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Biomedical subjects

Terry Hamblin

Publications and source records attributed to Terry Hamblin.

11 recordsLinked to original sources
PubMed2005

Natural products and the treatment of leukemia.

Plants have been the source of many medicines in the pharmacopoeia. So much so that an industry has arisen selling plant extracts as health foods. To a great degree it operates over the internet and it chiefly caters to the worried well. However, cancer patients frequently take plant extracts in addition to their prescribed medicines. These extracts are not biologically inactive, and many have important pro-apoptotic effects on cancer cell-lines in vitro. In this issue a study of the in vivo effects of green tea extract in low grade lymphomas is reported. The results are sufficiently encouraging to initiate a formal clinical trial.

Anticarcinogenic Agents↗
PubMed2005

Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk-adapted therapeutic strategies.

BACKGROUND AND OBJECTIVES: Many years ago it was established that prompt treatment of early stage chronic lymphocytic leukemia (CLL), the stage at which almost two-thirds of CLL patients present, has no benefit over a management of watching and waiting, then treating progression. However, this fact was based on series treated ineffectually with chlorambucil, which were not stratified according to prognostic markers. DESIGN AND METHODS: The prognosis and clinical course of CLL are heterogeneous. While some patients may have a normal life expectancy without requiring treatment, others die of drug-resistant disease as early as within two years of presentation. However, unlike the situation in non-Hodgkin's lymphoma, there is no standard Prognostic Index that can be used to group patients with CLL according to likely outcome or to guide treatment. RESULTS: A number of clinical and biological factors of prognostic relevance, which may add to the classical assessment provided by the staging systems, have been identified. These include clinical characteristics, such as age, gender and performance status, and laboratory parameters reflecting the tumor burden or disease activity, such as lymphocyte count, lactate dehydrogenase (LDH) increase, bone marrow infiltration pattern or lymphocyte doubling time. Recently more informative prognostic parameters have been identified: serum markers such as soluble CD23, b2-microglobulin or thymidine kinase and genetic markers of tumor cells, such as genomic aberrations, gene abnormalities (p53, ATM), the mutation status of the variable segments of the immunoglobulin heavy chain genes (IGVH) or surrogate markers for these factors, such as CD38 and ZAP-70. INTERPRETATION AND CONCLUSIONS: From the clinician's perspective the importance of this new knowledge is how it affects treatment. It is now possible to produce molecular remissions even in advanced disease using combinations of purine analogs and monoclonal antibodies. Moreover, potentially curative therapeutic modalities such as autologous and allogeneic stem cell transplantation are becoming safer. Clinical trials of effective treatment stratified by more reliable prognostic markers are surely now warranted.

Biomarkers↗
PubMed2004

Common patterns of B cell perturbation and expanded V4-34 immunoglobulin gene usage in autoimmunity and infection.

Features of the lymphocyte population in systemic lupus erythematosus (SLE) include a disordered B cell profile and production of autoantibodies. An additional distinctive perturbation is the overexpression of V4-34-encoded serum immunoglobulins (Ig). A similar rise in V4-34-encoded Ig occurs in normal subjects following infection with certain herpesviruses, and is found in Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). To assess common and distinctive features of B cells in patients with SLE and IM, we compared the B cell profile and V4-34 gene involvement in patients with SLE and IM. B cell profiles from patients with IM paralleled those of patients with SLE, showing a differential loss of naïve and memory B cells and the maintenance of plasmablast/early plasma cells. Class-switched V4-34-encoded IgG from plasmablast/early plasma cells was evident both in patients with SLE and IM and revealed common features of oligoclonal expansions with most having undergone somatic hypermutation. It has been proposed that, in healthy individuals, expression of the V4-34 gene is specifically censored prior to isotype switch as a control on autoreactivity. If so, censoring is bypassed following EBV infection, after which equilibrium is restored. Continuing high serum levels in SLE may arise either by disordered regulation, or by subclinical reactivation of endogenous virus.

Amino Acid Sequence↗
PubMed2003

Adaptor protein 3-dependent microtubule-mediated movement of lytic granules to the immunological synapse.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. Individuals with HPS type 2 (HPS2) lack the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting, and are also immunodeficient. Here we characterize an HPS2 mutation and demonstrate that AP-3 deficiency leads to a loss of cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Although the lysosomal protein CD63 was mislocalized to the plasma membrane, perforin and granzymes were correctly localized to the lytic granules in AP-3-deficient CTLs. However, the lytic granules of AP-3-deficient CTLs were enlarged and were unable to move along microtubules and dock within the secretory domain of the immunological synapse. These data show that AP-3 is essential for polarized secretion from CTLs.

Adaptor Protein Complex 3↗
PubMed2002

Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia.

The mutational status of tumor immunoglobulin V(H) genes is providing a powerful prognostic marker for chronic lymphocytic leukemia (CLL), with patients having tumors expressing unmutated V(H) genes being in a less favorable subset. However, the biologic differences correlating with V(H) gene status that could determine the clinical course of the disease are unknown. Here we show that differing responses to IgM ligation are closely associated with V(H) gene status. Specifically, 80% of cases with unmutated V(H) genes showed increased global tyrosine phosphorylation following IgM ligation, whereas only 20% of samples with mutated V(H) genes responded (P =.0002). There was also an association between response to IgM ligation and expression of CD38 (P =.015). The Syk kinase, critical for transducing B-cell receptor (BCR)- derived signals, was constitutively present in all CLL samples, and there was a perfect association between global phosphorylation and induction of phosphorylation/activation of Syk. Nonresponsiveness to anti-IgM could be circumvented by ligation of IgD (10 of 15 samples tested) or the BCR-associated molecule CD79alpha (12 of 15 samples tested). These results suggest that multiple mechanisms underlie nonresponsiveness to anti-IgM in CLL and that retained responsiveness to anti-IgM contributes to the poor prognosis associated with the unmutated subset of CLL. The prognostic power of the in vitro response to IgM ligation remains to be determined in a large series, but the simple technology involved may present an alternative or additional test for predicting clinical course.

ADP-ribosyl Cyclase↗