Biomedical subjects

Arkadiusz Z Dudek

Publications and source records attributed to Arkadiusz Z Dudek.

11 recordsLinked to original sources

PubMed2006

Hematopoietic stem cell transplant-related airflow obstruction.

PURPOSE OF REVIEW: Airflow obstruction is a rare but fatal complication following allogeneic hematopoietic stem cell transplantation. It is noninfectious, relatively late, and primarily affects small airways, ultimately leading to their obliteration. If airflow obstruction is consistent with obliteration histologically, the condition is often called bronchiolitis obliterans. This review of literature published recently evaluates progress made in this field. RECENT FINDINGS: Changes reported in analysis of pulmonary function test results and their follow-up might be helpful to better manage bronchiolitis obliterans and to detect and treat it earlier. Graft-versus-host reaction possibly underlies the development of this fatal disease. Findings from high-resolution computed tomography might aid in the diagnostic process. Anti-inflammatory therapy, azithromycin and lung transplant might be an option to treat bronchiolitis obliterans. SUMMARY: The pathomechanism of bronchiolitis obliterans remains unclear and it remains a fatal complication of hematopoietic stem cell transplantation. An appropriate model to study hematopoietic stem cell transplantation-related airflow obstruction, consensus diagnostic criteria, and prospective trials for treatment are necessary to overcome the challenge presented by bronchiolitis obliterans.

Airway Obstruction↗

PubMed2006

Computational methods in developing quantitative structure-activity relationships (QSAR): a review.

Virtual filtering and screening of combinatorial libraries have recently gained attention as methods complementing the high-throughput screening and combinatorial chemistry. These chemoinformatic techniques rely heavily on quantitative structure-activity relationship (QSAR) analysis, a field with established methodology and successful history. In this review, we discuss the computational methods for building QSAR models. We start with outlining their usefulness in high-throughput screening and identifying the general scheme of a QSAR model. Following, we focus on the methodologies in constructing three main components of QSAR model, namely the methods for describing the molecular structure of compounds, for selection of informative descriptors and for activity prediction. We present both the well-established methods as well as techniques recently introduced into the QSAR domain.

Models, Molecular↗

PubMed2005

Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer.

BACKGROUND: Only 15% of patients with non-small cell lung cancer (NSCLC) treated with oral epidermal growth factor tyrosine kinase inhibitor gefitinib, as a second-line therapy have objective responses. Fifty percent will have improvement of lung cancer related symptoms. It will be critical to identify patients who will benefit clinically from this therapy even when there is no objective response seen on imaging studies. We have performed a retrospective analysis of 76 patients who received gefitinib as a therapy for previously treated metastatic NSCLC at the University of Minnesota Comprehensive Cancer Center in order to describe characteristics of patients who will likely derive benefits from gefitinib therapy. METHODS: All patients treated with gefitinib therapy at the University of Minnesota from September 2001 to January 2004 were entered into the study. The Log-rank Test and Cox proportional hazards regression were used to assess the effect of the number of previous therapy lines, histology subtype, performance status, gender, stage of disease at initial diagnosis, and presence of skin rash on time to disease progression and overall survival (OS). Fisher's Exact Test and multiple logistic regressions were used to assess the effect of these covariates on disease response. RESULTS: Seventy-six patients entered the study, with a median age of 60 years (range 37-82). There were 37 female and 39 male patients; 47 patients had adenocarcinoma, 22 had squamous and 7 had other NSCLC histologies. Six patients had no prior therapy, 23 had one, 32 had two, 8 had three, and 7 had four prior therapies for lung cancer. Fifty-six were current smokers. Median time to disease progression was 3 months (95% CI: 3.0, 6.0). There was no difference in time to disease progression whether patients had one or more prior therapies. Patients with brain metastases (26 patients) benefited from gefitinib therapy at least equally well as those without brain metastatic disease. Patients with adenocarcinoma histology with bronchoalveolar features had superior median time to progression versus other lung cancer histology (14 months versus 3 months, p=0.076), which translated into survival advantage in this group >24 months (95% CI: 0.76, 24+) versus 6.6 months (p=0.0096). Patients with EGFR positive tumors had median survival of 10.2 months (95% CI: 1.45, 16.94) versus 3.7 months (95% CI: 2.66, 4.74) with EGFR negative tumors. Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months (95% CI: 1.43, 2.83) (p=0.023). This last factor was the best predictor of improved time to disease progression in multiple regression analysis (p=0.0405). CONCLUSION: A subgroup of patients with NSCLC will benefit from gefitinib therapy. Objective responses will likely be seen in half the patients with mutation of internal domain of EGFR; however, a larger group of patients will also enjoy prolonged disease stabilization and clinical benefit. We suggest that adenocarcinoma with bronchoalveolar features and the presence of skin rash may be used as predictors of gefitinib benefit.

Adult↗

PubMed2005

Diminished neo-antigen response to keyhole limpet hemocyanin (KLH) vaccines in patients after treatment with chemotherapy or hematopoietic cell transplantation.

Relapse is the most common cause of treatment failure for advanced cancer, even those treated with autologous hematopoietic cell transplantation (HCT). Effective tumor-specific immunotherapy may decrease relapse, however, this will fail if the immune system is unable to respond. We developed a strategy to test immune responses with a single injection of the bona fide neo-antigen KLH. The model was first tested in 37 normal volunteers using three KLH vaccines: Intracel KLH, Biosyn KLH, and Biosyn KLH + adjuvant. Despite finding the immunogenic epitope conserved in both products, intact Intracel KLH induced a better response compared to a purified 350/390 kDA subunit of KLH contained in the Biosyn KLH product. Addition of a synthetic oil adjuvant (Montanide ISA51) restored the response to a single injection of Biosyn KLH. A quantitative readout measured by a KLH-specific cellular and humoral response with isotype switching 1 month after KLH vaccination was established. To test the integrity of the adaptive immune response in cancer patients, we vaccinated 14 patients post-HCT and 19 patients with advanced cancer with KLH vaccines that elicited a 100% response rate in normal volunteers. In marked contrast to normal subjects, both responses were significantly impaired up to 16 months after autologous HCT with an intermediate response in advanced cancer patients. KLH vaccines are safe and require only a single injection to test neo-antigen responses providing an optimal platform for definitive testing of strategies to improve diminished immune recovery after chemotherapy or post-HCT.

Biomarkers↗

PubMed2005

Circulating angiogenic cytokines in patients with advanced non-small cell lung cancer: correlation with treatment response and survival.

Tumor angiogenesis is stimulated by a pro-angiogenic shift in both inducers and inhibitors of endothelial growth. To study this shift, we measured serum and plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), endostatin, and thrombospondin 1 (TSP1) in 21 advanced non-small cell lung cancer (NSCLC) patients and 46 healthy control subjects. In addition, we assessed the relevance of these levels to disease outcome. Cytokine levels were prospectively measured in plasma and serum by enzyme-linked immunosorbent assay at three times: before chemotherapy and at 1 and 12 weeks following initiation of chemotherapy. In NSCLC patients, serum VEGF levels (sVEGF) were elevated (p<0.001), whereas serum and plasma TSP1 levels were lower (p=0.012 and p=0.004, respectively) than in healthy control subjects. Pretreatment plasma endostatin and serum bFGF levels were higher in NSCLC patients than in healthy controls (p=0.05 and 0.01, respectively). Change in sVEGF at week 12 after initiation of chemotherapy correlated with response to therapy (p=0.002). Patients with pretreatment sVEGF levels <500 pg/mL had a median survival of 11 months, but those with sVEGF >500 pg/mL had only a 6 months' median survival (p < 0.03). In NSCLC patients, VEGF levels are increased, whereas TSP1 levels are decreased, which may trigger and sustain tumor angiogenesis. High levels of serum VEGF at the time of presentation with NSCLC may predict worse survival.

Adult↗

PubMed2004

Platelet factor 4 and interleukin-8 CXC chemokine heterodimer formation modulates function at the quaternary structural level.

The apparent complexity of biology increases as more biomolecular interactions that mediate function become known. We have used NMR spectroscopy and molecular modeling to provide direct evidence that tetrameric platelet factor-4 (PF4) and dimeric interleukin-8 (IL8), two members of the CXC chemokine family, readily interact by exchanging subunits and forming heterodimers via extension of their antiparallel beta-sheet domains. We further demonstrate using functional assays that PF4/IL8 heterodimerization has a direct and significant consequence on the biological activity of both chemokines. Formation of heterodimers enhances the anti-proliferative effect of PF4 on endothelial cells in culture, as well as the IL8-induced migration of CXCR2 vector-transfected Baf3 cells. These results suggest that CXC chemokine biology, and perhaps cytokine biology in general, may be functionally modulated at the molecular level by formation of heterodimers. This concept, in turn, has implications for designing chemokine/cytokine variants with modified biological properties.

Animals↗

PubMed2003

Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis.

Platelet factor 4 (PF4) is an abundant platelet alpha-granule C-X-C chemokine that has weak chemotactic potency but strongly inhibits hematopoiesis through an unknown mechanism. We find that PF4 binds to human CD34+ hematopoietic progenitor cells (HPCs) with a median effective concentration of 1 microg/mL but not after exposure to chondroitinase ABC. PF4 enhances adhesion of HPCs to intact stroma. Committed progenitors also adhere avidly to immobilized PF4. This adhesion is time-dependent, requires metabolic activity, causes cytoskeletal rearrangement, and induces cell-cycle inhibition. Using extracellular acidification rate to indicate transmembrane signaling, we find that interleukin-8 (IL-8), but not PF4, activates CD34+ progenitors, and PF4 blocks IL-8-mediated activation. Surface plasmon resonance analysis shows that PF4 binds IL-8 with high (dissociation constant [Kd] = 42 nM) affinity. Nuclear magnetic resonance analysis of IL-8 and PF4 in solution confirms this interaction. We conclude that PF4 has the capacity to influence hematopoiesis through mechanisms not mediated by a classical high-affinity, 7-transmembrane domain chemokine receptor. Instead, PF4 may modulate the hematopoietic milieu both directly, by promoting progenitor adhesion and quiescence through interaction with an HPC chondroitin sulfate-containing moiety, and indirectly, by binding to or interfering with signaling caused by other, hematopoietically active chemokines, such as IL-8.

Antigens, CD34↗

PubMed2003

Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes.

Bronchiolitis obliterans (BrOb), a late complication of bone marrow transplantation (BMT), is associated with chronic graft-versus-host disease (GVHD) and is frequently fatal. To identify the risk factors associated with BrOb, the factors affecting survival, treatment outcomes, and causes of death of patients with BrOb, we retrospectively analyzed 2859 BMT recipients. No cases of BrOb occurred among 1070 autologous BMT recipients. Among 1789 allogeneic BMT recipients, we identified 47 patients with BrOb. In multivariate analysis, older recipients or donors and acute GVHD were significantly associated with the development of BrOb. Among patients with BrOb, 5-year survival from the time of transplantation was only 10%, versus 40% among allogeneic BMT recipients without BrOb. The clinical course of BrOb had a significant effect on survival: 79% survived 5 years from the time of BrOb diagnosis if BrOb improved versus 13% if there was no improvement after the first-line therapy. Predictors of response included older donors and recipients, a previous diagnosis of chronic GVHD, and diagnosis of BrOb 6 months after transplantation; each of these significantly increased the likelihood of a favorable response to treatment. BrOb had high mortality rate of 55%, and pulmonary failure was the leading cause of death. More effective BrOb therapy is needed, especially for patients with unfavorable presentation.

Adolescent↗

PubMed2003

Molecular targets in the inhibition of angiogenesis.

Angiogenesis, the process of blood vessel formation, is crucial for malignant tumour growth and metastases; therefore, it has become an attractive target for anticancer therapy. Theoretically applicable to most solid tumours, this therapy may be advantageous over existing cytotoxic therapy, since it is directed at genetically stable endothelium growing within tumours rather than at malignant cells, which acquire resistance to treatment. Many promising angiogenesis inhibitors have been developed, although their activity has yet to be demonstrated in human clinical trials. To improve therapeutic benefit, this may require further insight into tumour angiogenesis, development of appropriate surrogate markers of activity, treatment of early stage neoplastic disease and probably a combination of different classes of antiangiogenesis agents to overcome redundant mechanisms of angiogenesis control.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Pilot phase II study of gemcitabine and vinorelbine in patients with recurrent or refractory small cell lung cancer.

The aim of this phase II study was to evaluate toxicity, response, time to progression, and overall survival in patients with recurrent or progressive small cell lung cancer (SCLC) receiving the combination of gemcitabine and vinorelbine. This two stages Simon design trial was stopped after 17 patients were enrolled and response rate did not reach a level to justify continuation to the second stage. One patient had received three previous chemotherapy combinations, 5 had two prior chemotherapy regimens, and the remaining 11 had been treated with one prior line of therapy. Their median age was 62 years (35-72). Vinorelbine was administered at 25 mg/m(2) followed by gemcitabine 1000 mg/m(2), on days 1 and 8, every 3 weeks. Sixteen patients were evaluable for toxicity and 11 for response. Grade 3 neutropenia was seen in 5 patients (33%) and 3 patients had grade 4 neutropenia (20%). Three patients had grade 3 thrombocytopenia. No grade 4 non-hematological toxicities were seen. A total of 85 infusions were given, with 1 patient (6%) obtaining a partial response (PR) for a duration of 148 days. Three additional patients had stable disease (19%), but only in 1 patient for longer than 24 weeks. The median time to progression was 47 days for all patients (range 25-196). After a median follow-up of 184 days, 13 patients died (76%). Median overall survival was 164 days. The combination of gemcitabine and vinorelbine has limited activity in relapsed SCLC.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Ensemble of linear models for predicting drug properties.

We propose a new classification method for the prediction of drug properties, called random feature subset boosting for linear discriminant analysis (LDA). The main novelty of this method is the ability to overcome the problems with constructing ensembles of linear discriminant models based on generalized eigenvectors of covariance matrices. Such linear models are popular in building classification-based structure-activity relationships. The introduction of ensembles of LDA models allows for an analysis of more complex problems than by using single LDA, for example, those involving multiple mechanisms of action. Using four data sets, we show experimentally that the method is competitive with other recently studied chemoinformatic methods, including support vector machines and models based on decision trees. We present an easy scheme for interpreting the model despite its apparent sophistication. We also outline theoretical evidence as to why, contrary to the conventional AdaBoost ensemble algorithm, this method is able to increase the accuracy of LDA models.

ATP Binding Cassette Transporter, Subfamily B, Mem↗