ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.
Subject(s)
Biomarkers, Tumor/metabolism , Interleukin-10/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Receptors, Interleukin-10/metabolism , Apoptosis , Biomarkers, Tumor/genetics , Blotting, Western , Cell Cycle , Cell Proliferation , High-Throughput Nucleotide Sequencing , Humans , Immunoenzyme Techniques , Interleukin-10/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Interleukin-10/genetics , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Tissue Array Analysis , Tumor Cells, CulturedABSTRACT
Fracture of the penis is a well-recognized clinical entity. The ideal management has evolved and repair remains largely surgical. We present the etiology and pathophysiology of this condition and outline the therapeutic options.
Subject(s)
Penile Diseases , Hematoma/diagnostic imaging , Hematoma/pathology , Humans , Male , Penile Diseases/diagnostic imaging , Penile Diseases/pathology , Penile Diseases/physiopathology , Penile Diseases/surgery , UltrasonographyABSTRACT
The role of leukocyte adhesion molecules in endotoxin-induced organ injury was evaluated by administering intraperitoneal Salmonella enteritidis lipopolysaccharide (LPS) to wild-type (WT) mice, P-selectin-deficient mice, intercellular adhesion molecule (ICAM)-1-deficient mice, and P-selectin-ICAM-1 double-mutant mice. In WT mice, there was a sevenfold increase in the number of neutrophils present in the pulmonary vascular lavage fluid, and there were sevenfold more intracapillary neutrophils by electron-microscopic (EM) morphometry at 4 h after intraperitoneal LPS compared with that in control mice. Extravascular albumin accumulation increased approximately twofold in the lungs and liver of WT mice treated with LPS. In the double-mutant mice, although overall mortality after intraperitoneal LPS was not attenuated, there was a significant delay in mortality in the P-selectin-ICAM-1-deficient mutants compared with that in WT mice after intraperitoneal LPS (P < 0.01). Moreover, compared with LPS-treated WT mice, lung and liver extravascular albumin accumulation was significantly lower in LPS-treated P-selectin-ICAM-1 double-mutant mice. Lung myeloperoxidase activity, normalized per 1,000 circulating neutrophils, increased after endotoxin in WT and P-selectin-deficient mice but not in P-selectin-ICAM-1 double-mutant mice. In addition, lung and liver myeloperoxidase activity per 1,000 circulating neutrophils in endotoxin-treated ICAM-1-deficient mice and P-selectin-ICAM-1 double mutants was significantly lower compared with that in endotoxin-treated WT mice. These data suggest that P-selectin and ICAM-1 significantly contribute to lung and liver injury after systemic endotoxemia.
Subject(s)
Chemical and Drug Induced Liver Injury , Endotoxins/pharmacology , Intercellular Adhesion Molecule-1/physiology , Lung Diseases/chemically induced , Neutrophils/physiology , P-Selectin/physiology , Animals , Blood Cells/pathology , Cell Movement/drug effects , Intercellular Adhesion Molecule-1/metabolism , Leukocyte Count/drug effects , Leukocytes/pathology , Lipopolysaccharides/pharmacology , Liver/metabolism , Liver/pathology , Liver Diseases/pathology , Lung/metabolism , Lung/pathology , Lung Diseases/pathology , Mice , Neutrophils/pathology , P-Selectin/metabolism , Pulmonary Circulation/physiology , Serum Albumin/metabolism , Therapeutic IrrigationABSTRACT
This article provides an overview of some of the current issues involved in sedation and anxiolysis in the intensive care unit. The problems involved in trying to monitor sedation levels are discussed, as are some of the newer options available for physiologic monitoring of the central nervous system. The problem of abnormal mental states in the intensive care unit and the range of antidepressant therapy now available are also covered. The importance of sleep deprivation and the properties of the neuromuscular blockers are also discussed.
