.24 +/- 0.13, 0.51 +/- 0.11, 0.14 +/- 0.06 and 0.63 +/- 0.15, respectively. Cytogenetic analysis revealed the presence of abnormal karyotypes in 22 patients. Fourteen patients (50%) had clonal chromosome aberrations which included: monosomy 1, 9, 17, 18, 21, and X chromosome, and trisomy of chromosomes 7, 9, 20, 21 and 22. The clonal structural aberrations were i(6q), inv(12) (q15q24), del(5) (p13p15), del(10) (q24). No homogeneously staining regions (HSR) were observed. Four patients with resistance to anti-neoplastic drugs showed the presence of double minute chromosomes (dmin) ranging in frequency from 5 to 50%.

Adult

Possible association of rare autosomal folate sensitive fragile sites and idiopathic mental retardation: a blind controlled population study.

The expression of folate sensitive fragile sites (FS) was assessed in cord blood lymphocyte cultures obtained from 790 newborns (NB) and in peripheral blood lymphocyte cultures from 326 institutionalized mentally retarded residents (MR). The mean rate of expression of common FS and the occurrence of rare FS was significantly higher in the MR population. Age, sex and history of chronic medication use did not appear to influence common FS expression in the MR population, 3/790 (0.38%) NB and 5/326 (1.53%) MR exhibited rare autosomal folate sensitive FS, a 4-fold difference in incidence (P = 0.009, Poisson test). Four of the five MR who expressed rare FS were considered to have idiopathic MR (4/179 or 2.2%). The occurrence of rare FS in 1/147 (0.68%) MR with known etiology is not significantly different from the frequency of occurrence in the NB population (P = 0.428, Poisson test). In this population, rare FS appear to be overrepresented in the idiopathic etiology MR group.

Abnormalities, Multiple

Penicillin dosage.

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Actinomycosis

Transposition of the abl proto-oncogene in Philadelphia--negative chronic myeloid leukaemia and acute lymphocytic leukaemia.

Transposition of the abl gene was demonstrated in seven Philadelphia (Ph'-) negative patients with either chronic myeloid leukaemia (CML) or acute lymphocytic leukaemia (ALL) by chromosomal in situ hybridization. In six out of seven CML patients and one out of two ALL patients, a significant accumulation of abl hybridization grains was localized to chromosome 22. Hybridization with both abl and sis resulted in the consistent formation of double hybridization events on chromosome 22. Transposition of abl was not apparent in one patient with Ph'-negative CML and in one patient with Ph'-negative ALL. The data suggest that transposition of abl to chromosome 22 is a feature of a particular subgroup of Ph'-negative leukaemias.

Chromosome Mapping

Mechanism of ethanol-induced jejunal microvascular and morphologic changes in the dog.

To study the mechanism of morphologic and microvascular effects of intraluminal ethanol, we perfused jejunal segments of the dog with 6% (wt/vol) ethanol for 0 (control), 10, 20, 30, 60, and 90 min, and measured the time-dependent changes in (a) the prevalence of villi with epithelial damage (i.e., villi with intact blebs plus those with broken blebs) and those without epithelial damage (undamaged villi), (b) the height of the villus core and the patency of lacteals, (c) jejunal albumin loss, and (d) permeability of microvessels of the villus tip by colloidal carbon vascular labeling. We found that (a) the prevalence of villi with epithelial damage or with intact bleb increased progressively during the first 20 min of ethanol perfusion and then declined gradually; (b) the height of the villus core and the patency of lacteals in the undamaged villi and in those with intact bleb decreased during the first 20 min and then gradually increased; and (c) jejunal albumin loss and the prevalence of villi with carbon labeling increased for the first 30 min, after which the former declined gradually whereas the latter remained at a plateau. These findings suggest that contraction of the villus core and compression of the lymphatics are the primary cause of ethanol-induced epithelial damage, which is accentuated by increased microvascular permeability and consequent protein leakage. The mechanism of recovery of most parameters, in spite of continuous ethanol perfusion, remains to be investigated.

Animals

Reduced expression of aphidicolin-induced common fragile sites in peripheral lymphocyte chromosomes of patients with B-cell chronic lymphocytic leukemia.

The occurrence and frequency of aphidicolin-induced common chromosomal fragile sites were examined in 12 B-cell chronic lymphocytic leukemia (B-CLL) patients (ten males and two females) and three normal individuals. The mononuclear cells separated by Ficoll-Hypaque gradient were cultured in vitro for 96 hours stimulated by pokeweed mitogen (PWM) in combination with T-leukemia cell conditioned medium or 10% B-cell growth factor. For the final 24 hours the cells were treated with aphidicolin (0.07 microgram/ml). Results indicate that there was a significant reduction in the overall mean frequency of common fragile sites in CLL patients with a wide individual variation. Fragile sites were found to be localized either on a single chromatid or both chromatids, but rarely involved homologous chromosomes. No definite relationship between the frequency of fragile sites and the staging of CLL disease was observed. A significant reduction and variability in the frequency of fragile sites suggest the heterogenous nature of B-CLL and probably a different mechanism of induction of fragile sites in CLL cells compared to controls.

Aphidicolin

Relationship of embryotoxicity to genotoxicity of lead nitrate in mice.

Frequency of sister chromatid exchanges (SCEs), nucleolar organizing regions (NORs) and chromosomal aberrations were analysed, in maternal bone marrow and fetal liver and/or lung cells of ICR Swiss Webster mice, following maternal exposure to lead nitrate on gestational day 9. The number of implantations and morphological changes in day 18 fetuses, following the treatment, were also noted. Chemical analysis of lead in maternal and fetal tissues showed that it is readily transferred across the placenta. Lead caused a moderate, but statistically significant, increase in the frequency of SCEs in maternal bone marrow cells and significant reduction in NORs at the 2 highest dose levels (150 and 200 mg/kg b.w.). Lead treated animals showed several specific chromosomal aberrations, mostly deletions in maternal bone marrow and fetal cells. Aneuploidy was found to be frequently associated with the lowest dose levels of lead nitrate (100 mg/kg). Maternal treatment with lead nitrate also significantly increased embryonic resorptions and reduced placental weights. The results suggest that the embryotoxic effects of lead might be associated with the chromosomal changes.

Animals

Embryotoxicity and in vivo cytogenetic changes following maternal exposure to cadmium chloride in mice.

Cadmium is a well-known teratogen in laboratory animals and a widespread environmental pollutant. The frequencies of sister chromatid exchanges (SCEs), nucleolar organizing regions (NORs) and chromosomal aberrations were analysed in maternal bone marrow and fetal liver and/or lung cells of mice, following maternal treatment with cadmium chloride, on gestational days 8 through 10. The embryotoxic effects and morphological changes on day 18 fetuses were also studied. Cadmium chloride is readily transferred across the placenta and significant levels were detected in both the placenta and fetus. No significant changes in the frequencies of SCEs or NORs in maternal and fetal cells were observed following exposure to cadmium chloride. Fetal tissues showed mitotic inhibition at the highest dose levels (8.4 and 11.4 mg/kg, b.w.). Maternal treatment with cadmium chloride increased embryonic resorptions and fetal lethality, as well as reduced placental weight; however, it did not produce significant chromosomal changes except at the highest dose level (11.4 mg/kg).

Abnormalities, Drug-Induced

Effect of test expectancy on preferred study strategy use and test performance.

Among undergraduates in a carefully controlled design, 9 students who took notes studied longer than groups of 30 and 17 who did not. No differences were observed on test scores, retention interval, comprehension scores, or reading rate. Whether students expected multiple-choice or free-recall testing, strategies were similar, suggesting study oriented to rote learning.

Achievement

Expression and distribution of aphidicolin-induced fragile sites in chronic myeloid leukaemia, acute lymphocytic leukaemia and acute myeloid leukaemia.

New information is revealed concerning the frequency of expression and distribution of aphidicolin-induced fragile sites in eight leukaemic patients, namely, four chronic myeloid leukaemic patients (CML), three acute lymphocytic leukaemic (ALL) patients, and one acute myeloid leukaemic (AML) patient. The cytogenetic data demonstrate a statistically significant (p less than 10(-6] increase in the frequency of aphidicolin-induced fragile sites in seven of the eight leukaemic patients compared with healthy age-matched and sex-matched controls. The chromosomal band locations of the aphidicolin-induced fragile sites from 400 metaphase spreads of these leukaemic patients reveal a nonrandom distribution in the karyotype. Some aphidicolin-induced fragile sites in these leukaemic patients were located at chromosome bands known to be induced specifically by folic acid, distamycin A, bromodeoxyuridine or azacytidine. The cross-induction of fragile sites in the leukaemic patients may be indicative of shared molecular homology in the sequence composition of nonrandom chromosomal DNA.

Aphidicolin

Aspartate transcarbamylase from Leishmania donovani. A discrete, nonregulatory enzyme as a potential chemotherapeutic site.

Leishmania donovani is a protozoal pathogen that belongs to the kinetoplastida order. Unlike in other eucaryotic systems, the first three enzymes of the de novo pyrimidine biosynthetic pathway are not components of a multifunctional protein system. The three enzyme activities in the crude extract were separated on a Sephacryl S-200 column. Aspartate carbamoyltransferase (EC 2.1.3.2) has been purified to apparent homogeneity. The enzyme has an approximate molecular weight of 135,000 and seems to be a tetramer of equivalent subunits of molecular weight 35,000. The enzyme shows strictly hyperbolic kinetics with both the substrates under a variety of conditions and is not inhibited by nucleotide phosphates. Km for carbamyl phosphate is 3.1 x 10(-4) M and for aspartate is 7.6 x 10(-3) M. Apparently, the enzyme has no regulatory role in pyrimidine biosynthesis. N-(Phosphonoacetyl)-L-aspartic acid is a powerful competitive inhibitor (Ki = 5 x 10(-7) M) for this enzyme with carbamyl phosphate as substrate. This inhibitor completely inhibits the growth of the vector form of organism at 60 microM and significantly affects the growth of the pathogenic form in a macrophage assay system. The potency of the inhibitor is comparable with allopurinol which is undergoing human clinical trial as an antileishmanial drug.

Animals