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Biomedical subjects

A Raza

Publications and source records attributed to A Raza.

At least 73 records · Page 4Linked to original sources
PubMed1999

Biologic characteristics of 164 patients with myelodysplastic syndromes.

Rates of proliferation, apoptosis and cytokine expression were measured in bone marrow (BM) biopsies of 164 myelodysplastic syndrome (MDS) patients. There were 107 males and 57 females. Median age was 69 years and 101 had refractory anemia (RA), 17 RA with ringed sideroblasts (RARS), 38 with RA and excess blasts (RAEB) and 8 with RAEB in transformation (RAEB-t). Apoptosis measured by in-situ end labeling (ISEL) was directly related to the number of macrophages (p = 0.028, n = 83). Mean tumor necrosis factor alpha (TNF-alpha) and ISEL positivity were higher in RAEB + RAEB-t patients (p = 0.0554 and p = 0.06 respectively) while hemoglobin was higher for RA + RARS group (p = 0.0472). Patients with high apoptosis had lower white blood cell counts (p = 0.0009), lower percentage of blasts (p = 0.0009) and higher number of macrophages (p = 0.0086). We conclude that measurements of apoptosis, proliferation and cytokine expression provide important biological information which helps to distinguish RA + RARS patients from RAEB + RAEB-t patients, and may be of additive prognostic significance.

Adolescent↗
PubMed1999

Marrow cytokine transcripts and the secondary hematologic disorders.

A comparison was made of the cytokine transcripts in normal, monoclonal, MDS, and AML marrow aspirates. While both normal and monoclonal marrow aspirates contain transcripts for SCF, few MDS or AML marrow aspirates contain these transcripts. Similarly, IL1ra transcripts are found with reduced frequency in MDS and AML marrow aspirates. The fall in SCF transcripts between monoclonal and MDS marrow aspirates parallels the appearance of apoptosis and the reduced in vitro proliferative ability which are characteristics of MDS marrow aspirate cells. The frequent IL1beta production by MDS and AML marrow aspirate cells, with few marrow aspirates producing IL1ra transcripts, suggests that unbalanced IL1beta effects may contribute to the proliferative advantage of MDS and AML cells over their normal counterparts.

Bone Marrow↗
PubMed1999

The relative extent and propensity of CD34+ vs. CD34- cells to undergo apoptosis in myelodysplastic marrows.

The paradox of peripheral cytopenias despite cellular bone marrow (BM) observed in myelodysplastic syndromes (MDS) has been associated with excessive intramedullary apoptosis of hematopoietic cells. Since MDS is regarded as a stem cell disorder, the present studies were undertaken to examine the relative susceptibility and propensity of early progenitor CD34+ cells to undergo apoptosis as compared to more maturing/matured CD34- cells. Five serial studies were performed on 4 independent groups of 36 newly diagnosed MDS patients. First, in 2 separate groups of 16 and 8 patients each, measurement of the extent of apoptosis in CD34+ and CD34- fractions of the BM aspirate mononuclear cells was carried out using independent biparametric flow cytometry methods, CD34 labeling/terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) (n = 16), and CD34 labeling/reduced uptake of nucleic acid staining dye LDS751 (n = 8). The difference in the median degrees of apoptosis in CD34+ vs. CD34- cells was not statistically significant by either technique (P = 0.583 and P = 0.674 for TUNEL and LDS751, respectively). In the next group of 4 MDS patients, a double-labeling was performed on plastic embedded marrow biopsy sections, to detect CD34 antigen with specific monoclonal antibody and apoptosis by in situ end labeling (ISEL) of fragmented DNA. Despite high overall apoptosis (56.2% +/- 18.4%), only an occasional CD34+ cell was found to be simultaneously labeled with ISEL. Finally, in the last group of 8 MDS patients, CD34+ cells were separated from CD34- cells on affinity column and cultured in serum containing medium for 4 hours. At 0- and 4-hour time points, ISEL was carried out to label apoptotic cells. In addition, a fluorometric assay was employed to estimate the activity of a proapoptotic enzyme, Caspase 3. Both the net increase in % ISEL labeled cells (apoptotic index or AI) and Caspase-3 activity were significantly lower in CD34+ cells as compared to CD34- cells (AI, 0.87% +/- 0.5% vs. 3.97% +/- 1.4%, n = 6, P = 0.028 and Caspase-3 Units/mg protein, 46.9 +/- 25.0 vs. 71.7 +/- 23.03, n = 5, P = 0.042, respectively). We conclude that when estimated in a total population of mononuclear cells, CD34+ cells and CD34- cells show comparable degrees of apoptosis. However, once separated the CD34+ fraction demonstrates lower propensity to undergo apoptosis, thereby suggesting the CD34- fraction as being a possible source for proapoptotic signaling.

Aged↗
PubMed1999

Spontaneous down-regulation of Fas-associated phosphatase-1 may contribute to excessive apoptosis in myelodysplastic marrows.

In this study, we examined the role of Fas-signaling in the apoptotic pathway in myelodysplastic syndromes (MDS). Ficoll-separated mononuclear cells from 18 bone marrow aspirate specimens obtained from 17 MDS patients, 4 normal healthy donors, and 3 acute myeloid leukemia patients transformed from MDS (t-AML) were studied for mRNA expression of Fas-L, Fas, and the effectors of their signaling, Caspase 1 and Caspase 3, using reverse transcriptase polymerase chain reaction. Fas-L, Fas, and Caspase 1 were detectable in all of the samples in the three groups. Caspase 3 was detectable both in MDS and t-AML specimens but was negligible in normal cells. The apoptotic index (AI%) determined by in situ end labeling of fragmented DNA in 4-hour cultures of mononuclear cells was significantly higher in MDS cells compared to normal or t-AML cells (mean +/- SEM: 2.3% +/- 0.4% in MDS, n = 10 vs. 0.6% +/- 0.2%, n = 4, P = 0.014 in normal cells, and 0.2% +/- 0.2%, n = 3, P = 0.007 in t-AML cells). Treatment of MDS cells with anti-Fas-L antibody suppressed apoptosis (AI%: 2.1% +/- 0.6% in untreated vs. 1.37% +/- 0.5% in treated, n = 6, P = 0.02), indicating functional participation of Fas-signaling in MDS. Further, it was found that Fas-L, Fas, and Caspase 1 mRNA expression remained unchanged in 4 hours. Caspase 3 expression appeared in normal cells after 4 hours and was present at both 0 and 4 hours in MDS and t-AML cells. In contrast to persistent expression in normal and t-AML cells, cells from the 5 MDS patients studied consistently showed significantly lowered or undetectable expression of a negative regulator of Fas, called Fas-associated phosphatase-1 (Fap-1) after 4 hours. Thus, the high AI% in MDS corresponds to a rapid decline in Fap-1. Furthermore, in tumor necrosis factor alpha (TNF-alpha) treated HL60 promyelocytic cells, a definite periodicity in the expression of different mRNAs was observed with upregulation of TNF-alpha itself at 30 minutes, increased expression of Fas and the appearance of Fas-L after 2 hours, and a decrease in Fap-1 expression after 8 hours. These results suggest that TNF-alpha not only induces the effectors of Fas-signaling but also may downregulate the inhibitor. We conclude that a spontaneous and rapid down-regulation of Fap-1, possibly induced by TNF-alpha, a cytokine shown to be present in excess in MDS marrows, may underlie the increased apoptotic death of hematopoietic cells in these patients. Interference with Fap-1 turnover may provide a new therapeutic modality for MDS.

Apoptosis↗
PubMed1998

Initial transforming event in myelodysplastic syndromes may be viral: case for cytomegalovirus.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders which begin in a pluripotential bone marrow (BM) stem cell. This early stem cell is believed to acquire a growth advantage over its neighbors as a result of an initial transforming event, the nature of which has remained obscure. In this paper, we propose that pathogens such as those belonging to the herpesvirus family of DNA viruses may play a role in the initial transformation of the stem cell. The case for cytomegalovirus (CMV) as a representative of this family of viruses is discussed at length and a molecular mechanism which may be involved in the oncogenic activity of CMV is proposed. No proof has been presented to implicate CMV directly in MDS, but circumstantial evidence which supports such a possibility is provided.

Apoptosis↗
PubMed1998

Hypothesis: myelodysplastic syndromes may have a viral etiology.

An 'initial transforming event(s)' in a pluripotential bone marrow (BM) stem cell confers a growth advantage upon it leading to clonal expansion accompanied by dysplastic maturation resulting in myelodysplastic syndromes (MDS). The nature of this 'initial' event in MDS is obscure. We propose that MDS can begin as a viral disease. It may be a dormant lentivirus which is made oncogenic by 'promoting events' such as immunosuppression, or a second viral infection. The infected cell may not be a BM stem cell, but a cell belonging to the BM stroma or to the immune system. Dysregulated cytokine production as a consequence of the infection can change the BM microenvironment in such a way that optimal growth support is provided only to a rapidly proliferating stem cell. Karyotypically marked (or unmarked) abnormal stem cells may exist or arise frequently but do not thrive in a 'normal' cytokine milieu. However, with the changed BM landscape, these abnormal clones may enjoy a growth advantage leading to a monoclonal hypercellular BM and variable cytopenias. Circumstantial evidence to support the possibility that the initial transforming event in MDS is a viral insult is presented in this hypothesis paper.

Cell Transformation, Viral↗
PubMed1998

Apparent expansion of CD34+ cells during the evolution of myelodysplastic syndromes to acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are highly proliferative bone marrow (BM) disorders where the primary lesion presumably affects a CD34+ early progenitor or stem cell. We investigated the proliferative characteristics of CD34+ cells of 33 untreated MDS patients (19 RA, 5 RARS, 7 RAEB, 2 RAEBt) and five patients with acute myeloid leukemia after MDS (sAML). All patients received a 1-h infusion of the thymidine analogue iodoor bromodeoxyuridine intravenously before a BM aspirate and biopsy was taken. A double-labeling immunohistochemistry technique by monoclonal anti-CD34 (QBend/10) and anti-IUdR/BrdU antibodies was developed and performed. By this technique we recognised CD34+ and CD34- cells actively engaged in DNA synthesis or not. As MDS evolves a significant increase occurred in the percentage of CD34+ cells of all myeloid cells (mean value: RA/RARS 1.67%; RAEB(t) 8.68%; sAML 23.83%) as well as in the percentage of proliferating CD34+ cells of all myeloid cells (RA/RARS 0.19%; RAEB(t) 0.43%; and sAML 3.30%). This was associated with a decreasing trend in the overall myeloid labeling index (LI: RA/RARS 25.8%, RAEB(t) 24.6% and sAML 21.5%). This decrease in overall myeloid LI is due to an exponential increase in the proportion of CD34+ cells of the proliferating compartment during MDS evolution (RA/RARS 0.35%, RAEB(t) 1.44% and sAML 11.98% of all S-phase cells). These CD34+ cells appeared to proliferate more slowly than their more mature CD34 negative counterparts, since we found a progressive increment in the mean total cell cycling time (Tc) of all myeloid cells during MDS progression (RA/RARS 39.8, RAEB(t) 45.2 and sAML 65.8 h). This study showed that during MDS evolution to sAML the CD34+ compartment develops a growth advantage leading to apparent expansion.

Acute Disease↗
PubMed1998

Endobrst: simple and safe is best.

Minimal-access treatment for ureteropelvic junction (UPJ) obstruction is becoming increasingly complex. Is there still a place for the simple procedure of balloon dilatation? To examine the symptomatic and renographic results of patients at least 6 months after balloon disruption of an obstructed UPJ, we carried out a prospective audit of outcome as judged by DTPA renograms and clinical follow-up. The procedure has been performed on a total of 21 renal units (20 patients) with follow-up of 6 to 30 months (mean 22 months). Of these, 18 (86%) were asymptomatic at 3 months, although this success rate dropped to 17 (81%) by 6 months. Renographic split function improved in 11 renal units, and excretion improve in 14. Perioperative complications were few and associated with stent insertion. Three of the patients in whom the procedure failed went on to nephrectomy (14%); all had poor renal function (split <20%) at presentation. Although the quoted success rates are lower for endoluminal balloon rupture of stenosis treatment than open pyeloplasty, the former technique has significantly less morbidity. Our nephrectomy rate reflects our less than ideal early patient selection, and our balloon dilation technique is not recommended as a salvage procedure for patients in whom nephrectomy is inevitable. The learning curve is quick to climb, and this is a fundamentally simple procedure with medium-term results that remain encouraging.

Adult↗
PubMed1998

Tumor necrosis factor-alpha levels decrease with anticytokine therapy in patients with myelodysplastic syndromes.

Tumor necrosis factor-alpha (TNF-alpha) levels were measured in the serum (sTNF-alpha) or bone marrow (BM) biopsies of 43 patients with myelodysplastic syndromes (MDS) who subsequently received therapy with a combination of pentoxifylline and ciprofloxacin (PC) with or without dexamethasone (PCD). All 43 patients received only PC therapy for 12 weeks, after which 18 of 36 nonresponders received PCD. A total of 18 of 43 patients showed a hematologic or cytogenetic response or both. BM TNF-alpha levels were semiquantitatively assessed using immunohistochemistry on a scale of 0-8+ and in the serum using enzyme linked immunoassay. The median TNF-alpha for the entire group was 3.0 in BM and 6.9 pg/ml in the serum, and 14 patients had no detectable levels. Responders had higher BM levels (median 3.5 vs. 2.0) than nonresponders, although this was not statistically significant. During PC therapy, a decline in BM TNF-alpha level was seen in the entire group, which was significant at 2 weeks (p = 0.02), 8 weeks (p = 0.001), and 12 weeks (p = 0.0001). Both responders (p = 0.01) and nonresponders (p = 0.03) had a decline at 8 weeks, but at 12 weeks, only the responders continued to show a significant decline (p = 0.03). We conclude that MDS patients with high BM TNF-alpa levels have a better chance of responding to PCD therapy and that the therapy is quite successful in reducing the TNF-alpha levels in a sustained fashion. Future studies need to be directed at identifying agents that would be more potent suppressors of the proapoptotic cytokines in these patients.

Aged↗
PubMed1997

Detection of hyperdiploid malignant cells in body cavity effusions by fluoresence in situ hybridization on ThinPrep slides.

BACKGROUND: Benign body cavity effusions sometimes cannot be distinguished from malignant ones by conventional cytology. The authors performed fluorescence in situ hybridization (FISH) on ThinPrep slides using chromosome specific probes to see if hyperdiploid malignant cells could be detected in 20 body cavity effusions. The results were then compared with those of conventional cytology. METHODS: A total of 20 body cavity effusions from 19 patients were studied using conventional cytology and FISH. Probes specific for chromosomes 3, 8, 10, and 12 were used to detect hyperdiploidy on ThinPrep slides (Cytyc Corporation, Boxborough, MA). RESULTS: A total of 13 patients had malignant conditions (either prior history of malignancy or the presence of malignancy anywhere in the body). Conventional cytology and FISH were both positive in 5 of these patients (6 samples) and negative in 2 patients. The results for one sample were inconclusive by both methods. There were 5 discrepant cytology-FISH results in patients with malignant conditions. One sample was positive by FISH and negative by cytology, one was positive by FISH and "atypical" by cytology, and three were inconclusive by FISH and negative by cytology. FISH results were either negative (in 4 samples) or inconclusive (in 2 samples) in the 6 patients with benign conditions. CONCLUSIONS: FISH can detect hyperdiploid malignant cells in body cavity effusions and is especially useful when the major cell population consists of malignant cells that cannot be differentiated from mesothelial or "atypical" cells. It is less useful in detecting a small population of malignant cells hidden in an inflammatory or reactive cell background. More studies are needed to establish diagnostic criteria further and to assess the clinical usefulness of this procedure.

Adult↗
PubMed1997

Local anesthesia for fine-needle aspiration biopsy of palpable breast masses: the effectiveness of a jet injection system.

To determine the effectiveness of the Biojector 2000 needle-free lidocaine injection system in achieving satisfactory local anesthesia for fine-needle aspiration (FNA) of palpable breast lesions, we studied 29 female patients. Each patient served as her own control and had two FNA biopsies performed on the lesion. The first FNA biopsy was preceded by either no anesthesia, ethyl chloride cold spray, or traditional needle lidocaine injection. The second FNA was preceded by the Biojector 2000. Twenty-four patients (83%) reported that they preferred the Biojector 2000 over either no anesthesia, ethyl chloride spray, or needle and syringe lidocaine injection. The Biojector 2000 needle-free injection system is an effective and useful method of local anesthesia for FNA of palpable breast masses.

Adult↗
PubMed1997

Cytokines, molecular biological abnormalities, and acute myelogenous leukemia.

Leukemia cell proliferation is dependent upon cytokines produced by the leukemia cells or by the microenvironment under stimulation by leukemia cells. Abnormal expression of the p53, rb, and ras genes is associated with cytokine production, suggesting that abnormal expression can affect leukemia cells by affecting intracellular growth controls and by stimulating cytokine production. While these observations suggest that cytokines can be used to stimulate leukemia proliferation during cytotoxic therapy increasing the sensitivity to treatment, they also suggest that inhibition of cytokine affects could increase clinical responses by reducing leukemia cell regrowth between courses of therapy.

Animals↗
PubMed1997

Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase.

Chronic myelogenous leukemia (CML) has a progressive course but little is known about the biologic characteristics of disease progression. This study was designed to assess the changes in cell proliferative characteristics, apoptosis, the expression of the bcl-2 and c-myc genes between the time of initial diagnosis and entrance into the blastic phase of the disease. We observed that the rate of cell proliferation decreased and the cell death rate did not significantly change as the disease accelerated. The level of bcl-2 expression was significantly higher in accelerated/blastic phase cells than in the chronic phase cells in the population as a whole, however, the bcl-2 expression level did not change in blast cell subpopulation. c-myc Expression was significantly higher in the blast cell subpopulation of accelerated/blastic phase than in that of earlier phases of the disease. In conclusion, the characteristics of CML cells, namely proliferation rate, c-myc and bcl-2 change during the course of the disease. It is possible that the change in c-myc expression plays a causative role in evolution of the blastic phase from the chronic phase.

Adult↗
PubMed1997

Regrowth resistance as a likely significant contributor to treatment failure in drug-sensitive neoplastic diseases.

Attempts to improve the effectiveness of therapy for neoplastic diseases have largely focused on increasing the cytotoxic efficacy of therapy. While this approach is logical, there is another approach, based on the concept of regrowth resistance, which offers an alternate means of improving treatment outcome. The term "regrowth resistance" refers to the reduction in treatment efficacy resulting from the regrowth of neoplastic cells between courses of therapy or even between doses of radiation therapy. Regrowth resistance is likely to play a significant role in determining the outcome of treatment in rapidly proliferating neoplasms. A reduction in the rate of tumor regrowth would increase the net effectiveness of cytotoxic therapy and would also inhibit the development of resistance to cytotoxic therapies.

Cell Division↗
PubMed1997

Excessive proliferation matched by excessive apoptosis in myelodysplastic syndromes: the cause-effect relationship.

The paradox of pancytopenia despite cellular bone marrows (BM) was investigated in 120 patients with myelodysplastic syndromes (MDS). Detailed cell cycle kinetics were examined following in vivo infusions of iodo--and/or bromodeoxyuridine (IUdR/BrdU), while the incidence of apoptosis was measured by in situ end labeling (ISEL) of fragmented DNA. Results showed that MDS are highly proliferative disorders with an equally high incidence of apoptotic intramedullary cell death accounting for the paradox of cellularity/cytopenia. By double-labeling BM biopsy sections for ISEL/BrdU we found the peculiar situation of "signal antonymy" where S-phase cells were frequently apoptotic, a phenomenon so far only seen in MDS biopsies. The cause-effect relationship of this excessive proliferation/apoptosis is discussed at length.

Apoptosis↗
PubMed1997

Cell cycle kinetic studies in 68 patients with myelodysplastic syndromes following intravenous iodo- and/or bromodeoxyuridine.

Sixty-eight patients with myelodysplastic syndromes (MDS) received sequential infusions of iodo- and/or bromodeoxyuridine for cell kinetic analysis. Bone marrow biopsy sections were treated by appropriate antibodies and a labeling index (LI), duration of S-phase (Ts), and total cell cycle time (Tc) of myeloid cells were determined. The mean LI was 28.4%, Ts was 11.8 hours and Tc was 40.7 hours. The %LI decreased as the disease evolved from refractory anemia toward transformation to acute leukemia (p = 0.04). Double-labeling of biopsy sections for apoptosis and proliferation showed that 30-90% of S-phase cells in MDS patients were simultaneously apoptotic or "antonymous." We conclude that MDS are highly proliferative disorders in which the ineffective hematopoiesis is probably the result of excessive apoptosis rather than slow proliferation.

Apoptosis↗