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1.
BMC Cancer ; 24(1): 174, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38317104

RESUMEN

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).


Asunto(s)
Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Paraproteinemias , Mieloma Múltiple Quiescente , Humanos , Adulto , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Mieloma Múltiple/diagnóstico , Proyectos Piloto , Calidad de Vida , Progresión de la Enfermedad , Biomarcadores , Ejercicio Físico
2.
Parasite Immunol ; 38(5): 317-25, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27027867

RESUMEN

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.


Asunto(s)
Malaria Cerebral/inmunología , Malaria Falciparum/inmunología , Malaria/inmunología , Monocitos/inmunología , Antígenos CD/análisis , Niño , Citocinas/análisis , Femenino , Antígenos HLA-DR/análisis , Humanos , Lactante , Integrinas/análisis , Masculino , Monocitos/química , Receptores Toll-Like/análisis
3.
Brain Behav Immun ; 44: 32-6, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25451608

RESUMEN

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.


Asunto(s)
Afecto , Inflamación/psicología , Umbral del Dolor/psicología , Estrés Psicológico , Adolescente , Adulto , Estudios Cruzados , Femenino , Humanos , Salmonella typhi , Vacunación , Adulto Joven
4.
Blood Cancer J ; 14(1): 50, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38499538

RESUMEN

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.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Cadenas Ligeras de Inmunoglobulina , Espectrometría de Masas , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Supervivencia sin Progresión , Trasplante Autólogo , Ensayos Clínicos Controlados Aleatorios como Asunto
5.
J Dent Res ; 100(11): 1220-1227, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34077690

RESUMEN

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.


Asunto(s)
COVID-19 , Vacunas , Atención Odontológica , Humanos , SARS-CoV-2 , Estudios Seroepidemiológicos , Reino Unido/epidemiología
6.
J Immunol Methods ; 494: 113046, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33775672

RESUMEN

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.


Asunto(s)
Anticuerpos Antivirales/sangre , Prueba Serológica para COVID-19 , COVID-19 , SARS-CoV-2/metabolismo , Adulto , COVID-19/sangre , COVID-19/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad
7.
J Exp Med ; 170(3): 691-702, 1989 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-2788706

RESUMEN

A single intravenous injection of a relatively small number of T cells contained in the population of rat thoracic duct lymphocytes (TDL) is sufficient to restore to normal the peripheral T cell pool of athymic PVG.rnu/rnu nude rats. The donor T cells expand greater than 10-15-fold, self-renew, and restore immunocompetency to nude recipients permanently (greater than 2 yr). We asked whether the T cell repertoire was affected by the expansion and self-renewal process. Nude recipients were injected with syngeneic PVG TDL that had been allospecifically depleted (negatively selected) by consecutive passage from blood to thoracic duct lymph through two irradiated (DAxPVG)F1 intermediate rats. Negatively selected TDL were tested before transfer by the P----F1 popliteal LN GVH assay and showed a greater than 90% depletion of specific reactivity to DA alloantigens. Surviving cells or their progeny were recovered from LN or TDL of nude recipients 8 and 12 mo after transfer. The deficit in GVH reactivity to the DA haplotype persisted, but normal GVH activity was demonstrated against a third party (AOxPVG)F1 alloantigen. The "hole" in the repertoire could not be attributed to tolerance induced by the co-transfer of contaminating irradiated F1 TDL. PVG TDL passaged consecutively through (AOxPVG)F1 and (DAxPVG)F1 intermediates and devoid of (AOxPVG)F1 cells remained specifically depleted to both AO and DA haplotypes when recovered from nude recipients 4 and 13 mo later, but displayed GVH activity to a third-party (BNxPVG)F1 alloantigen. Thus the exact specificity of the T cell repertoire of the original inoculum was faithfully maintained in nude recipients throughout the initial phase of rapid expansion and the continued self-renewal of the mature peripheral T cell pool.


Asunto(s)
Isoantígenos/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/análisis , Reacción Injerto-Huésped , Células Madre Hematopoyéticas/fisiología , Ganglios Linfáticos/inmunología , Ratas , Ratas Desnudas , Linfocitos T/trasplante , Conducto Torácico
8.
Leukemia ; 32(1): 102-110, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28584253

RESUMEN

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.


Asunto(s)
Mieloma Múltiple/diagnóstico , Mieloma Múltiple/patología , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Deleción Cromosómica , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Modelos de Riesgos Proporcionales , Translocación Genética/genética , Trasplante Autólogo/métodos
9.
Leukemia ; 19(10): 1751-9, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16121216

RESUMEN

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.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Leucemia Mieloide/enzimología , Acetilación , Enfermedad Aguda , Adulto , Antígenos CD34/metabolismo , Butiratos/farmacología , Metilación de ADN , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ácidos Hidroxámicos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/genética , Células Mieloides , Células Tumorales Cultivadas , Ácido Valproico/farmacología , Vorinostat
10.
Blood Cancer J ; 6(12): e506, 2016 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-27935580

RESUMEN

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.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Bortezomib/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Ácidos Hidroxámicos , Estimación de Kaplan-Meier , Lenalidomida , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Mieloma Múltiple/patología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/patología , Oligopéptidos/administración & dosificación , Factores de Riesgo , Talidomida/administración & dosificación , Vorinostat
11.
J Appl Physiol (1985) ; 98(2): 565-71, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15322070

RESUMEN

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.


Asunto(s)
Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Citocinas/sangre , Carbohidratos de la Dieta/metabolismo , Esfuerzo Físico/fisiología , Adaptación Fisiológica/fisiología , Adulto , Prueba de Esfuerzo , Humanos , Espacio Intracelular/metabolismo , Masculino , Distribución Tisular
12.
Leukemia ; 17(3): 568-75, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12646946

RESUMEN

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.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Linfoma de Burkitt/patología , Ácido Clofíbrico/farmacología , Hipolipemiantes/farmacología , Acetato de Medroxiprogesterona/farmacología , Linfoma de Burkitt/tratamiento farmacológico , División Celular/efectos de los fármacos , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , Transducción Genética , Células Tumorales Cultivadas , Proteína bcl-X
13.
Exp Hematol ; 27(3): 451-60, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10089907

RESUMEN

Hormones such as 1 alpha, 25-dihydroxy vitamin D3 (D3), all-trans retinoic acid, and 9-cis retinoic acid stimulate differentiation of myeloid progenitor cells via their interaction with specific hormone receptors. However, the sensitivity of cells to these agents is not merely governed by the expression of their receptors and the availability of ligand to bind them. Recent studies from our group suggested that the actions of D3 and retinoids on myelopoiesis also are influenced by endogenous mechanisms involving other steroid hormones. In this study we examined the influence of local estrogen metabolism on the differentiation of HL60 cells and normal primitive myeloid progenitor cells. Quantitative thin-layer chromatography (TLC) analyses showed that HL60 and normal cells are able to generate estrone (E1) from estradiol (E2). Neither cell population generated significant amounts of E2 from E1. Reverse transcriptase polymerase chain reaction and Northern analyses confirmed that normal and leukemic myeloid progenitor cells expressed mRNA for the type I and IV isoforms of 17 beta-hydroxysteroid dehydrogenase. Conversion of E2 to E1 was upregulated within 24 hours when HL60 cells were treated with either all-trans retinoic acid or D3 at doses that induce their differentiation toward neutrophils or monocytes, respectively. Similarly, D3-induced monocyte differentiation of normal myeloid progenitor cells was associated with increased capacity to generate E1 from E2. When HL60 cells or normal myeloid progenitor cells were exposed to exogenous E1 they became more sensitive to the differentiation-inducing effects of D3. Data presented provide further evidence for the local modulation of myelopoiesis by intracrine mechanisms. In particular, our findings suggest that local metabolism of steroids by normal as well as leukemic myeloid cells influences their responsiveness to D3 and retinoids.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/fisiología , Estradiol/metabolismo , Estrona/metabolismo , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Isoformas de Proteínas/fisiología , 17-Hidroxiesteroide Deshidrogenasas/biosíntesis , 17-Hidroxiesteroide Deshidrogenasas/genética , Aromatasa/metabolismo , Diferenciación Celular/efectos de los fármacos , Colecalciferol/farmacología , Inducción Enzimática/efectos de los fármacos , Sangre Fetal/citología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HL-60/efectos de los fármacos , Células HL-60/enzimología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/enzimología , Humanos , Monocitos/citología , Proteínas de Neoplasias/metabolismo , Neutrófilos/citología , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesis , Receptores de Estrógenos/metabolismo , Tretinoina/farmacología
15.
Transplantation ; 41(6): 745-51, 1986 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2424158

RESUMEN

During a primary response to antigen, lymph nodes (LN) receive antigen-specific lymphocytes (ASL) from the recirculatory pool via specialized postcapillary venules (SPCV). Preliminary experiments demonstrated a three-fold increase in entry of 51Cr-labeled thoracic duct lymphocytes (TDL) into the rat popliteal LN 3-4 days after alloantigenic stimulation. This increased entry was accounted for by an associated 4-5-fold increase in LN blood flow. It was unclear whether recruitment of ASL occurred within the SPCV lumen leading to selective entry of ASL--or, more conventionally, that entry of lymphocytes was a random process and that recruitment of ASL occurred in the extravascular space by selective retention. Thus a double-labeling technique was used to study the migratory characteristics of two populations of thoracic duct lymphocytes (TDL) that had been passaged from blood to lymph. The first population, passaged through a semiallogeneic animal, was negatively selected, and thus 99% depleted of ASL; the second population, passaged through a syngeneic animal, contained a normal complement of naive ASL. The two populations were combined before i.v. injection into syngeneic recipients. At 24 hr the right popliteal LN, which had previously been stimulated with the specific antigen, showed a preferential localization of the TDL containing ASL compared with the left (unstimulated) popliteal LN. This preferential localization was not present at 1 hr after injection. In the light of background data on the kinetics of lymphocyte traffic it is concluded that ASL were selected not at the luminal surface of SPCV but in the LN after they had left the bloodstream.


Asunto(s)
Movimiento Celular , Isoantígenos/inmunología , Ganglios Linfáticos/fisiología , Activación de Linfocitos , Linfocitos/fisiología , Animales , Velocidad del Flujo Sanguíneo , Epítopos/inmunología , Inyecciones Intravenosas , Ganglios Linfáticos/inmunología , Transfusión de Linfocitos , Linfocitos/inmunología , Tamaño de los Órganos , Ratas , Ratas Endogámicas , Factores de Tiempo
16.
Mol Cell Endocrinol ; 149(1-2): 169-83, 1999 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-10375029

RESUMEN

Induction of growth arrest and monocyte differentiation of HL-60 leukemia cells by 1alpha,25 dihydroxyvitamin D3 (1alpha,25(OH)2D3) is well established. By contrast, we have observed, that 1alpha,25(OH)2D3 and its metabolites play separate roles in clonal expansion and survival of differentiating HL-60 cells. Cells that had differentiated by 48 h (CD14 positive) grew slower than control cells, whereas CD14 negative cells were growing faster at this time point. Inhibiting 1alpha,25(OH)2D3 or 1alpha,25(OH)2-20-epi-D3 metabolism, by the 25(OH)D3-24-hydroxylase inhibitor ketoconazole, abolished hyperproliferation of CD14 negative cells. Instead, both the onset of differentiation and subsequent apoptosis were enhanced. These events were associated with immediate up-regulation of the cyclin-dependent kinase inhibitor p21(waf1) and a lack of sustained expression, respectively. Stimulation and inhibition of growth by vitamin D3-related compounds was observed to be concentration and metabolite specific. Low amounts of 1alpha,25(OH)2-20-epi-D3 and 1alpha,24,25(OH)3-20-epi-D3 stimulated HL-60 cell growth. At higher concentrations, 1alpha,25(OH)2-20-epi-D3 was a more potent inducer than 1alpha,24,25(OH)3-20-epi-D3 of HL-60 differentiation; 1alpha,25(OH)2-20-epi-24-oxo-D3 was exclusively pro-differentiative at all concentrations. 1alpha,25(OH)2-20-epi-D3 and 1alpha,24,25(OH)3-20-epi-D3 stimulated proliferation of KG-1a leukemia cells, but neither of these compounds nor 1alpha,25(OH)3-20-epi-24-oxo-D3 exerted pro-differentiative effects on these cells. These findings shed new light on the pro- and anti-proliferative effects of 1alpha,25(OH)2D3 and lead to the postulate that metabolism of 1alpha,25(OH)2D3 and its 20-epi analog regulates different subsets of genes so as to co-ordinate population expansion and the differentiation process. Furthermore, 1alpha,25(OH)2D3 metabolism and/or sensitivity to the effects of metabolites may be altered in transformed cells to derive a clonal advantage.


Asunto(s)
Apoptosis/fisiología , Calcitriol/análogos & derivados , Calcitriol/metabolismo , Diferenciación Celular/fisiología , Sistema Enzimático del Citocromo P-450 , Apoptosis/efectos de los fármacos , Calcitriol/farmacología , Diferenciación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , División Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/metabolismo , Inhibidores Enzimáticos/farmacología , Células HL-60 , Humanos , Cetoconazol/farmacología , Modelos Biológicos , Esteroide Hidroxilasas/antagonistas & inhibidores , Vitamina D3 24-Hidroxilasa
17.
Leuk Res ; 21(7): 623-34, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9301683

RESUMEN

Sensitivity of the human promyeloid cell line HL60 to physiological differentiating agents [e.g. all-trans retinoic acid (all-trans RA) and 1 alpha, 25-dihydroxyvitamin (D3)] is increased by exposure of cells to "anti-inflammatory agents" (e.g. indomethacin) and to steroids [e.g. medroxyprogesterone acetate (MPA)] and post "priming" with a low dose (10(-8) M) of all-trans RA. Co-treatment of serum free-grown HL60 cells (HL60-ITS) with indomethacin and D3 reduces the dose of D3 required for monocyte differentiation from 10(-7) to 6.25 x 10(-9) M. This potentiating effect was observed to be almost absent when experiments where undertaken using serum-grown HL60 cells (HL60-FCS). The agent present in serum that interferes with indomethacin- and MPA-potentiation of the sensitivity of HL60 cells to D3 has been identified as the thyroid hormone 3,5,3'-L-triiodothyronine (T3). "Priming" of HL60-ITS cells with a low dose of all-trans RA reduces the amount of D3 required for the induction of monocyte differentiation to the same degree as co-treatment with either indomethacin or MPA (to 5 x 10(-9) M). However, the combined effect of all-trans RA "priming" and T3 treatment of HL60-ITS cells was induction of apoptosis. Treatment with either agent alone did not result in increased levels of apoptotic cells. These data reveal that T3 has an important influence on the capacity of HL60 cells to undergo differentiation and can promote apoptosis of these cells. Drug combinations, such as a differentiation potentiating agent, for example, indomethacin or MPA, and a differentiation inducer, for example, all-trans RA or D3, may have important therapeutic significance. Serum levels of T3 would be anticipated to influence the outcome.


Asunto(s)
Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células HL-60/citología , Indometacina/farmacología , Metilprednisolona/farmacología , Tretinoina/farmacología , Triyodotironina/farmacología , Antiinflamatorios no Esteroideos/farmacología , Calcitriol/farmacología , Medios de Cultivo , Medio de Cultivo Libre de Suero , Interacciones Farmacológicas , Sinergismo Farmacológico , Células HL-60/efectos de los fármacos , Humanos , Modelos Biológicos
18.
Immunobiology ; 168(3-5): 362-79, 1984 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6530238

RESUMEN

In AO rats the afferent lymphatics to the right cervical lymph nodes (LN) were interrupted and the LN were encased in silicone rubber tubes to prevent reunion of the lymphatics. At regular intervals over the next 12 weeks the following were measured in comparison with the intact contralateral LN - LN weight, influx of lymphocytes from the blood, blood flow, the incorporation of 125IUdR and the incorporation of 35S-sulphate into high endothelial venules (HEV). Systematic histological observations are also reported. One day after deafferentization lymphocyte influx was significantly reduced although blood flow was unchanged and a temporary increase in LN weight was associated with crowding of the lymphatic sinuses with small lymphocytes. The subsequent decline in lymphocyte influx was biphasic and quicker than the decline of other parameters--being undetectable by 6 weeks. Flattening of HEV and diminished secretion of 35S-sulphate was noted at 1 week and progressive degeneration and eventual disappearance of the HEV network was seen by 6-12 weeks. Doubtlessly because of lack of antigenic stimulation 125IUdR incorporation, and numbers of lymphoblasts, plasma cells and finally germinal centres were progressively reduced. The numbers of macrophages and interdigitating cells (IDC) were greatly reduced by 3 weeks and very few were present at 6 weeks probably because most or all arrive in afferent lymph and have a limited life span in the LN. At 12 weeks the LN was difficult to recognize as such since only stromal cells and occasional small lymphocytes remained. In supplementary experiments u.v. irradiation of the LN at the time of deafferentization reduced lymphocyte influx without affecting blood flow suggesting that a u.v. sensitive cell like the IDC may influence lymphocyte influx. In conclusion the involution of the deafferentized LN is partly due to the lack of antigen but progression to the complete loss of specialized structure and function is probably due to lack of other factors including non-lymphoid cells that normally arrive in afferent lymph.


Asunto(s)
Ganglios Linfáticos/fisiología , Linfa/citología , Animales , Movimiento Celular/efectos de la radiación , Femenino , Idoxuridina/metabolismo , Ganglios Linfáticos/irrigación sanguínea , Ganglios Linfáticos/citología , Linfocitos/fisiología , Masculino , Ratas , Ratas Endogámicas , Sulfatos/metabolismo , Factores de Tiempo , Rayos Ultravioleta
19.
J Clin Pathol ; 46(6): 517-21, 1993 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8331172

RESUMEN

AIM: To investigate the hypothesis that complement mediates the recruitment of mononuclear osteoclast precursors to the exposed mineralised bone surface. METHODS: Synthetic hydroxyapatite was incubated in vitro with fresh human serum, with and without complement activation inhibitors. Assays for complement components and the generation of the C3 breakdown product C3d were done. C3 deposition in human fetal tibia primary spongiosa was localised immunohistochemically and complement receptors CR1, CR2, CR3, and CR4 were localised cellularly. Immunohistochemical and enzyme histochemical characterisation of the mononuclear and multinuclear osteoclasts was made with emphasis on their association with complement C3 deposition. RESULTS: Components of complement bind to synthetic hydroxyapatite crystals and, at lower concentrations, C3d was generated in the fluid phase. C3 was deposited in a focal and linear distribution on newly formed bone trabecular surfaces in the primary spongiosa. In a similar distribution CD61, CD68, and tartrate resistant acid phosphatase positive mononuclear osteoclasts were shown in close apposition to the bone trabecular surface. These mononuclear osteoclasts, unlike multinucleate osteoclasts, expressed the complement receptors CR3 and CR4. CR1 and CR2, however, could not be shown on either mononuclear or multinuclear osteoclasts. CONCLUSION: It is suggested that C3 deposition on mineralised bone surfaces mediates the recruitment of mononuclear osteoclasts to this site. As the mononuclear osteoclasts fuse to form the multinucleate osteoclast, complement receptor expression is lost.


Asunto(s)
Desarrollo Óseo/fisiología , Proteínas del Sistema Complemento/fisiología , Osteoclastos/fisiología , Huesos/embriología , Activación de Complemento/fisiología , Complemento C3/metabolismo , Complemento C3d/biosíntesis , Cristalización , Técnicas de Cultivo , Humanos , Hidroxiapatitas , Inmunohistoquímica , Receptores de Complemento/análisis
20.
Toxicology ; 55(1-2): 161-71, 1989 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-2711402

RESUMEN

The distribution and excretion of the plant toxin ricin were studied in rats after intravenous injection. 125I-labelled ricin was equal in toxicity to native ricin. Following injection, the liver was the major organ of localisation - 46% of injected dose at 0.5 h. The spleen and muscle were next with 9.9% and 13%, respectively, at 0.5 h. Ricin was relatively concentrated in the spleen (33% of injected dose/g of tissue) compared with the liver (7.4%/g) and the bone marrow (5.5%/g). The concentration in the lymph nodes was very low (1.2%/g). Ricin was quickly cleared from the animal; only 11% of the initial radioactivity remained 24 h later with 70% excreted in the urine. Excretion into the intestine via the bile duct was less than 5% by 24 h, 10-12% of the radioactivity was found in the intestinal contents or intestinal wall between 3 h and 12 h, and much of this was reabsorbed since less than 2% was recovered in faeces.


Asunto(s)
Ricina/toxicidad , Animales , Conductos Biliares/metabolismo , Transporte Biológico , Médula Ósea/metabolismo , Inyecciones Intravenosas , Mucosa Intestinal/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Linfocitos/metabolismo , Músculos/metabolismo , Ratas , Ricina/farmacocinética , Ricina/orina , Bazo/metabolismo , Factores de Tiempo
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