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1.
Blood Cancer J ; 14(1): 50, 2024 Mar 18.
Article in English | MEDLINE | ID: mdl-38499538

ABSTRACT

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.


Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Humans , Immunoglobulin Light Chains , Mass Spectrometry , Multiple Myeloma/diagnosis , Multiple Myeloma/therapy , Progression-Free Survival , Transplantation, Autologous , Randomized Controlled Trials as Topic
2.
BMC Cancer ; 24(1): 174, 2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38317104

ABSTRACT

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).


Subject(s)
Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Paraproteinemias , Smoldering Multiple Myeloma , Humans , Adult , Monoclonal Gammopathy of Undetermined Significance/therapy , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Multiple Myeloma/diagnosis , Pilot Projects , Quality of Life , Disease Progression , Biomarkers , Exercise
3.
J Dent Res ; 100(11): 1220-1227, 2021 10.
Article in English | MEDLINE | ID: mdl-34077690

ABSTRACT

Dental care professionals (DCPs) are thought to be at enhanced risk of occupational exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, robust data to support this from large-scale seroepidemiological studies are lacking. We report a longitudinal seroprevalence analysis of antibodies to SARS-CoV-2 spike glycoprotein, with baseline sampling prior to large-scale practice reopening in July 2020 and follow-up postimplementation of new public health guidance on infection prevention control (IPC) and enhanced personal protective equipment (PPE). In total, 1,507 West Midlands DCPs were recruited into this study in June 2020. Baseline seroprevalence was determined using a combined IgGAM enzyme-linked immunosorbent assay and the cohort followed longitudinally for 6 mo until January/February 2021 through the second wave of the coronavirus disease 2019 pandemic in the United Kingdom and vaccination commencement. Baseline seroprevalence was 16.3%, compared to estimates in the regional population of 6% to 7%. Seropositivity was retained in over 70% of participants at 3- and 6-mo follow-up and conferred a 75% reduced risk of infection. Nonwhite ethnicity and living in areas of greater deprivation were associated with increased baseline seroprevalence. During follow-up, no polymerase chain reaction-proven infections occurred in individuals with a baseline anti-SARS-CoV-2 IgG level greater than 147.6 IU/ml with respect to the World Health Organization international standard 20-136. After vaccination, antibody responses were more rapid and of higher magnitude in those individuals who were seropositive at baseline. Natural infection with SARS-CoV-2 prior to enhanced PPE was significantly higher in DCPs than the regional population. Natural infection leads to a serological response that remains detectable in over 70% of individuals 6 mo after initial sampling and 9 mo from the peak of the first wave of the pandemic. This response is associated with protection from future infection. Even if serological responses wane, a single dose of the Pfizer-BioNTech 162b vaccine is associated with an antibody response indicative of immunological memory.


Subject(s)
COVID-19 , Vaccines , Dental Care , Humans , SARS-CoV-2 , Seroepidemiologic Studies , United Kingdom/epidemiology
4.
J Immunol Methods ; 494: 113046, 2021 07.
Article in English | MEDLINE | ID: mdl-33775672

ABSTRACT

BACKGROUND: Frequently SARS-CoV-2 results in mild or moderate disease with potentially lower concentrations of antibodies compared to those that are hospitalised. Here, we validated an ELISA using SARS-CoV-2 trimeric spike glycoprotein, with targeted detection of IgG, IgA and IgM (IgGAM) using serum and dried blood spots (DBS) from adults with mild or moderate disease. METHODS: Targeting the SARS-CoV-2 trimeric spike, a combined anti-IgG, IgA and IgM serology ELISA assay was developed using 62 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 624 COVID-19 negative samples. The assay was validated using 73 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 359 COVID-19 negative serum samples with an additional 81 DBSs. The assay was further validated in 226 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 426 COVID-19 negative clinical samples. RESULTS: A sensitivity and specificity of 98.6% (95% CI, 92.6-100.0), 98.3% (95% CI, 96.4-99.4), respectively, was observed following validation of the SARS-CoV-2 ELISA. No cross-reactivities with endemic coronaviruses or other human viruses were observed, and no change in results were recorded for interfering substances. The assay was stable at temperature extremes and components were stable for 15 days once opened. A matrix comparison showed DBS to correlate with serum results. Clinical validation of the assay reported a sensitivity of 94.7% (95% CI, 90.9-97.2%) and a specificity of 98.4% (95% CI, 96.6-99.3%). CONCLUSIONS: The human anti-IgGAM SARS-CoV-2 ELISA provides accurate and sensitive detection of SARS-CoV-2 antibodies in non-hospitalised adults with mild or moderate disease. The use of dried blood spots makes the assay accessible to the wider community.


Subject(s)
Antibodies, Viral/blood , COVID-19 Serological Testing , COVID-19 , SARS-CoV-2/metabolism , Adult , COVID-19/blood , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged
6.
Leukemia ; 32(1): 102-110, 2018 01.
Article in English | MEDLINE | ID: mdl-28584253

ABSTRACT

Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14) and 1.68 (P=2.18 × 10-14), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27) for all patients and 3.19 (P=1.23 × 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.


Subject(s)
Multiple Myeloma/diagnosis , Multiple Myeloma/pathology , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Chromosome Deletion , Clinical Trials, Phase III as Topic , Disease-Free Survival , Female , Humans , Male , Middle Aged , Multiple Myeloma/genetics , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Proportional Hazards Models , Translocation, Genetic/genetics , Transplantation, Autologous/methods
7.
Blood Cancer J ; 6(12): e506, 2016 12 09.
Article in English | MEDLINE | ID: mdl-27935580

ABSTRACT

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Multiple Myeloma/drug therapy , Neoplasms, Second Primary/drug therapy , Thalidomide/analogs & derivatives , Adult , Aged , Aged, 80 and over , Bortezomib/administration & dosage , Disease-Free Survival , Female , Humans , Hydroxamic Acids , Kaplan-Meier Estimate , Lenalidomide , Male , Middle Aged , Multiple Myeloma/epidemiology , Multiple Myeloma/pathology , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/pathology , Oligopeptides/administration & dosage , Risk Factors , Thalidomide/administration & dosage , Vorinostat
8.
Parasite Immunol ; 38(5): 317-25, 2016 05.
Article in English | MEDLINE | ID: mdl-27027867

ABSTRACT

Malaria in malaria-naïve adults is associated with an inflammatory response characterized by expression of specific activation markers on innate immune cells. Here, we investigate activation and adhesion marker expression, and cytokine production in monocytes from children presenting with cerebral malaria (CM, n = 36), severe malarial anaemia (SMA, n = 42) or uncomplicated malaria (UM, n = 66), and healthy aparasitemic children (n = 52) in Blantyre, Malawi. In all malaria groups, but particularly in the two severe malaria groups, monocyte expression of CD11b, CD11c, CD18, HLA-DR and CD86, and percentages of TNF-α- and IL-6-producing monocytes were lower than in healthy controls, while expression of CD11a, TLR2 and TLR4 was lower in children with severe malaria compared with controls. These levels mostly normalized during convalescence, but percentages of cytokine-producing monocytes remained suppressed in children with SMA. In all malaria groups, especially the SMA group, a greater proportion of monocytes were loaded with haemozoin than among controls. In a P. falciparum hyperendemic area, monocytes in children with acute symptomatic malaria have reduced expression of adhesion molecules and activation markers and reduced inflammatory cytokine production. This immune suppression could be due to accumulation of haemozoin and/or previous exposure to P. falciparum.


Subject(s)
Malaria, Cerebral/immunology , Malaria, Falciparum/immunology , Malaria/immunology , Monocytes/immunology , Antigens, CD/analysis , Child , Cytokines/analysis , Female , HLA-DR Antigens/analysis , Humans , Infant , Integrins/analysis , Male , Monocytes/chemistry , Toll-Like Receptors/analysis
9.
Brain Behav Immun ; 44: 32-6, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25451608

ABSTRACT

INTRODUCTION: Experimental animal studies provided evidence for a synergistic effect of immunological and psychological stressors on subsequent sickness behaviours. Up to now, little corroborating evidence for such synergy exists for humans, in whom it may provide a mechanism leading to the expression of functional somatic symptoms. The aim of the present study was to determine an interaction between stress(-vulnerability) and an immunological activation on experimental pain sensitivity, i.e., pressure pain threshold and tolerance in healthy humans. METHODS: In healthy female participants (n=25, mean age 22.3 years), negative affectivity (NA) and experienced stress were assessed by questionnaire before receiving a Salmonella typhi vaccine or saline control in a randomized blinded cross-over design. Pressure pain threshold was assessed at the lower back and calves and pain tolerance was assessed at the thumbnail, before and six hours after each injection. RESULTS: Vaccination induced leukocytosis (+100%) and increased serum IL-6 (+670%). NA predicted decreased pain tolerance after vaccination (ß=-.57, p=.007), but not after placebo (ß=.25, p=.26). Post-hoc analyses also demonstrated an association with administration order. DISCUSSION: NA moderated the effects of inflammation on pain tolerance. This finding is consistent with a synergistic model whereby inflammation may lower the threshold for pain reporting in individuals with increased vulnerability for somatic symptom reporting.


Subject(s)
Affect , Inflammation/psychology , Pain Threshold/psychology , Stress, Psychological , Adolescent , Adult , Cross-Over Studies , Female , Humans , Salmonella typhi , Vaccination , Young Adult
10.
J Thromb Haemost ; 9(5): 1056-66, 2011 May.
Article in English | MEDLINE | ID: mdl-21342432

ABSTRACT

OBJECTIVES: Monocytes include several subsets with different and sometimes divergent roles in immunity, atherogenesis and reparative processes. OBJECTIVES: We aimed to perform detailed immunophenotypic and functional characterization of human monocyte subsets. PATIENTS/METHODS: Analysis of surface markers of blood and bone marrow monocyte subsets and functional characterization of blood monocyte subsets in healthy volunteers was performed using flow cytometry. RESULTS: In the present study, we show the presence of three subsets which could be unequivocally distinguished by surface expression of CD14, CD16 and CCR2 as CD14(+)CD16(-)CCR2(+) (Mon1), CD14(+)CD16(+)CCR2(+) (Mon2) and CD14(low)CD16(+)CCR2(-) (Mon3) subsets. In comparison with the classic Mon1, the Mon2 subset had the highest expression of Tie2, CXCR4, CD163, CD115, receptors to inter-cellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), and the highest surface levels of apolipoprotein B and ferritin. In contrast, Mon3 had maximal expression of VCAM-1 receptors and CD204. The Mon2 and Mon3 subsets had significantly lower activity of the NFκB pathway than Mon1. Mon1 and Mon2 had similar phagocytic activity, which was significantly higher compared with Mon3. All three subsets were present in bone marrow, although the relative proportion of Mon2 in bone marrow was about 2.5-fold higher compared with that seen in blood. Significant differences in cytokine production in response to endotoxin stimulation were observed between the three monocyte subsets. CONCLUSION: Given their immunophenotypic similarity, the newly characterized Mon2 population may represent the previously reported pluripotent progenitor/pro-angiogenic monocytes.


Subject(s)
Cardiovascular Diseases/blood , Immunophenotyping/methods , Monocytes/cytology , Adult , Apolipoproteins B/metabolism , Cell Separation , Female , Ferritins/metabolism , Flow Cytometry/methods , Humans , Lipopolysaccharide Receptors/biosynthesis , Male , Phagocytosis , Receptors, CCR2/metabolism , Receptors, IgG/biosynthesis
11.
Blood Cancer J ; 1(10): e39, 2011 Oct.
Article in English | MEDLINE | ID: mdl-22829072

ABSTRACT

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity.

12.
Leukemia ; 23(2): 292-304, 2009 Feb.
Article in English | MEDLINE | ID: mdl-18923439

ABSTRACT

B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ+MPA), induce apoptosis of unsorted and CD19(+ve)-selected CLL cells and abrogate the pro-proliferative activity of CD40(L). This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ+MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D(2) (PGD(2)) synthesis by CLL cells, and treatment with PGD(2) and its antineoplastic derivative 15dDelta(12,14,)PGJ(2) recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD(2) receptor antagonist, BW868C, did not block BEZ or PGD(2) activity against CLL cells. The potency of BEZ+MPA against CLL cells mirrored that of chlorambucil, and BEZ+MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.


Subject(s)
Apoptosis/drug effects , Bezafibrate/pharmacology , CD40 Ligand/antagonists & inhibitors , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Medroxyprogesterone Acetate/pharmacology , Prostaglandin D2/analogs & derivatives , Cell Proliferation/drug effects , Drug Combinations , Drug Synergism , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Mitochondrial Proteins , Prostaglandin D2/agonists , Reactive Oxygen Species , Signal Transduction , Superoxides , Tumor Cells, Cultured
13.
Clin Otolaryngol ; 31(2): 130-3, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16620332

ABSTRACT

OBJECTIVES: To determine whether otitis media with effusion (OME) is associated with elevated serum immunoglobulin E (IgE) and IgE specific for house dust mite. DESIGN: Forty-seven children who had evidence of bilateral OME, both otoscopically and on tympanometry, on two separate occasions, 3 months apart were admitted for ventilation tubes. Forty-eight children admitted for minor eye surgery who had otoscopically normal ears and no history of middle ear problems were used as controls. Bloods samples were taken under anaesthesia. Total IgE and IgE radioallergosorbent test (RAST) to house dust mite was measured by the Pharmacia Unicap 100 system. The results from the two groups were compared. SETTING: Birmingham Children's Hospital. PARTICIPANTS: Children between the ages of 3 and 10. Children with Down's syndrome, cleft lip and palate, ciliary abnormalities, known immunodeficiencies and cardiac abnormalities were excluded. MAIN OUTCOME MEASURES: Total IgE and RAST to house dust mite. A RAST of >0.35 was taken to be positive. RESULTS: There was no statistical difference between the control and study groups for the total IgE. Six children from both study and control groups had a raised house dust mite RAST. There was no difference in the levels between either group. CONCLUSIONS: Our findings indicate that there is no direct relationship between OME and biochemical evidence of allergy, specifically to house dust mite.


Subject(s)
Allergens/immunology , Hypersensitivity, Immediate/complications , Immunoglobulin E/blood , Otitis Media with Effusion/immunology , Pyroglyphidae/immunology , Animals , Antibody Specificity , Case-Control Studies , Chi-Square Distribution , Child , Child, Preschool , Cohort Studies , Female , Humans , Immunoglobulin E/immunology , Male , Otitis Media with Effusion/etiology , Radioallergosorbent Test
14.
Leukemia ; 19(10): 1751-9, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16121216

ABSTRACT

Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34+ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34+ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.


Subject(s)
Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Histones/metabolism , Leukemia, Myeloid/enzymology , Acetylation , Acute Disease , Adult , Antigens, CD34/metabolism , Butyrates/pharmacology , DNA Methylation , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Humans , Hydroxamic Acids/pharmacology , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/genetics , Myeloid Cells , Tumor Cells, Cultured , Valproic Acid/pharmacology , Vorinostat
15.
J Appl Physiol (1985) ; 98(2): 565-71, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15322070

ABSTRACT

The present study was undertaken to examine the role of the exercise-induced stress hormone response on the regulation of type 1 and type 2 T lymphocyte intracellular cytokine production. Subjects performed 2.5 h of cycling exercise at 65% maximal O2 uptake while ingesting a 6.4% carbohydrate (CHO) solution, 12.8% CHO solution, or a placebo. Peripheral whole blood samples were stimulated and stained for T lymphocyte surface antigens (CD4 and CD8). Cells were then permeabilized, stained for intracellular cytokines, and analyzed using flow cytometry. Exercise resulted in a decrease (P < 0.05) in the number and percentage of IFN-gamma positive CD4+ and CD8+ T lymphocytes. These stimulated cells produced less IFN-gamma immediately postexercise (P < 0.05) and 2-h postexercise (P < 0.05) compared with preexercise. However, CHO ingestion, which attenuated the exercise-induced stress hormone response compared with placebo (P < 0.05), prevented both the decrease in the number and percentage of IFN-gamma-positive CD4+ and CD8+ T lymphocytes and the suppression of IFN-gamma production from stimulated CD4+ and CD8+ T lymphocytes. There was no effect of exercise on the number of, or cytokine production from, IL-4-positive CD4+ or CD8+ T lymphocytes. These data provide support for the role of exercise-induced elevations in stress hormones in the regulation of type 1 T lymphocyte cytokine production and distribution.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/metabolism , Cytokines/blood , Dietary Carbohydrates/metabolism , Physical Exertion/physiology , Adaptation, Physiological/physiology , Adult , Exercise Test , Humans , Intracellular Space/metabolism , Male , Tissue Distribution
16.
Br J Haematol ; 126(3): 348-54, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15257706

ABSTRACT

Monoclonal immunoglobulin free light chains (FLC) are found in the serum and urine of patients with a number of B-cell proliferative disorders, including multiple myeloma. Automated immunoassays, which can measure FLC in serum, are useful for the diagnosis and monitoring of light chain (AL) amyloidosis, Bence Jones myeloma and non-secretory myeloma patients. We report the results of a study investigating the utility of serum FLC measurements in myeloma patients producing monoclonal intact immunoglobulin proteins. FLC concentrations were measured in presentation sera from 493 multiple myeloma patients with monoclonal, intact immunoglobulin proteins. Serial samples were assayed from 17 of these patients and the FLC measurements were compared with other disease markers. Serum FLC concentrations were abnormal in 96% of patients at presentation. FLC concentrations fell more rapidly in response to treatment than intact immunoglobulin G (IgG) and showed greater concordance with serum beta2 microglobulin concentrations and bone marrow plasma cell assessments. It was concluded that serum FLC assays could be used to follow the disease course in nearly all multiple myeloma patients. In addition, because of their short serum half-life, changes in serum FLC concentrations provide a rapid indication of the response to treatment.


Subject(s)
Immunoglobulin Light Chains/blood , Multiple Myeloma/blood , Biomarkers/blood , Half-Life , Humans , Immunoglobulin Light Chains/metabolism , Multiple Myeloma/drug therapy , Nephelometry and Turbidimetry , Recurrence , Reference Values , Retrospective Studies
17.
Leukemia ; 17(3): 568-75, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12646946

ABSTRACT

Current therapies for Burkitt's lymphoma (BL) utilise combined cytotoxic chemotherapy, but these treatments are not always available in areas where the disease is endemic and are also markedly less successful in AIDS-related BL. Therefore, additional therapies are urgently required. We demonstrate here that combined fibrates and MPA exert powerful, antiproliferative actions against well-characterised Daudi, Raji and L3055 BL cell lines and primary BL cells. Detailed studies in L3055 demonstrated that this activity was mediated by induced apoptosis and confirmed by observations that overexpression of the antiapoptotic genes bcl-2 or bcl-x(L) conferred significant protection against the drugs. Importantly, since fibrates and MPA are inexpensive and stable with minimal-associated toxicities, we suggest that these drugs should be considered as adjuncts to currently available treatments for BL in endemic and AIDS-related disease.


Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Apoptosis/drug effects , Burkitt Lymphoma/pathology , Clofibric Acid/pharmacology , Hypolipidemic Agents/pharmacology , Medroxyprogesterone Acetate/pharmacology , Burkitt Lymphoma/drug therapy , Cell Division/drug effects , Drug Interactions , Drug Therapy, Combination , Humans , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/pharmacology , Transduction, Genetic , Tumor Cells, Cultured , bcl-X Protein
19.
Br J Haematol ; 113(4): 1035-43, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11442499

ABSTRACT

Oral clodronate (1600 mg/d) has been shown to significantly reduce the incidence of skeletal complications in multiple myeloma. Preliminary analysis of a double-blind placebo-controlled trial of this treatment indicated that clodronate might prolong survival in patients without vertebral fractures at presentation. This issue was re-examined after further follow-up of the patients recruited into the Medical Research Council (MRC) VIth Myeloma Study. The trial examined the effects of clodronate on the natural history of skeletal disease in multiple myeloma; 619 patients were randomized between June 1986 and May 1992 commencing 15 d after the start of ABCM [adriamycin, BCNU (carmustine), cyclophosphamide, melphalan] chemotherapy or 43 d after ABCMP (ABCM + prenisolone); 535 patients who received clodronate or placebo were included in the analysis. The presence or absence of spinal fractures was assessed centrally from spinal X-rays; long-bone fractures were assessed locally. With a median follow-up of 8.6 years, there was no overall significant difference in survival between the two treatment groups (O/E, chi2 = 0.78, P = 0.38). Among the subgroup of 153 patients with no skeletal fractures at presentation there was a significant survival advantage (O/E, chi2 = 7.52, P = 0.006) in favour of the 73 patients receiving clodronate, with median survivals being, respectively, 59 months (95% CI 43-71 months) and 37 months (95% CI 31-52 months), and 5-year survivals being 46% and 35%. The original analysis of this study shows that there is a benefit in taking 1600 mg clodronate daily for patients with myelomatosis to prevent the development of new skeletal disease. Bearing in mind the limitations of subgroup analysis, the present study indicates that treatment may prolong survival in patients without overt skeletal disease at diagnosis. These observations, however, require confirmation in prospective clinical trials.


Subject(s)
Analgesics, Non-Narcotic/therapeutic use , Clodronic Acid/therapeutic use , Multiple Myeloma/drug therapy , Aged , Chi-Square Distribution , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Multiple Myeloma/complications , Multiple Myeloma/mortality , Prognosis , Prospective Studies , Regression Analysis , Spinal Fractures/complications , Spinal Fractures/drug therapy , Spinal Fractures/mortality , Survival Analysis
20.
Exp Cell Res ; 266(1): 126-34, 2001 May 15.
Article in English | MEDLINE | ID: mdl-11339831

ABSTRACT

When 1 alpha,25-dihydroxyvitamin D(3) (D(3)) induces HL60 cells to differentiate to monocytes, a burst of approximately three shortened cell cycles ("maturation divisions") precedes exit from cell cycle and completion of maturation. Here we show that similar maturation divisions occur during neutrophil differentiation induced by all-trans-retinoic acid (ATRA), but without shortening of the cell cycle. Both ATRA and D(3) initiate these maturation divisions as cells pass through a "window of sensitivity" during early G1. We also investigated whether the initiation of maturation divisions and of the expression of CD11b, an early-expressed maturation marker, are linked. Cells treated with D(3) or ATRA start to express CD11b after 9--14 h, before completing the first maturation division. Elutriation was used to isolate small HL60 cells (almost all in G1) and larger cells (in G1 and S phases) from unsynchronized populations. When these were cultured with D(3) or ATRA, most reentered cycle synchronously, multiplied, and differentiated. Following D(3) treatment, the G1-enriched small cells expressed CD11b slightly faster than unsynchronized cultures or fractions dominated by late G1 cells and/or S phase cells. D(3)-induced CD11b expression occurred at a similar rate even in G1 cells that were held at the G1/S boundary by thymidine. In conclusion, changes in the control of the cell cycle that characterize the onset of monocytic and neutrophil differentiation are only triggered in early G1, but CD11b expression can be initiated from most points in the cell cycle. Differentiating agents must therefore regulate the proliferation and the maturation of differentiating myeloid cells by mechanisms that are at least partly independent.


Subject(s)
Antineoplastic Agents/pharmacology , Calcitriol/pharmacology , Calcium Channel Agonists/pharmacology , Cell Differentiation/physiology , Cell Division/physiology , HL-60 Cells/metabolism , Macrophage-1 Antigen/metabolism , Tretinoin/pharmacology , Cell Differentiation/drug effects , Cell Division/drug effects , G1 Phase/drug effects , G1 Phase/physiology , Gene Expression Regulation, Developmental/drug effects , Gene Expression Regulation, Developmental/physiology , HL-60 Cells/cytology , HL-60 Cells/drug effects , Hematopoiesis/drug effects , Hematopoiesis/physiology , Humans , Monocytes/drug effects , Monocytes/metabolism , Myeloid Cells/cytology , Myeloid Cells/drug effects , Myeloid Cells/metabolism , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Periodicity
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