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D P Steensma

Publications and source records attributed to D P Steensma.

At least 19 recordsLinked to original sources
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↗
PubMed2005

On the TRAIL of a new therapy for leukemia.

The cytokine TRAIL (tumor necrosis factor alpha-related apoptosis-inducing ligand) as well as agonistic antibodies that bind to the TRAIL receptors, death receptor 4 (DR4) and DR5, are undergoing preclinical and early clinical evaluation as potential therapeutic agents for a variety of hematological and nonhematological malignancies. Here, we briefly review the normal biological function of TRAIL, the mechanism of cytotoxicity of TRAIL receptor ligands, and their effects on normal myeloid progenitors, myelodysplastic marrow and leukemic cells, including acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), in vitro. Recent observations suggesting that DR4 is the predominant receptor for the cytotoxic effects of TRAIL in CLL and that histone deacetylase inhibitors synergize with TRAIL in CLL in vitro are described and discussed. Collectively, the reviewed studies not only illustrate the potential therapeutic usefulness of TRAIL and the agonistic antibodies, but also highlight the need for additional preclinical evaluation of these agents.

Apoptosis↗
PubMed2001

A high bone marrow plasma cell labeling index in stable plateau-phase multiple myeloma is a marker for early disease progression and death.

The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain-restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P < .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.

Bone Marrow↗
PubMed2001

The narrow path.

Explore the source record for details and available documents.

Female↗
PubMed2001

Amifostine alone and in combination with erythropoietin for the treatment of favorable myelodysplastic syndrome.

Ten anemic patients with favorable myelodysplastic syndrome (MDS) were first treated with two 5-week courses of amifostine alone (each course consisted of 200 mg/m(2) of the drug given intravenously three times a week for 3 weeks), followed by an additional two courses combined with subcutaneous erythropoietin (EPO) (150 U/kg, three times a week for 8 weeks). The study patients either had previously failed to respond to treatment with EPO or had pretreatment serum EPO levels of more than 100 mU/ml. None of the patients experienced a complete or partial response in anemia or other cytopenias. We conclude that amifostine alone or in combination with EPO has limited therapeutic activity in MDS.

Aged↗
PubMed2001

Hereditary red blood cell disorders in middle eastern patients.

Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.

Anemia, Hemolytic, Congenital↗
PubMed2001

"Congo" red: out of Africa?

CONTEXT: Congo red is the essential histologic stain for demonstrating the presence of amyloidosis in fixed tissues. To the best of my knowledge, nothing has been written about why the stain is named "Congo." OBJECTIVE: To understand the etymology and history of the Congo red histologic stain. DESIGN: Primary sources were consulted extensively, including 19th-century corporate documents, newspapers, legal briefs, patents, memoirs, and scientific papers. SETTING: Sources were obtained from multiple university libraries and German corporate archives. RESULTS: To Europeans in 1885, the word Congo evoked exotic images of far-off central Africa known as The Dark Continent. The African Congo was also a political flashpoint during the Age of Colonialism. "Congo" red was introduced in Berlin in 1885 as the first of the economically lucrative direct textile dyes. A patent on Congo red was filed by the AGFA Corporation of Berlin 3 weeks after the conclusion of the well-publicized Berlin West Africa Conference. During these important diplomatic talks, German Chancellor Otto von Bismarck presided over a discussion of free trade issues in the Congo River basin. A challenge to AGFA's Congo red patent led to a precedent-setting decision in intellectual property law. CONCLUSIONS: The Congo red stain was named "Congo" for marketing purposes by a German textile dyestuff company in 1885, reflecting geopolitical current events of that time.

Africa↗
PubMed2000

Littoral cell angioma associated with portal hypertension and resected colon cancer.

Littoral cell angioma (LCA) is a rare vascular tumor of the spleen with an unknown etiology and unclear natural history. An association with synchronous malignancy has been described. We report the case of a 54-year-old woman who had progressive splenomegaly over 3 years following resection of a colon adenocarcinoma. The splenomegaly was associated with portal hypertension and severe thrombocytopenia. Splenectomy was performed, and the histologic and immunocytochemical features of the spleen specimen were consistent with LCA. The relationship between LCA and malignancy is reviewed.

Adenocarcinoma↗
PubMed2000

Lymphadenopathy.

Lymphadenopathy can occur in any age group, in symptomatic or asymptomatic patients, and in a single site or at multiple sites. Lymphadenopathy is associated with numerous disorders. An abnormal lymph node may be observed or palpated by the patient, found by a health care worker, or discovered through radiologic evaluation. Lymphadenopathy may be a part of a complex case presentation, or the clinical cause may be straightforward. Patients with potentially curable malignant disorders may have lymphadenopathy as the first sign of their disease. This review of lymphadenopathy summarizes general considerations, discusses which patients might be considered for biopsy, reviews which nodes are most likely to be diagnostic, outlines initial diagnostic considerations on a region-by-region basis, and reviews a broad differential diagnosis for adenopathy.

Age Factors↗
PubMed2000

Autoimmune hemolytic anemia in a patient with autosomal dominant chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is a heterogeneous immunodeficiency syndrome characterized by recurrent candidal infections of the skin, nails, and mucous membranes. The syndrome can be associated with autoimmune conditions, especially endocrine disorders. Typically, inheritance is autosomal recessive, and abnormal T-cell-mediated immunity is thought to be the underlying deficit. We describe a 27-year-old man with chronic mucocutaneous candidiasis inherited in an autosomal dominant fashion, in whom both lymphocyte blastogenesis and delayed-type skin reactivity to Candida antigens were normal. Notable features of the case include autoimmune hemolytic anemia, probable hypoparathyroidism, and hypogonadal hypogonadism.

Adult↗