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1.
Philos Ethics Humanit Med ; 17(1): 6, 2022 02 14.
Article in English | MEDLINE | ID: mdl-35152913

ABSTRACT

Mental health professionals working in hospitals or community clinics inevitably face the realisation that we possess imperfect conceptual means to understand mental disorders. In this paper the authors bring together ideas from the fields of Philosophy, Psychiatry, Cognitive Psychology and Linguistics to reflect on the ways we represent phenomena of high practical importance that we often take for granted, but are nevertheless difficult to define in ontological terms. The paper follows through the development of the concept of psychosis over the last two centuries in the interplay of three different conceptual orientations: the categorical, dimensional and network approaches. Each of these represent the available knowledge and dominant thinking styles of the era in which they emerged and take markedly different stances regarding the nature of mental phenomena. Without particular commitment to any ontological positions or models described, the authors invite the reader into a thinking process about the strengths and weaknesses of these models, and how they can be reconciled in multidisciplinary settings to benefit the process of patient care.


Subject(s)
Psychiatry , Psychotic Disorders , Humans , Internet , Mental Processes , Philosophy
2.
PLoS One ; 15(3): e0229900, 2020.
Article in English | MEDLINE | ID: mdl-32142532

ABSTRACT

BACKGROUND: In spite of demonstrating prognostic and possibly predictive benefit in retrospective cohorts and meta-analyses of cancer populations, including colorectal cancer (CRC), prospective evaluation of the relationship between neutrophil to lymphocyte ratio (NLR) and treatment outcomes in previously untreated mCRC patients receiving bevacizumab-based therapy has not yet been performed. METHODS: An open-label, single arm, multi-centre study. Patients received first-line bevacizumab plus XELOX or mFOLFOX6 (Phase-A) and continued bevacizumab plus FOLFIRI beyond first progression (Phase-B). Analyses included the association of NLR with phase A progression free survival (PFS) and overall survival (OS). A sub-study investigated the safety in patients with the primary in situ tumor. An exploratory sub-study examined relationships of circulating proteomic markers with PFS. RESULTS: Phase-A enrolled 128 patients; median age was 64 years (range: 26-84), 70 (55%) were female, 71 (56%) were PS-0 and 51 (40%) had primary in situ tumor. Fifty-three (41%) patients entered Phase-B. The median baseline (b) NLR was 3.2 (range: 1.5-20.4) with 32 (25%) patients having bNLR > 5. The PFS hazard ratio (HR) by bNLR > 5 versus ≤ 5 was 1.4 (95% CI: 0.9-2.2; p = 0.101). The median PFS was 9.2 months (95% CI: 7.9-10.8) for Phase-A and 6.7 months (95% CI: 3.0-8.2) for Phase-B. The HR for OS based on bNLR > 5 versus ≤ 5 was 1.6 (95% CI: 1.0-2.7; p = 0.052). The median OS was 25 months (95% CI: 19.2-29.7) for the full analysis set and 14.9 months for Phase-B. Baseline levels of nine proteomic markers showed a relationship with PFS. Treatment related toxicities were consistent with what has previously been published. There were 4 (3%) instances of GI perforation, of which, 3 (6%) occurred in the primary in situ tumor group. CONCLUSIONS: Results from this study are aligned with the previously reported trend towards worse PFS and OS in patients with higher bNLR. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01588990; posted May 1, 2012.


Subject(s)
Bevacizumab/administration & dosage , Colorectal Neoplasms/drug therapy , Inflammation/drug therapy , Prognosis , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/adverse effects , Biomarkers, Tumor/genetics , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine/administration & dosage , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Inflammation/genetics , Inflammation/pathology , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Organoplatinum Compounds/administration & dosage , Oxaloacetates/administration & dosage , Translational Research, Biomedical
3.
BMC Cancer ; 13: 120, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23497305

ABSTRACT

BACKGROUND: The use of bevacizumab in combination with fluoropyrimidine-containing chemotherapy is a well-established first-line and second-line treatment for patients with metastatic colorectal cancer (mCRC). However, there remains a need for reproducible, validated, inexpensive and accessible prognostic markers to aid treatment selection. The optimal treatment duration and the role of bevacizumab in certain patient subgroups, considered at particular risk of bevacizumab-mediated toxicity, also require further investigation. The aim of the ASCENT study [an Australian translational Study to evaluate the prognostic role of inflammatory markers in patients with metastatic ColorEctal caNcer Treated with bevacizumab (Avastin™)] is to evaluate the relationship between the host inflammatory response as measured by neutrophil/lymphocyte ratio (NLR) and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment. METHODS/DESIGN: This open-label, prospective, single arm, phase IV, Australian multi-centre study evaluates the relationship between the host inflammatory response as measured by NLR and treatment outcomes in patients with previously untreated mCRC receiving bevacizumab-based first- and second-line treatment. 150 patients will be recruited from 16 centres around Australia. Patients will receive trial treatments in two phases: Phase A: XELOX or mFOLFOX6 plus bevacizumab administered from study start until first disease progression; and Phase B: FOLFIRI plus bevacizumab administered from first disease progression until second disease progression. The primary analysis will test the association between NLR and progression free survival using a proportional Hazards Model. Secondary analyses will investigate whether the relationship can be improved upon with other prognostic biomarkers, and further characterise the safety of bevacizumab following treatment initiation, and when continued after progression in combination with standard chemotherapy regimens (presented through summary statistics and Kaplan Meier curves). DISCUSSION: Quantifying the relationship between NLR and PFS will inform decision making on the extent to which this simple metric may be applied clinically. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01588990.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/blood , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Colorectal Neoplasms/blood supply , Colorectal Neoplasms/secondary , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Disease Progression , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Inflammation/blood , Leucovorin/administration & dosage , Lymphocytes/cytology , Male , Neutrophils/cytology , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Oxaloacetates , Prognosis , Proportional Hazards Models , Prospective Studies , Pyrimidines/administration & dosage , Reproducibility of Results
4.
Int J Radiat Oncol Biol Phys ; 85(1): 157-62, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-22543205

ABSTRACT

PURPOSE: To report quality of life (QOL) results for patients receiving chemoradiation therapy for pancreatic cancer. METHODS AND MATERIALS: Eligible patients (n=41 locally advanced, n=22 postsurgery) entered the B9E-AY-S168 study and received 1 cycle of induction gemcitabine (1000 mg/m2 weekly ×3 with 1-week break) followed by 3-dimensional conformal radiation therapy (RT) (54 Gy locally advanced and 45 Gy postsurgery) and concomitant continuous-infusion 5-fluorouracil (5FU) (200 mg/m2/d throughout RT). After 4 weeks, patients received an additional 3 cycles of consolidation gemcitabine chemotherapy. Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26 questionnaires at baseline, before RT/5FU, at end of RT/5FU, before consolidation gemcitabine, and at treatment completion. RESULTS: The patterns of change in global QOL scores differed between groups. In the locally advanced group global QOL scores were +13, +8, +3, and +1 compared with baseline before RT/5FU (P=.008), at end of RT/5FU, before consolidation gemcitabine, and at treatment completion, respectively. In the postsurgery group, global QOL scores were -3, +4, +15, and +17 compared with baseline at the same time points, with a significant improvement in global QOL before consolidation gemcitabine (P=.03). No significant declines in global QOL were reported by either cohort. CONCLUSIONS: This study demonstrates that global QOL and associated function and symptom profiles for pancreatic chemoradiation therapy differ between locally advanced and postsurgery patients, likely owing to differences in underlying disease status. For both groups, the treatment protocol was well tolerated and did not have a negative impact on patients' global QOL.


Subject(s)
Adenocarcinoma/therapy , Chemoradiotherapy/methods , Deoxycytidine/analogs & derivatives , Fluorouracil/therapeutic use , Pancreatic Neoplasms/therapy , Quality of Life , Radiation-Sensitizing Agents/therapeutic use , Radiotherapy, Conformal/methods , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/therapeutic use , Female , Humans , Induction Chemotherapy/methods , Male , Middle Aged , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Prospective Studies , Surveys and Questionnaires , Treatment Outcome , Gemcitabine
5.
Int J Radiat Oncol Biol Phys ; 70(5): 1438-46, 2008 Apr 01.
Article in English | MEDLINE | ID: mdl-18164859

ABSTRACT

PURPOSE: The aim of this Phase II study was to examine whether concurrent continuous infusion 5-fluorouracil (CI 5FU) plus three-dimensional conformal planning radiotherapy sandwiched between gemcitabine chemotherapy is effective, tolerable, and safe in the management of pancreatic cancer. METHODS AND MATERIALS: Patients were enrolled in two strata: (1) resected pancreatic cancer at high risk of local relapse (postsurgery arm, n = 22) or (2) inoperable pancreatic cancer in head or body without metastases (locally advanced arm, n = 41). Gemcitabine was given at 1,000 mg/m(2) weekly for 3 weeks followed by 1 week rest then 5-6 weeks of radiotherapy and concurrent CI 5FU (200 mg/m(2)/day). After 4 weeks' rest, gemcitabine treatment was reinitiated for 12 weeks. RESULTS: For the two arms combined, treatment-related Grade 3 and 4 toxicities were reported by 25 (39.7%) and 7 (11.1%) patients, respectively. No significant late renal or hepatic toxicity was observed. In the postsurgery arm (R1 54.5%), median time to progressive disease from surgery was 11.0 months, median time to failure of local control was 32.9 months, and median survival time was 15.6 months. The 1- and 2-year survival rates were 63.6% and 31.8%. No significant associations between outcome and mutations in K-ras or TP53 or microsatellite instability were identified. Post hoc investigation of cancer antigen 19-9 levels found baseline levels and increases postbaseline were associated with shorter survival (p = 0.0061 and p < 0.0001, respectively). CONCLUSIONS: This three-dimensional chemoradiotherapy regimen is safe and promising, with encouraging local control for a substantial proportion of patients, and merits testing in a randomized trial.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Radiotherapy, Conformal/methods , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , CA-19-9 Antigen/blood , Combined Modality Therapy/adverse effects , Combined Modality Therapy/methods , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Liver Neoplasms/secondary , Lung Neoplasms/secondary , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local/prevention & control , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Prognosis , Prospective Studies , Radiotherapy, Conformal/adverse effects , Survival Analysis , Treatment Outcome , Gemcitabine
6.
Lung Cancer ; 56(3): 433-43, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17346847

ABSTRACT

BACKGROUND: In the treatment of advanced cancer, a physician's ability to accurately identify a patient's attitude towards treatment is critical. This paper describes the extent of any differences observed between patient attitudes towards chemotherapy for advanced non-small cell lung cancer (NSCLC) as assessed by patients themselves versus their physicians. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC who received gemcitabine plus cisplatin or carboplatin were enrolled into this prospective observational study. Patients and their physicians completed questionnaires containing descriptions of seven patient-specific attitudes. A pre-defined algorithm was used to categorize patients into one of the three 'need' categories based on the questionnaire responses: (A) "maximum extension of survival with acceptance of high toxicity", (B) "maximum extension of survival only if coupled with normal life style", and (C) "relief of symptoms". Each patient was categorized based on his own response, as well as his physician's response. RESULTS: A total of 1895 patients were enrolled from 19 countries across 3 continents. Data from 1884 patients were analysed. Based on patient versus physician responses, respectively, the distribution of patients was 60% versus 39% in need category A, 26% versus 33% in B, and 14% versus 29% in C. Patient self-assessed versus physician-assessed need category identification was aligned for 891 patients (47.3%): 541 (29%) in A, 218 (12%) in B, 132 (7%) in C. While there was slight agreement between the identification of 'need' categories by physicians and patients (kappa=0.18, 95% CI: 0.15-0.21), physicians also tended to place patients further down the scale (towards C) than patients placed themselves (P<0.001). CONCLUSIONS: Patients have varying needs from cancer chemotherapy and it may not always be correctly identified by the treating physician. Physicians may underestimate patient's desire for extended survival compared with symptom relief.


Subject(s)
Antineoplastic Agents/therapeutic use , Attitude to Health , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Patient Compliance/psychology , Physician-Patient Relations , Adolescent , Adult , Aged , Aged, 80 and over , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/psychology , Cisplatin/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Drug Therapy, Combination , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/psychology , Male , Middle Aged , Neoplasm Staging , Outcome Assessment, Health Care , Patient Satisfaction , Prospective Studies , Ribonucleotide Reductases/antagonists & inhibitors , Surveys and Questionnaires , Gemcitabine
7.
Eur J Cancer ; 42(12): 1797-806, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16846734

ABSTRACT

PURPOSE: The purpose was to evaluate the activity and toxicity of split-dose paclitaxel or docetaxel in combination with gemcitabine in patients with metastatic breast cancer (MBC) who had previously received anthracyclines. PATIENTS AND METHODS: A total of 210 patients were randomly assigned to one of three treatment arms: gemcitabine 1,250 mg/m(2) Days 1 and 8 and paclitaxel 175 mg/m(2) as a 3-h infusion on Day 1 (GP1); gemcitabine 1,000 mg/m(2) Days 1 and 8 and paclitaxel 100 mg/m(2) as a 1-h infusion on Days 1 and 8 (GP2); gemcitabine 1,000 mg/m(2) Days 1 and 8 and docetaxel 40 mg/m(2) as a 1-h infusion on Days 1 and 8 (GD). Cycles were repeated every 3 weeks. RESULTS: For the 204 patients evaluable for response assessment, the response rates were 48.6% for GP1, 52.2% for GP2, and 52.3% for GD. Median response duration, time to treatment failure, and time to progression (TTP) were similar in each arm. Median TTP for GP1, GP2 and GD was 7.5, 7.0 and 7.4 months, respectively. For the 208 patients evaluable for safety, the most common grade 3/4 toxicity for each regimen was neutropaenia, with 64%, 57%, and 68% for GP1, GP2, and GD, respectively. Grade 4 neutropaenia, grade 3/4 anaemia, febrile neutropaenia, and diarrhoea were more common in the docetaxel arm, as was the use of intravenous antibiotics and blood transfusions. CONCLUSION: The study confirmed the high activity of gemcitabine-taxane combinations in MBC. Split-dose paclitaxel had similar activity and toxicity to the 3-weekly administration. The split-dose docetaxel regimen had similar activity to the paclitaxel combinations though associated with higher toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Docetaxel , Female , Humans , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Taxoids/administration & dosage , Taxoids/adverse effects , Treatment Failure , Gemcitabine
8.
Eur J Immunol ; 36(5): 1168-78, 2006 May.
Article in English | MEDLINE | ID: mdl-16619284

ABSTRACT

The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-gamma secretion as well as proliferation of CD4+ T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive individuals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.


Subject(s)
Epitopes, T-Lymphocyte , Immunologic Memory , Merozoite Surface Protein 1/immunology , Peptide Fragments/immunology , Plasmodium falciparum/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Amino Acid Sequence , Animals , Humans , Interferon-gamma/biosynthesis , Lymphocyte Activation , Middle Aged , Molecular Sequence Data , Th1 Cells/immunology , Th2 Cells/immunology
9.
J Thorac Oncol ; 1(2): 135-40, 2006 Feb.
Article in English | MEDLINE | ID: mdl-17409842

ABSTRACT

BACKGROUND: The aim of this single-arm phase II study was to evaluate the efficacy, feasibility, and safety of the gemcitabine-carboplatin-paclitaxel combination as neoadjuvant chemotherapy in patients with operable non-small cell lung cancer (NSCLC). METHODS: Patients with stage IB, II, or IIIA NSCLC were given three cycles of chemotherapy followed by tumor resection. Each 21-day cycle consisted of gemcitabine 1000 mg/m on days 1 and 8, carboplatin AUC 5 on day 1, and paclitaxel 175 mg/m on day 1. RESULTS: Forty-four patients were enrolled: 18.2% of patients had stage IB, 15.9% had stage II, and 65.9% had stage IIIA NSCLC. All patients received three cycles of treatment. The clinical tumor response rate was 76.2% (32 of 42 patients; 95% CI, 60.5-87.9%). Thirty-six patients had a complete tumor resection, five of whom had a complete pathological response with no viable tumor cells in the resected tumor on histological examination. Median time to progression was 13.6 months (95% CI, 8.9, >16 months), and 26 of 44 patients (59.1%) had progressed. The 1-year disease-free survival rate was 53.6% (95% CI, 38.7-68.5%), and the 1-year survival rate was 86.0% (95% CI, 75.7-96.4%). Grade 3 and 4 neutropenia each occurred in 38.6% of patients, and grade 3 infection occurred in 2.3% of patients; grade 3 and 4 thrombocytopenia occurred in 25.0% and 0% of patients, respectively. CONCLUSION: The gemcitabine-carboplatin-paclitaxel combination showed promising efficacy and seemed to be safe and feasible as neoadjuvant chemotherapy in patients with operable-stage NSCLC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Immunosuppressive Agents/therapeutic use , Lung Neoplasms/drug therapy , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/administration & dosage , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Staging , Paclitaxel/administration & dosage , Ribonucleotide Reductases/antagonists & inhibitors , Severity of Illness Index , Survival Rate/trends , Gemcitabine
11.
Nat Med ; 10(4): 406-10, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15034567

ABSTRACT

Many human T-cell responses specific for epitopes in Plasmodium falciparum have been described, but none has yet been shown to be predictive of protection against natural malaria infection. Here we report a peptide-specific T-cell assay that is strongly associated with protection of humans in The Gambia, West Africa, from both malaria infection and disease. The assay detects interferon-gamma-secreting CD4(+) T cells specific for a conserved sequence from the circumsporozoite protein, which binds to many human leukocyte antigen (HLA)-DR types. The correlation was observed using a cultured, rather than an ex vivo, ELISPOT assay that measures central memory-'type T cells rather than activated effector T cells. These findings provide direct evidence for a protective role for CD4(+) T cells in humans, and a precise target for the design of improved vaccines against P. falciparum.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Epitopes/immunology , Malaria, Falciparum/prevention & control , Protozoan Proteins/immunology , Adolescent , Adult , Amino Acid Sequence , Conserved Sequence , Enzyme-Linked Immunosorbent Assay , Humans , Immunologic Memory , Malaria, Falciparum/immunology , Middle Aged , Molecular Sequence Data
12.
J Infect Dis ; 188(8): 1239-44, 2003 Oct 15.
Article in English | MEDLINE | ID: mdl-14551895

ABSTRACT

The present study is an investigation of the safety and immunogenicity of DNA and modified vaccinia virus Ankara (MVA) candidate vaccines, each encoding the malaria DNA sequence multiple epitope-thrombospondin related adhesion protein (ME-TRAP), against Plasmodium falciparum. DNA ME-TRAP and MVA ME-TRAP are safe and immunogenic for effector and memory T cell induction. MVA ME-TRAP, with or without prior DNA ME-TRAP immunization, was more immunogenic and more cross-reactive in malaria-exposed individuals than in malaria-naive individuals, a finding suggesting that recombinant MVA vaccines are particularly promising for the development of a malaria vaccine for exposed populations. Both CD4(+) and CD8(+) T cells were induced by these vaccines.


Subject(s)
Malaria Vaccines/adverse effects , Malaria Vaccines/immunology , Vaccines, DNA/adverse effects , Vaccines, DNA/immunology , Vaccinia virus/genetics , Adult , Africa , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Humans , Immunization Schedule , Lymphocyte Activation , Malaria Vaccines/administration & dosage , Malaria, Falciparum/immunology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/immunology , Protozoan Proteins/genetics , Protozoan Proteins/immunology , Vaccines, DNA/administration & dosage
13.
Nat Med ; 9(6): 729-35, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12766765

ABSTRACT

In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans.


Subject(s)
Immunization, Secondary , Malaria Vaccines/immunology , T-Lymphocytes/immunology , Vaccines, DNA/immunology , Vaccines, Synthetic/immunology , Vaccinia virus/immunology , Animals , Antigens, Protozoan/immunology , Humans , Immunization Schedule , Interferon-gamma/immunology , Interferon-gamma/metabolism , Lymphocyte Activation , Malaria, Falciparum/prevention & control , Malaria, Falciparum/therapy , Peptides/immunology , Peptides/metabolism , Plasmids , Plasmodium falciparum/genetics , Plasmodium falciparum/immunology , Protozoan Proteins/immunology , T-Lymphocytes/metabolism , Vaccinia virus/genetics
14.
AIDS ; 16(17): 2285-93, 2002 Nov 22.
Article in English | MEDLINE | ID: mdl-12441800

ABSTRACT

OBJECTIVES: An accurate test for Mycobacterium tuberculosis infection is urgently needed. The tuberculin skin test (TST) lacks sensitivity, particularly in HIV-infected individuals, and has poor specificity because of antigenic cross-reactivity with Bacillus Calmette-Guérin (BCG) vaccination. ESAT-6 and CFP-10 are antigens expressed in Mycobacterium tuberculosis, but not in Mycobacterium bovis BCG and most environmental mycobacteria. We investigated whether T cells specific for these antigens could serve as accurate markers of M. tuberculosis infection in an area of high tuberculosis and HIV prevalence. METHODS: Using the rapid ex-vivo enzyme-linked immunospot (ELISPOT) assay for IFN-gamma, we enumerated T cells specific for ESAT-6, CFP-10 and purified protein derivative (PPD) in blood samples from 50 Zambian tuberculosis patients, 75 healthy Zambian adults, and 40 healthy UK residents. TSTs were performed in 49 healthy Zambian adults. RESULTS: All (100%; n = 11) and 90% (n = 39) of HIV-negative and HIV-positive tuberculosis patients, respectively, had detectable ESAT-6- or CFP-10-specific T cells. The ESAT-6/CFP-10-based ELISPOT assay was positive in 37 out of 54 HIV-negative healthy Zambians, suggesting a 69% prevalence of latent M. tuberculosis infection. Fewer HIV-positive Zambians possessed ESAT-6/CFP-10-specific T cells, but the impact of HIV infection was less on this assay than on the PPD-based ELISPOT or TST. CONCLUSION: The ESAT-6/CFP-10-based ELISPOT assay detects active tuberculosis in HIV-positive individuals with high sensitivity. It is more specific, and possibly more sensitive, than PPD-based methods of detecting latent M. tuberculosis infection, and may potentially improve the targeting of isoniazid preventative therapy to HIV-positive individuals with latent tuberculosis infection.


Subject(s)
HIV Infections/complications , Mycobacterium tuberculosis/immunology , T-Lymphocytes/immunology , Tuberculosis, Pulmonary/diagnosis , Adolescent , Adult , Aged , Antigens, Bacterial/immunology , BCG Vaccine , Bacterial Proteins/immunology , Enzyme-Linked Immunosorbent Assay/methods , Epitope Mapping , Female , Humans , Male , Middle Aged , Mycobacterium tuberculosis/physiology , Prospective Studies , Sensitivity and Specificity , Tuberculin Test , Tuberculosis, Pulmonary/complications , Tuberculosis, Pulmonary/immunology , Virus Latency
15.
Infect Immun ; 70(3): 1417-21, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11854228

ABSTRACT

Plasmodium falciparum malaria is a major cause of death in the tropics. The 19-kDa subunit of P. falciparum merozoite surface protein 1 (MSP-1(19)), a major blood stage vaccine candidate, is the target of cellular and humoral immune responses in animals and humans. In this phase I trial of MSP-1(19), immunization of nonexposed human volunteers with either of the two allelic forms of recombinant MSP-1(19) induced high levels of antigen-specific Th1 (gamma interferon) and Th2 (interleukin 4 [IL-4] and IL-10) type lymphokines. The adjustment of the antigen dose and number of immunizations regulated the level of specificity of immune responses and Th1/Th2 bias of responses induced by vaccination. Novel conserved and allelic T-cell epitopes which induced cross-strain immune responses were identified. Importantly, responses to many of these novel epitopes were also present in adults exposed to malaria, both in east (Kenya) and west Africa (The Gambia). These data suggest that epitope-specific naturally acquired MSP-1(19) immune responses in endemic populations can be boosted by vaccination.


Subject(s)
Malaria Vaccines/immunology , Malaria, Falciparum/prevention & control , Merozoite Surface Protein 1/immunology , Protozoan Proteins , T-Lymphocytes, Helper-Inducer/immunology , Vaccination , Adolescent , Adult , Endemic Diseases , Gambia , Humans , Interferon-gamma/biosynthesis , Kenya , Malaria, Falciparum/immunology , Middle Aged , Peptide Fragments/immunology , Protein Subunits , Recombinant Proteins/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Vaccines, Synthetic/immunology
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