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Biomedical subjects

R F McClure

Publications and source records attributed to R F McClure.

17 recordsLinked to original sources
PubMed2006

Risk stratification for survival and leukemic transformation in essential thrombocythemia: a single institutional study of 605 patients.

Unlike the case with thrombosis, prognostic models for survival and leukemic transformation (LT) in essential thrombocythemia (ET) are not available. Among 605 patients with ET seen at our institution and followed for a median of 84 months, 155 died and LT was documented in 20 patients (3.3%). In a multivariable analysis, hemoglobin level below normal (females<120 g/l; males<135 g/l) was identified as an independent risk factor for both inferior survival and LT. Additional risk factors for survival included age > or =60 years, leukocyte count> or =15 x 10(9)/l, smoking, diabetes mellitus and thrombosis. For LT, platelet count> or =1000 x 10(9)/l but not cytoreductive therapy was flagged as an additional independent risk factor. In fact, four of the 20 patients (20%) with LT were untreated previously. We used the above information to construct prognostic models that effectively discriminated among low-, intermediate- and high-risk groups with respective median survivals of 278, 200 and 111 months (P<0.0001), and LT rates of 0.4, 4.8 and 6.5% (P=0.0009) respectively. Presence of JAK2V617F did not impact either survival or LT and mutational frequency was similar among the different risk groups.

Adolescent↗
PubMed2006

Novel FISH probes designed to detect IGK-MYC and IGL-MYC rearrangements in B-cell lineage malignancy identify a new breakpoint cluster region designated BVR2.

Detection of translocations involving MYC at 8q24.1 in B-cell lineage malignancies (BCL) is important for diagnostic and prognostic purposes. However, routine detection of MYC translocations is often hampered by the wide variation in breakpoint location within the MYC region, particularly when a gene other than IGH, such as IGK or IGL, is involved. To address this issue, we developed and validated four fluorescence in situ hybridization (FISH) probes: two break apart probes to detect IGK and IGL translocations, and two dual-color, dual-fusion FISH (D-FISH) probes to detect IGK-MYC and IGL-MYC. MYC rearrangements (four IGK-MYC, 12 IGL-MYC and four unknown partner gene-MYC) were correctly identified in 20 of 20 archival BCL specimens known to have MYC rearrangements not involving IGH. Seven specimens, all of which lacked MYC rearrangements using a commercial IGH/MYC D-FISH probe, were found to have 8q24 breakpoints within a cluster region >350-645 kb 3' from MYC, provisionally designated as Burkitt variant rearrangement region 2 (BVR2). FISH is a useful ancillary tool in identifying MYC rearrangements. In light of the discovery of the distally located BVR2 breakpoint cluster region, it is important to use MYC FISH probes that cover a breakpoint region at least 1.0 Mb 3' of MYC.

B-Lymphocytes↗
PubMed2006

Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia.

An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (P<0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n=50) compared to controls (median 66%, n=9) or other myeloproliferative disorder patients (median 53%, n=11; P=0.002). Apoptotic resistance in MMM correlated with anemia (P=0.01) and the JAK2-V617F (P=0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n=5) than with intermediate burden (median 39%, n=23) or wild-type JAK2 (median 47%, n=22; P=0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.

Alleles↗
PubMed2006

JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained.

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.

Acute Disease↗
PubMed2004

Use of multiple displacement amplification to amplify genomic DNA before sequencing of the alpha and beta haemoglobin genes.

AIMS: To evaluate the technique of multiple displacement amplification (MDA) for whole genome amplification from small volume blood samples before sequencing in a clinical test to identify haemoglobin gene mutations. METHODS: Phage phi29 DNA polymerase was used to perform MDA, starting with either 1 micro l of blood or 1 ng of previously isolated blood DNA from 23 patients. The amplified products were then evaluated using a clinical test that involves sequencing the haemoglobin genes to detect mutations. The results were compared with the current clinical test method that uses genomic DNA isolated using column based technology. RESULTS: The MDA technique produced large quantities (theoretically approximately 2 mg) of DNA. The amplification procedure was extremely easy and took about four hours (less than one hour of hands on technician time and three hours for amplification). When MDA products were used in the same clinical test protocol as genomic DNA isolated using column technology, there was 100% concordance for detection of a variety of point mutations in the alpha1, alpha2, and beta globin genes. CONCLUSIONS: The MDA technique is useful for overcoming the problem of insufficient genomic DNA in clinical specimens requiring haemoglobin gene sequencing and could be useful for other clinical applications.

Base Sequence↗
PubMed2001

Serous borderline tumor of the paratestis: a report of seven cases.

We report the clinical, morphologic, immunophenotypic, and ploidy findings of seven cases of serous borderline tumor of the paratestis. Mean patient age was 56 years (range, 14-77 years), and the clinical presentation was that of a testicular mass. Tumors ranged in size from 1 to 6 cm (mean, 3.5 cm). Six tumors arose from the tunica albuginea, and two of these tumors were intratesticular. One tumor arose from the tunica vaginalis. Serous borderline tumor of the paratestis is histologically identical to its ovarian counterpart. The tumors were cystic with numerous intracystic blunt papillae lined by stratified epithelial cells with minimal to mild cytologic atypia. Psammoma bodies were present in two cases. In all cases, the neoplastic cells stained strongly and diffusely for cytokeratin 7, estrogen receptor, and CD15, and six of seven cases were positive for progesterone receptor and MOC-31. The cells did not stain for cytokeratin 20, carcinoembryonic antigen, calretinin, and HER2/neu. Proliferative activity, as assessed by MIB-1 staining, ranged from 1.3% to 10% (mean, 5.5%). Five of six tumors were diploid, and one was tetraploid. Patients were treated by radical orchiectomy and followed up from 4 months to 18 years (mean, 48 months; median, 8.5 months). No recurrences or metastases occurred. Serous borderline tumor of the paratestis is morphologically and immunophenotypically identical to ovarian serous borderline tumor. To date, no serous borderline tumor of the paratestis reported in the literature or in our series has recurred or metastasized after resection.

Adenocarcinoma↗
PubMed1999

Constitutive Fas ligand gene transcription in Sertoli cells is regulated by Sp1.

The transcriptional regulation of the Fas ligand (FasL) gene in Sertoli cells was investigated, as these cells are known to have constitutive expression of FasL and hence maintain an "immune privileged" environment within the testicle. Using the Sertoli cell line TM4, it was demonstrated that a gene segment of the 5'-untranslated region located between -318 and -237 relative to the translation start site is required for constitutive FasL transcription. Deletion and mutation analysis demonstrate that an Sp1 rather than an NFAT or NFKB-like DNA binding motif present within this region is necessary and sufficient for constitutive FasL gene transcription. Nuclear extracts of Sertoli cells contain Sp1 and Sp3 that specifically binds to the Sp1 motif present in the FasL gene, and overexpression of Sp1 but not Sp3 leads to a further increase of transcription from the FasL promoter-enhancer region. The data presented demonstrates that constitutive FasL gene transcription in Sertoli cells is regulated by Sp1. In addition, it is shown that basal FasL expression in Jurkat T cells is also controlled by Sp1 and this is in contrast to induced FasL expression, which is NFAT-dependent.

Animals↗
PubMed1999

Isolated isochromosome 17q: a distinct type of mixed myeloproliferative disorder/myelodysplastic syndrome with an aggressive clinical course.

A clinicopathologic study was performed on 15 patients with haematological malignancies in which isochromosome 17q [i(17q)] was the sole structural chromosome abnormality identified in bone marrow. The data indicated that an isolated i(17q) is associated with a distinct type of mixed chronic myeloproliferative/myelodysplastic disorder with an aggressive clinical course. The patients ranged in age from 37 to 83 years (median 60) with a M:F ratio of 3:1. All cases were chronic myeloid disorders with mixed proliferative and dysplastic features, making classification difficult. 11 patients tested for BCR/ABL gene fusion were normal. A low bone marrow blast count (<5%) at presentation was a typical finding. All cases had severe myeloid dysplasia which included non-segmented neutrophils and an increase in the monocyte/macrophage lineage. Fluorescence in situ hybridization (FISH) analysis of one case showed the i(17q) to involve all myeloid lineages, but not the lymphocytes. For cases with complete follow-up (n = 11) the median survival was 2.5 years (range 0.83-5.25) and 64% progressed to AML prior to death. The following features were identified which defined the haematological disorder associated with an isolated i(17q): (1) adult patient, (2) chronic myeloid disorder with clonal involvement of all myeloid lineages, (3) mixed chronic myeloproliferative/myelodysplastic features, (4) severe hyposegmentation of neutrophil nuclei, (5) prominence of the monocyte/macrophage lineage, (6) high risk for progression to AML, and (7) median survival of 2.5 years.

Adult↗
PubMed1999

Do students studying therapy have more problems?

This study examined several questions on whether graduate students studying therapy reported more personal counseling or traumas than other students. The 66 students studying therapy did not report significantly different experiences or attitudes than 52 students in other areas, indicating that they did not seem to have more emotional problems or traumas than others.

Adult↗
PubMed1978

Admitting personal problems and outcomes in hospitalized psychiatric patients.

Willingness to admit that one has a serious emotional problem is part of a complex of attitudes that have a significant effect on behavioral outcomes of hospitalized psychiatric patients. Specifically, patients who admitted emotional problems were more likely to want to change than non-admitters. Further, admitters stayed in the hospitals a significantly shorter time and were less likely to return to the hospital within a year than patients not willing to admit problems. Other similar findings indicated that admitting problems and desire to change were better predictors of patients' outcome than staff physicians' opinions.

Adult↗
PubMedDate not supplied

Instructive case report. A 26-year-old Indian woman with seizures and multiple intracranial mass lesions.

We describe the case of a 26-year-old Indian woman who presented to our institution with seizures and papilledema. Her diagnosis was originally thought to be neurocysticercosis, but later confirmed to be intracranial tuberculoma. Antituberculous therapy with isoniazid, rifampin, pyrazinamide and ethambutol was initiated. Improvement in the patient's neurological symptoms with diminution in size of the intracerebral lesions was observed. This case illustrates the difficulty in distinguishing intracranial tuberculoma from neurocysticercosis. Radiological features that distinguish these two diseases are described. Both diseases must be considered in regions endemic for tuberculosis and cysticercosis.

Adult↗