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Biomedical subjects

H Wagner

Publications and source records attributed to H Wagner.

At least 73 records · Page 4Linked to original sources

Muscle angiogenic growth factor gene responses to exercise in chronic renal failure.

Patients with chronic renal failure (CRF) have impaired exercise capacity even after erythropoietin treatment. We recently showed that although this is explained in part by reduced convective O(2) delivery to muscles, there is also an impairment of O(2) transport from muscle capillaries to the mitochondria. Given the importance of the capillary surface area for capillary mitochondrial O(2) transport and reports of reduced capillarity in CRF, we hypothesized that the angiogenic gene response to exercise is impaired in such patients. Six patients with CRF and six control subjects matched for age, size, and sedentary lifestyle exercised on a single occasion for 1 h at similar work intensities averaging 50% of maximal capacity. Exercise was confined to the knee extensors of a single leg by means of a specially designed leg-kick ergometer. A percutaneous biopsy of the quadriceps was taken within 30 min of cessation of exercise and compared with a similar biopsy done at different times without any prior exercise for 24 h. Conventional Northern blots were prepared and probed for vascular endothelial growth factor (VEGF; the major putative angiogenic growth factor for muscle), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta(1). Data during both rest and exercise were successfully obtained in four subjects of each group. We also assessed muscle capillarity and mitochondrial oxidative capacity to relate to these changes. Mitochondrial oxidative capacity was normal, whereas capillary number per fiber was 12% lower than in normal subjects. VEGF mRNA abundance was increased after exercise by about one order of magnitude, with no reduction in response in CRF. For bFGF and TGF-beta(1), exercise elicited no response in either group. Reduced muscle capillarity in CRF does not, therefore, stem from reduced transcription of VEGF. To the extent that VEGF is important to exercise-induced angiogenesis in muscle, we suspect a posttranscriptional aberration in this response occurs in CRF to explain reduced capillarity.

Adolescent↗

Spatial attention modulates sound localization in barn owls.

Attentional influence on sound-localization behavior of barn owls was investigated in a cross-modal spatial cuing paradigm. After being cued to the most probable target side with a visual cuing stimulus, owls localized upcoming auditory target stimuli with a head turn toward the position of the sound source. In 80% of the trials, cuing stimuli pointed toward the side of the upcoming target stimulus (valid configuration), and in 20% they pointed toward the opposite side (invalid configuration). We found that owls initiated the head turns by a mean of 37.4 ms earlier in valid trials, i.e., mean response latencies of head turns were reduced by 16% after a valid cuing stimulus. Thus auditory stimuli appearing at the cued side were processed faster than stimuli appearing at the uncued side, indicating the influence of a spatial-selective attention mechanism. Turning angles were not different when owls turned their head toward a cued or an uncued location. Other types of attention influencing sound localization, e.g., a reduction of response latency as a function of the duration of cue-target delay, could not be observed. This study is the first attempt to investigate attentional influences on sound localization in an animal model.

Acoustic Stimulation↗

Diaphragmatic angiogenic growth factor mRNA responses to increased ventilation caused by hypoxia and hypercapnia.

This study investigates the effect of increased ventilation on the expression of messenger ribonucleic acid (mRNA) levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-beta1 (TGF-beta1) in the diaphragm of intact, awake, spontaneously breathing rats, compared with responses in paralysed, mechanically-ventilated animals at similar blood gas and ventilatory levels. Four groups of intact, rats were studied in a body box, each group breathing one of four gases: room air, 12% oxygen (O2), 5% carbon dioxide (CO2), or 12% O2+5% CO2 for 1 h. Another 4 groups of paralysed, mechanically-ventilated animals were matched for arterial blood gas and ventilatory level. The results showed that VEGF mRNA abundance was increased three-fold and that of bFGF 1.5-fold when 12% O2+5% CO2 were breathed, but TGF-beta1 did not change. A significant linear relationship of VEGF and bFGF mRNA to minute ventilation was observed in awake animals (r=0.98, p<0.02 and r=0.87, p<0.03, respectively). The paralysed, mechanically-ventilated animals showed no mRNA increases for any probe. Systemic hypoxia had no additional effect on VEGF or bFGF levels in the diaphragm. It was concluded that messenger ribonucleic acid for vascular endothelial growth factor and basic fibroblast growth factor in the diaphragm rises significantly as a result of active ventilation and not due to blood gas/pH changes or to passive muscle shortening per se.

Animals↗

Statistical validation of the mammaglobin-nested RT-PCR assay for tumor cell detection in blood of breast cancer patients.

A stochastic model was developed to validate the results obtained with the mammaglobin-nested RT-PCR assay for tumor cell detection in peripheral blood of breast cancer patients. Since the assay consists of four PCR setups per peripheral blood sample, the probabilities for receiving 0, 1, 2, 3, or 4 positive setups were calculated. In this model, samples with just 500 mammaglobin mRNA molecules are highly probable to result in at least three positive setups, whereas lower quantities shift the probabilities towards one or two positive setups. In the clinical trial, samples with one or two mammaglobin positive setups were detected in 6/143 (4%) patients with benign lesions of the breast, in 41/310 (13%) breast cancer patients with no evidence of disease and in 39/157 (25%) breast cancer patients with metastatic disease. On the contrary, no sample from patients with benign lesions of the breast resulted in three or four positive setups, but 5/310 (2%) breast cancer patients with no evidence of disease and 46/157 (29%) with metastatic disease. These results correspond with the model: an increased number of tumor cells in peripheral blood lead to a higher amount of mammaglobin mRNA molecules, and these samples may result in at least three positive setups. Samples with three orfour positive setups were mainly derived from breast cancer patients with metastatic disease and only occasionally from patients with no evidence of disease. On account of these results, samples with at least three positive setups are of prognostic value and regarded as tumor cell positive.

Breast Neoplasms↗

Conus hip prosthesis.

50 years ago, prosthetic replacement of the hip joint ushered in a new epoch in orthopaedics. Total hip replacement made it possible to remove a severely diseased, painful hip and restore normal function and a normal quality of life to the afflicted patient. The early results of total hip replacement are almost all spectacular and hip replacement has become the most successful type of orthopaedic surgery. These good results using an approach that was technically relatively simple resulted in a temptation to implant prosthetic hip joints with ever increasing frequency in ever younger patients. This led to the emergence of new problems, which were not so clearly recognised at the outset: it emerged that the stability of prosthetic hip joints was of limited duration. This had the following consequence: If a total hip prosthesis is implanted in an elderly person whose remaining life-expectancy is shorter than the longevity of the prosthesis, hip replacement is a life-long solution. We can therefore say that, for a patient who has only 10 to 15 years left to live, their hip problem is solved by total hip replacement. For young people, who still have a long life expectancy in front of them, it is different. They will experience failure of the artificial joint and require further surgery. The commonest and most important type of failure in total hip prostheses is aseptic loosening, which is associated with resorption of bone at the site of the prosthesis. The cause of this phenomenon has only gradually been recognised in the course of the years. Initially, the unanimous opinion was that the methacrylate cement, used to fix the components of the prosthesis in the bone, was the definitive cause of aseptic loosening because fissures and fractures of the cement were almost always found during surgical revision of loosened joints. There was talk of "cement disease" and great efforts were made to improve the quality of the cement and the cementing technique. Moreover, even today, there is no established answer to the question whether, over the course of many years, cement ages and becomes friable, a process that may have major implications for young patients. For this reason, ways of reliably fixing the prosthesis in the bone without methacrylate cement were also explored at the same time. Valuable pioneering work in this field was carried out with uncemented dental implants made of titanium and with a roughened surface. With these implants, the phenomenon of osseointegration, i.e. the deposition of bone directly on the roughened metal surface without any intervening connective tissue, was observed. This phenomenon has also been utilised successfully in hip prostheses: if artificial hips made of titanium alloy with a coarse-blasted surface and with a high primary mechanical stability are placed in the bone, osseointegration also occurs. In parallel with this development, Willert, from Göttingen, identified the most important cause of loosening of the prosthesis: he established that, when an artificial joint articulates, very fine particles of polyethylene are eroded from the prosthetic cup when the surfaces of the joint glide over one another and that these are only partially removed by the lymphatic system. A large proportion of the particles accumulates in the artificial joint and in the gap between the prosthesis and the bone, giving rise to foreign body granulomata, which resorb bone thus leading to loosening. The number of eroded particles is considerable. In 1998, Patricia Campbell, from Los Angeles, showed that 470,000 particles per step were produced from an articulation between a metal head and a polyethylene cup. This huge number gives an indication how small these particles are, since the linear erosion of the polyethylene surface only amounts to about 0.1 to 0.2 mm a year. This relatively recent recognition of "particle disease" has led to the investigation of other materials, which produce fewer erosion particles, for artificial joint articulations. Three possible options are available today, but it is not yet possible to decide for certain which of them is superior to the others: the longest experience has been with metal/metal articulation with articulatory pairings of cobalt/chromium/molybdenum alloy. In recent years, ceramic/ceramic articulations of aluminium oxide-ceramic and pairings of ceramic with highly crosslinked polyethylene have also been used. With these modern articulations, particle erosion can be reduced about 200 fold. If the erosion particles are an important cause of loosening of the prosthesis, it is reasonable to expect that, with these new joint pairings, the durability of an artificial joint can be substantially prolonged. The cone prosthesis described here has been developed on the basis of the knowledge and experience of the last 20 years. The conical anchoring of the stem, involving the placing of a conical implant in the conically reamed medullary cavity, results in continuous contact between the stem of the prosthesis and the bone, with a high degree of primary stability. The sharp longitudinal ribs on the stem, which cut a little into the bone, provide a high degree of rotational stability. In the case of conical fixation, the mechanical transmission of force varies with the diameter of the stem: the weight bearing surface of a cone in relation to its length is greater where the stem has a larger diameter than at the tip of the stem where the diameter is smaller. Therefore, for geometrical reasons, the conical fixation of the stem results in a transmission of force that is predominantly proximal and avoids proximal stress protection. The round cross-section permits free adjustment of the angle of anteversion and avoids any forced rotation as a result of bony deformity, which is very important in the case of dysplastic hips.

Adolescent↗

A Toll-like receptor recognizes bacterial DNA.

DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

Adaptor Proteins, Signal Transducing↗

Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma.

BACKGROUND: Elderly patients comprise a significant portion of patients with limited stage small cell lung carcinoma. However, the prognostic importance of age has been controversial, and concern for toxicity often hinders enthusiasm for offering full dose therapy. METHODS: In this retrospective analysis of Intergroup Trial 0096, the authors compared the outcome of patients 70 years or older to those younger than 70 years. Patients received cisplatin 60 mg/m(2), Day 1 and etoposide 120 mg/m(2), Days 1-3 for 4 cycles and either once or twice daily concurrent thoracic radiotherapy to 45 grays. RESULTS: Of 381 patients, 50 (13%) were age 70 years or older. The elderly group did not differ significantly from those younger than 70 years with respect to gender distribution, performance status, or weight loss. Severe hematologic toxicity (Grade 4-5: 61% vs. 84%; P < 0.01) and fatal toxicity (1% vs. 10%; P = 0.01) occurred more often among older patients. There were no differences in the frequency of nonhematologic toxicities. Response rate (88% vs. 80%; P = 0.11), event free survival rate (5 year, 19% vs. 16%; P = 0.18), time to local failure, and duration of response did not differ between groups. Overall survival rates (5 year, 22% vs. 16%; P = 0.05) favored those younger than 70 years. Much of the difference in overall survival rates between age groups occurred within the first 6 months on study. CONCLUSIONS: Elderly patients had similar response and survival rates compared with those younger than 70 years. However, toxicity, particularly hematologic, was greater among the elderly. Selected older patients, such as those with a good performance status, should be considered for optimum treatment approaches.

Age Factors↗

A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group.

BACKGROUND: We conducted a randomized trial to determine whether combination chemotherapy plus thoracic radiotherapy is superior to thoracic radiotherapy alone in prolonging survival and preventing local recurrence in patients with completely resected stage II or IIIa non-small-cell lung cancer. METHODS: After surgical staging and resection of the tumor (usually by lobectomy or pneumonectomy), the patients were randomly assigned to receive either four 28-day cycles of cisplatin (60 mg per square meter of body-surface area intravenously on day 1) and etoposide (120 mg per square meter intravenously on days 1, 2, and 3) administered concurrently with radiotherapy (a total of 50.4 Gy, given in 28 daily fractions) or radiotherapy alone (a total of 50.4 Gy, given in 28 daily fractions). RESULTS: Of the 488 patients who were enrolled in the study, 242 were assigned to receive radiotherapy alone and 246 were assigned to receive chemotherapy and radiotherapy. The median duration of follow-up was 44 months. Treatment-associated mortality was 1.2 percent in the group given radiotherapy alone and 1.6 percent in the group given chemotherapy and radiotherapy. The median survival was 39 months in the group given radiotherapy and 38 months in the group given chemotherapy and radiotherapy (P= 0.56 by the log-rank test). The relative likelihood of survival among patients assigned to receive chemotherapy and radiotherapy, as compared with those assigned to receive radiotherapy alone, was 0.93 (95 percent confidence interval, 0.74 to 1.18). Intrathoracic disease recurred within the radiation field in 30 of 234 patients (13 percent) in the group given radiotherapy and in 28 of 236 patients (12 percent) in the group given chemotherapy and radiotherapy (P=0.84); data on recurrence were not available for 18 patients. CONCLUSIONS: As compared with radiotherapy alone, adjuvant radiotherapy and chemotherapy with cisplatin and etoposide does not decrease the risk of intrathoracic recurrence or prolong survival in patients with completely resected stage II or IIIa non-small-cell lung cancer.

Adult↗

Chiral capillary electrophoresis as predictor for separation of drug enantiomers in continuous flow zone electrophoresis.

Separation of the enantiomers of chlorpheniramine and methadone in acidic buffers containing carboxymethyl-betacyclodextrin (CMCD) as chiral selector was investigated by capillary zone electrophoresis. For a range of pH and CMCD concentrations, the mobility difference and resolution of the enantiomers were determined. Then, conditions known to provide well resolved enantiomers and optimized chiral separation were applied to chiral continuous flow electrophoresis. In that approach, a thin film of fluid flowing between two parallel plates is employed as carrier for electrophoresis. The electrolytes and the sample are continuously admitted at one end of the electrophoresis chamber and are fractionated by an array of outlet tubes at the other. The number of pure enantiomeric fractions obtained by chiral continuous flow electrophoresis was found to be directly dependent on the enantiomeric mobility difference. For racemic chlorpheniramine separated in a betaine-acetic acid buffer at a total throughput of 5 mg/h, complete enantiomeric separation is shown to require a mobility difference of about 3 x 10(-9) m2/V s. Furthermore, compared to the previous investigations with hydroxypropyl-beta-cyclodextrin, CMCD was found to permit improved fractionation of methadone enantiomers. With a total racemic drug throughput of about 15 mg/h, continuous flow zone electrophoresis processing with CMCD as chiral selector is shown to have the potential of providing pure enantiomers on a mg/h scale. The results indicate that chiral capillary zone electrophoresis data can be employed as predictor for preparative scale chiral separations based upon continuous flow zone electrophoresis.

Chlorpheniramine↗

Increased resistance against acute polymicrobial sepsis in mice challenged with immunostimulatory CpG oligodeoxynucleotides is related to an enhanced innate effector cell response.

Recent reports support the concept that the major defect in polymicrobial sepsis is an impaired immunologic response to infection. Oligodeoxynucleotides containing CpG sequence motifs (CpG-ODN) were previously shown to induce immune protection in models of chronic infection with intracellular bacteria, parasites, and viruses due to their ability to augment IFN-gamma-dependent Th1 responses. Here, we demonstrate that challenging mice with CpG-ODN substantially increases the resistance against acute polymicrobial sepsis. Systemic levels of IL-12, IL-18, and IL-10 were not altered in CpG-ODN-treated mice as compared with controls. In contrast, administration of CpG-ODN resulted in a strongly enhanced accumulation of neutrophils at the primary site of infection. Neutrophils of CpG-ODN-treated mice exhibited an up-regulation of phagocytic receptors, an increased phagocytic activity, and an elevated production of reactive oxygen metabolites. These results suggest that the protective effects of CpG-ODNs in acute polymicrobial sepsis are related to an enhanced effector cell response of innate immunity. CpG-ODN may therefore represent potent agents for the treatment of sepsis-associated immunoparalysis.

Acute Disease↗

Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6.

Transition of immature antigen presenting cells (APCs) to the state of professional APCs is essential for initiation of cell-mediated immune responses to pathogens. Signal transduction via molecules of the Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) pathway is critical for activation of APCs either by pathogen-derived pattern ligands like lipopolysaccharides (LPS) or by CD40 ligation through T helper cells. The capacity of bacterial DNA (CpG-DNA) to induce APCs to differentiate into professional APCs represents an interesting discovery. However, the signaling pathways involved are poorly understood. Here we show that CpG-DNA activates the TLR/IL-1R signaling pathway via the molecules myeloid differentiation marker 88 (MyD88) and tumor necrosis factor receptor-associated factor 6 (TRAF6), leading to activation of kinases of the IkappaB kinase complex and the c-jun NH(2)-terminal kinases. Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond. The data suggest that CpG-DNA initiates signaling via the TLR/IL-1R pathway in APCs in a manner similar to LPS and to T helper cell-mediated CD40 ligation. Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo.

Adaptor Proteins, Signal Transducing↗

CpG-DNA-mediated transient lymphadenopathy is associated with a state of Th1 predisposition to antigen-driven responses.

Infections can influence concurrent and subsequent Th1 vs Th2 immune responses to Ags. Through pattern recognition of foreign unmethylated CpG dinucleotides, the vertebrate innate immune system can sense infectious danger and typically replies with a Th1-polarized adaptive immune response. We examined whether CpG-DNA exposure would influence subsequent responses to infection and soluble Ags. CpG-DNA injection led to local lymphadenopathy characterized by maintenance of cellular composition with some biasing toward elevated dendritic cell composition. Sustained local production of IL-12 and IFN-gamma from dendritic cells and T cells was shown. Prior injection by up to 2 wk with CpG-DNA protected BALB/c mice from Th2 driven lethal leishmaniasis. CpG-DNA injection by up to 5 wk before soluble Ag challenge resulted in the generation of Ag-specific CTL, Th1 recall responses to Ag, and Th1-polarized Ag-specific Abs. Thus, CpG-DNA instigated a local predisposition for intense CTL responses and Th1-polarized immune responses to subsequent infections or Ag challenge. The induction by the innate immune system of a locally contained hypersensitivity could represent a capacitating immune reaction yielding rapid conditioned responses to secondary infections.

Adoptive Transfer↗

Association between clinical disease activity and Epstein-Barr virus reactivation in MS.

OBJECTIVE: To assess the potential significance of Epstein-Barr virus (EBV) reactivation in disease activity in MS patients. METHODS: The prevalence of antibodies against herpes simplex virus type 1 (HSV-1), HSV-2, EBV, and cytomegalovirus was determined in a group of 108 MS patients and in 163 healthy control subjects. Sera were analyzed using combinations of novel assay systems employing highly purified viral and recombinant antigens. In addition, PCR for the detection of EBV DNA was performed in serial samples. RESULTS: In contrast to the control populations, antibodies against EBV were present in 100% of MS patients. Among the tested human herpesviruses, this high extent of seropositivity was only found for EBV. Primary infection was found exclusively in the control group (3.7%), whereas serologic evidence of EBV reactivation was seen in MS patients (13. 9%) as well as control subjects (17.2%). There was no temporal coincidence between EBV reactivation and disease activity in MS patients. However, in 19 patients followed monthly for 1 year, active viral replication as measured by increased immunoglobulin (Ig) M and IgA responses to EBV early antigens (p54 + p138) and positive serum DNA was seen in 72.7% of patients with exacerbations during the study period and in none of the patients with clinically stable disease. CONCLUSIONS: The results demonstrate an association between EBV reactivation and disease activity in MS patients over time, and suggest that EBV might play an indirect role in MS as an activator of the underlying disease process.

Adult↗

Synthetic endotoxin-binding peptides block endotoxin-triggered TNF-alpha production by macrophages in vitro and in vivo and prevent endotoxin-mediated toxic shock.

Lipid A, the conserved portion of endotoxin, is the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have important clinical applications. Here we show that peptides derived from Limulus anti-LPS factor (LALF), bactericidal/permeability increasing protein (BPI) and endotoxin-binding protein, bind to lipid A and block the recombinant LALF/lipid A interaction in vitro. Because their neutralizing capacity in vitro as well as in vivo has been limited, we created hybrid peptides comprising two endotoxin-binding domains. The hybrid molecule LL-10-H-14, containing endotoxin-binding domains from LALF and endotoxin-binding protein, turned out to be the most active peptide within the series of peptides tested here to inhibit the CD14/lipid A interaction and is able in vitro to block the endotoxin-induced TNF-alpha release of murine macrophages up to 90%. Furthermore, LL-10-H-14 not only reduced peak serum levels of TNF-alpha of mice when preinjected but also reduced TNF-alpha levels when given 15 min after the endotoxin challenge. As compared with other peptides, only LL-10-H-14 is able to strongly decrease endotoxin-stimulated TNF-alpha release by human macrophage cell lines as well as by PBMC. Furthermore, the hybrid peptide is protective against endotoxin-provoked lethal shock. As such, LL-10-H-14 could have prophylactic and/or therapeutic properties in humans for the management of septic shock.

Amino Acid Sequence↗

A candidate pathway for a visual instructional signal to the barn owl's auditory system.

Many organisms use multimodal maps to generate coherent neuronal representations that allow adequate responses to stimuli that excite several sensory modalities. During ontogeny of these maps, one modality typically acts as the dominant system the other modalities are aligned to. A well studied model for the alignment of sensory maps is the calibration of the auditory space map by the visual system in the optic tectum of the barn owl. However, a projection from the optic tectum to the site of plasticity in the auditory pathway that could deliver an instructive signal has not been found so far. We have analyzed the development of the connectivity between the bimodal (visual and auditory) map of space in the barn owl's optic tectum and the auditory space map in the inferior colliculus with tracing methods and intracellular fills. Neurons in the tectal stratum griseum centrale were found to be suited to deliver an alignment signal from the visual midbrain to the auditory pathway. These neurons are presumably part of the efferent tectal projection pathway that mediates head saccades. The implications of a sensory alignment signal possibly being delivered by a (pre)motor command pathway are discussed.

Animals↗

Alternating drug pairs with or without periodic reinduction in children with acute lymphoblastic leukemia in second bone marrow remission: a Pediatric Oncology Group Study.

BACKGROUND: Children with acute lymphoblastic leukemia (ALL) who experience hematologic recurrence while receiving chemotherapy or within 6 months after its cessation have a low cure rate. In this study (Pediatric Oncology Group Protocol 8303) two methods were examined for improving the outcome in these children. METHODS: After remission induction with prednisone, vincristine, daunorubicin, and asparaginase (PVDA) and consolidation chemotherapy with teniposide and cytarabine, patients received weekly continuation chemotherapy with rotating pairs of drugs, comprised of teniposide and cytarabine and vincristine and cyclophosphamide. In addition, they were randomized to receive or not receive repeated reinduction with PVDA. Patients with matched sibling donors were allowed to receive allogeneic bone marrow transplantation (BMT) instead of continued chemotherapy. RESULTS: Of 297 evaluable patients 258 (87%) achieved second complete hematologic remission. However, only 23 of these patients remained continuously free of leukemia > or =7 years after chemotherapy or BMT. Neither PVDA pulses nor BMT appeared to influence outcome at a statistically significant level. CONCLUSIONS: The results of the current study confirm prior reports of the low cure rate of children with ALL who experience hematologic recurrence during initial therapy or shortly after its cessation. New approaches are needed to prevent and retreat hematologic recurrence in pediatric ALL patients.

Antineoplastic Combined Chemotherapy Protocols↗

CpG-DNA activates in vivo T cell epitope presenting dendritic cells to trigger protective antiviral cytotoxic T cell responses.

MHC class I-restricted T cell epitopes lack immunogenicity unless aided by IFA or CFA. In an attempt to circumvent the known inflammatory side effects of IFA and CFA, we analyzed the ability of immunostimulatory CpG-DNA to act as an adjuvant for MHC class I-restricted peptide epitopes. Using the immunodominant CD8 T cell epitopes, SIINFEKL from OVA or KAVYNFATM (gp33) from lymphocytic choriomeningitis virus glycoprotein, we observed that CpG-DNA conveyed immunogenicity to these epitopes leading to primary induction of peptide-specific CTL. Furthermore, vaccination with the lymphocytic choriomeningitis virus gp33 peptide triggered not only CTL but also protective antiviral defense. We also showed that MHC class I-restricted peptides are constitutively presented by immature dendritic cells (DC) within the draining lymph nodes but failed to induce CTL responses. The use of CpG-DNA as an adjuvant, however, initiated peptide presenting immature DC progression to professional licensed APC. Activated DC induced cytolytic CD8 T cells in wild-type mice and also mice deficient of Th cells or CD40 ligand. CpG-DNA thus incites CTL responses toward MHC class I-restricted T cell epitopes in a Th cell-independent manner. Overall, these results provide new insights into CpG-DNA-mediated adjuvanticity and may influence future vaccination strategies for infectious and perhaps tumor diseases.

Animals↗