A Bayesian Hybrid Design With Borrowing From Historical Study.

In early phase drug development of combination therapy, the primary objective is to preliminarily assess whether there is additive activity from a novel agent when combined with an established monotherapy. Due to potential feasibility issues for conducting a large randomized study, uncontrolled single-arm trials have been the mainstream approach in cancer clinical trials. However, such trials often present significant challenges in deciding whether to proceed to the next phase of development due to the lack of randomization in traditional two-arm trials.

A PDZ tandem repeat folds and unfolds via different pathways.

Protein folding and unfolding experiments are interpreted under the assumption of microscopic reversibility, that is, that at equilibrium one process is the reverse of the other. Single-domain proteins illustrate the validity of such an interpretation, although reversibility does not necessarily hold under the different conditions typically used for folding and unfolding experiments. In fact, more complex proteins, which often exhibit irreversible unfolding, are generally considered not amenable to folding kinetics studies.

Folding and Binding Kinetics of the Tandem of SH2 Domains from SHP2.

The SH2 domains of SHP2 play a crucial role in determining the function of the SHP2 protein. While the folding and binding properties of the isolated NSH2 and CSH2 domains have been extensively studied, there is limited information about the tandem SH2 domains. This study aims to elucidate the folding and binding kinetics of the NSH2-CSH2 tandem domains of SHP2 through rapid kinetic experiments, complementing existing data on the isolated domains.

Selectivity of metsulfuron applied to soybean before sowing in different intervals and soils.

This work aimed to evaluate the selectivity of the herbicide metsulfuron applied at different times on the development of soybeans grown in soils with different characteristics. The experiment was conducted in a randomized block design, in a factorial scheme (4 x 4), with four replicates. Factor A was application time (0, 15, 30, and 45 days before sowing, DBS) and factor B was soil type (Erechim, Itaqui, Piratini, and Santa Maria).

Chemoimmunotherapy using pegylated liposomal Doxorubicin and interleukin-18 in recurrent ovarian cancer: a phase I dose-escalation study.

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m(2)) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy.

Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials.

Introduction: Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.

A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin lymphoma.

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma.

Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin.

The antitumor activity of monoclonal antibodies is mediated by effector cells, such as natural killer (NK) cells, that express Fc receptors for immunoglobulin. Efficacy of monoclonal antibodies, including the CD20 antibody rituximab, could be improved by agents that augment the function of NK cells. Interleukin (IL)-18 is an immunostimulatory cytokine that has antitumor activity in preclinical models.

Relationship between the contamination of gulls (Larus dominicanus) and oysters (Crassostrea gigas) with Salmonella serovar Typhimurium by PCR-RFLP.

Shellfish can bioaccumulate in their tissues pathogenic contaminants present in water and they have been related with several outbreaks of food-borne diseases worldwide. With their increased population in urban areas, gulls have been reported as an important source of water environment contamination. During a 10-month period, water, gulls feces and oyster samples were collected in a shellfish harvesting site and analyzed for total and fecal coliform counts (water) and Salmonella presence (gull feces and oyster meat).

Profiling serum biomarkers in patients with COPD: associations with clinical parameters.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology.

C-reactive protein in patients with COPD, control smokers and non-smokers.

Background: Patients with chronic obstructive pulmonary disease (COPD) have raised serum levels of C reactive protein (CRP). This may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as concomitant ischaemic heart disease (IHD) or smoking status. The aim of this study was to evaluate IHD and smoking as potential causes of raised CRP levels in COPD and to test the association between inhaled corticosteroid (ICS) use and serum CRP levels.

Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma.

Purpose: A strain of Salmonella typhimurium (VNP20009), attenuated by chromosomal deletion of the purI and msbB genes, was found to target to tumor and inhibit tumor growth in mice. These findings led to the present phase I study of the intravenous infusion of VNP20009 to patients with metastatic cancer.

Patients And Methods: In cohorts consisting of three to six patients, 24 patients with metastatic melanoma and one patient with metastatic renal cell carcinoma received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009.

CD40 ligand and lipopolysaccharide enhance the in vitro generation of melanoma-reactive T-cells.

Cancer vaccine trials require sensitive assays for evaluating T-cell responses in immunized patients. In addition, these methods are used for identifying novel tumor-associated antigens (TAA). Therefore, our aim was to improve the methods for evaluating patients receiving the cancer vaccines by enhancing the in vitro detection of tumor-specific T cells from the peripheral blood.

Describing the observed vertical transport of radiocesium in specific soils with three time-dependent models.

In this paper three transport models are applied to describe the vertical migration process of 137Cs in undisturbed soil. The same experimental data set is used for the calibration of each model. These data were obtained from areas in northeast Italy, where the 137Cs deposition following the Chernobyl accident ranged from 20 to 40 kBq m-2.

Human dendritic cells require multiple activation signals for the efficient generation of tumor antigen-specific T lymphocytes.

Dendritic cells (DC) are specialized cells of the immune system responsible for the initiation and regulation of both cellular and humoral responses. DC function is highly dependent on their level of maturation. In this study, we postulated that full DC maturation would require a combination of activating signals.

Efficient gene transfer to human peripheral blood monocyte-derived dendritic cells using human immunodeficiency virus type 1-based lentiviral vectors.

Dendritic cells (DCs) are potent antigen-presenting cells and are capable of activating naive T cells. Gene transfer of tumor antigen and cytokine genes into DCs could be an important strategy for immunotherapeutic applications. Dendritic cells derived from peripheral blood monocytes do not divide and are therefore poor candidates for gene transfer by Moloney murine leukemia virus (Mo-MuLV)-based retroviral vectors.

Replication-defective canarypox (ALVAC) vectors effectively activate anti-human immunodeficiency virus-1 cytotoxic T lymphocytes present in infected patients: implications for antigen-specific immunotherapy.

In the attempt to develop immunotherapeutic strategies for acquired immunodeficiency syndrome capable of activating effector cells in an antigen-specific manner while maintaining the broadest possible T-cell repertoire, we evaluated two canarypox (ALVAC)-based vectors for their capacity to induce ex vivo activation/expansion of human immunodeficiency virus (HIV)-specific CD8+ cytotoxic lymphocyte precursors (CTLp) obtained from HIV-1-infected donors. These two vectors, vCP205 encoding HIV-1 gp120 + TM (28 amino acid transmembrane anchor sequence) in addition to Gag/protease and vCP300 encoding gp120 + Gag/protease as well as Nef and Pol CTL determinants, are pancytotropic but replication incompetent in mammalian cells. Bulk peripheral blood mononuclear cells (PBMCs) or enriched CD8+ T cells were stimulated for 10 days with autologous ALVAC-infected PBMCs in the presence of different cytokine combinations (interleukin-2 [IL-2], IL-4, IL-7, and IL-12).

MAGE-1-specific precursor cytotoxic T-lymphocytes present among tumor-infiltrating lymphocytes from a patient with breast cancer: characterization and antigen-specific activation.

A potential target for development of tumor-specific immunotherapeutic strategies is the MAGE-1 gene. We have utilized a recently developed recombinant canarypox (ALVAC) virus vector containing the MAGE-1 gene (vCP235) to activate CTLs from a breast cancer patient bearing a MAGE-1+ tumor. Tumor-infiltrating lymphocytes (TILs) obtained from the tumor of a patient were stimulated in vitro with irradiated autologous peripheral blood mononuclear cells acutely infected with the vCP235 construct.

Oligoclonal CD8 lymphocytes from persons with asymptomatic human immunodeficiency virus (HIV) type 1 infection inhibit HIV-1 replication.

CD8 lymphocytes from asymptomatic human immunodeficiency virus (HIV) type 1-infected patients can suppress virus production from infected CD4 cells. Suppressive activity is separate and distinct from cytotoxic T lymphocyte (CTL) reactivities and is likely mediated by a soluble factor(s). The majority of HIV-1 suppression studies have been done in the context of bulk CD8 cell cultures.

CD4+ blood dendritic cells are potent producers of IFN-alpha in response to in vitro HIV-1 infection.

We determined the relative abilities of cell subpopulations from all major PBMC lineages of normal donors to produce IFN-alpha in response to in vitro stimulation with lymphocytotropic HIV-1 (IIIb and RF), monocytotropic HIV-1 (BaL), Sendai virus, and HSV-1. Active and inactive cell-free preparations of HIV-1 IIIb and cell-associated HIV-1 IIIb, and active cell-free preparations of the other viruses, induced comparable, maximal levels of acid-stable IFN-alpha in PBMC by 18 to 24 h. Negative selection and enrichment experiments indicated that HLA-DR+ "null" cells produced the majority of the IFN-alpha.

Human cytotoxic T-cell lines with restricted specificity for squamous cell carcinoma of the head and neck.

Human cytotoxic T-lymphocyte (CTL) lines with specificity restricted for autologous squamous cell carcinoma of the head and neck (SCCHN) were established from peripheral blood lymphocytes obtained at the time of surgery and again at two different times after surgery from a patient with cancer of the tongue. The CTL lines were cultured in the presence of interleukin (IL) 2, IL4, and autologous tumor (AuTu) cell monolayers. All three lines were CD3+CD8+CD11b-HLA-DR+ T-cell receptor alpha/beta+.