Kallikrein-mediated activation of PARs in inflammation and nociception

Kallikreins (KLKs) are secreted serine proteinases identified in a variety of cancers and in settings of inflammation.We have shown that KLKs in vitro can activate proteinase-activated receptors (PARs), a family of G-protein coupled receptors associated with inflammation. KLK14 activated both of PARs 2 and 4 and prevented thrombin from activating PAR₁. On the other hand, KLK6 was a specific activator of PAR₂. In an in vivo mouse inflammation model, kallikrein administration caused an oedema response comparable in magnitude and timing to that generated by trypsin. The oedema was accompanied by a decreased threshold of mechanical and thermal nociception. Our data demonstrate that by activating PARs 2 and 4 and by inactivating PAR1, widely-expressed kallikreins, like KLKs 6 and 14, may play a role in regulating the inflammatory response and pain perception.     

Thalidomide as salvage therapy for chronic graft-versus-host disease

Thalidomide has been reported to be an effective agent for treatment of chronic graft-versus-host disease (CGVHD). To determine the efficacy of this agent in patients with refractory CGVHD a total of 80 patients who failed to respond to prednisone (PSE) or PSE and cyclosporine (CSA) were treated with thalidomide. Sixteen patients (20%) had a sustained response, 9 with a complete remission and 7 with a partial response. Twenty-nine patients (36%) had thalidomide discontinued because of side effects, which included sedation, constipation, neuritis, skin rash, and neutropenia. Side effects were reversible with drug discontinuation except for mild residual neuritis in one case. Rashes and neutropenia have not previously been reported as thalidomide side effects when used for CGVHD treatment. We conclude thalidomide is immunosuppressive and active in the treatment of CGVHD. A high incidence of reversible side effects limited dose intensity and reduced the number of patients who could benefit from treatment.     

Further evidence of the in vivo role of erythropoietin or companion molecules induced by hypoxia on proliferation and continuing differentiation of BFU-e in PCDC

Normal and plethoric bone marrow cells were grown in plasma clot diffusion chambers (PCDC) implanted into the peritoneum of normal mice or mice submitted to 7 her of hypoxia (23,000 ft) daily, on a single day or on 2 consecutive days at different times after implantation of the PCDC's. Daily discontinuous hypoxia (DDH) produced more 6-day bursts than other treatments. Hypoxia on days 1 and 2 after implantation was nearly as effective as DDH on day-6 bursts. Later bouts of hypoxia or a singly hypoxic exposure on day 1 or 2 was less effective. Erythropoietin (Ep) levels were measured by bioassay on both diffusion chamber (DC) contents and serum. Serum Ep levels peaked at 160 mU/ml after a 7-hr hypoxic exposure while the DC content Ep levels were in the nondetectable range (less than 50 mU/ml). The data implies that either higher than normal Ep levels or a companion molecules (s) produced by hypoxia are required for 1-2 days early in the culture period of force an increasing number of BFU-d-e down the erythrocytic pathway and thus increase red cell production at times of need in vivo.     

Chronic leukemia with a hybrid surface phenotype (T lymphocytic/myelomonocytic): leukemic cells displaying natural killer activity and antibody-dependent cellular cytotoxicity

A patient with chronic leukemia exhibited uncommon clinical features, such as hypergammaglobulinemia and activation of intravascular coagulation after low-dose irradiation of the enlarged spleen. By light and electron microscopy, the leukemic cells resembled large granular lymphocytes. The following markers were simultaneously expressed on their surface: receptors for sheep erythrocytes and the Fc part of IgG; common T-cell antigens as revealed by a heteroantiserum (HuTLA) and monoclonal antibodies (OKT3, T411); antigens shared by cytotoxic/suppressor T cells (OKT8, T811) as well as myelomonocytic antigens defined by the OKM1 and M522 monoclonal antibodies. The leukemic cells showed both spontaneous (NK) and antibody-dependent (ADCC) cytotoxicity, but they did not suppress B-cell differentiation in vitro.     

Health status in routine clinical practice: validity of the clinical COPD questionnaire at the individual patient level

Background  

There is a growing interest to use health status or disease control questionnaires in routine clinical practice. However, the validity of most questionnaires is established using techniques developed for group level validation. This study examines a new method, using patient interviews, to validate a short health status questionnaire, the Clinical COPD Questionnaire (CCQ), at the individual patient level.     

Ovarian cancer specific kallikrein profile in effusions

OBJECTIVE: Kallikreins belong to the serine protease family and their roles as cancer associated markers have been proposed. However, a comprehensive and parallel analysis of different secreted kallikreins in ovarian cancer has not been performed. This study was undertaken to profile the secreted kallikreins in cancer effusion supernatants. METHODS: We applied ELISA to measure the protein levels of nine kallikreins (4-8, 10, 11, 13, and 14) in a total of 221 effusion supernatants obtained from ovarian cancer, benign non-neoplastic diseases and a variety of other neoplastic diseases. RESULTS: Our results demonstrated that ovarian cancer effusions contained higher levels of all kallikreins analyzed except kallikrein 4, as compared to benign effusions (p<0.0005) and other cancer types (p<0.03). Unsupervised principal component analyses demonstrated a unique cluster of ovarian cancer samples which were distinct from benign effusions and other cancer groups based on measurements of secreted kallikreins 5-8, 10, 11, 13 and 14. Supervised combinations of the eight kallikreins achieved areas under ROC curve of 0.994 and 0.961 in separating ovarian cancer from benign effusion groups and other cancer groups, respectively. Among kallikreins, kallikreins 6, 7, 8, and 10 showed the highest statistical power in distinguishing ovarian cancer from benign controls and other cancer groups and these kallikreins could diagnose false negative cases based on cytology. CONCLUSIONS: The above findings indicate that kallikreins 6, 7, 8 and 10 are the four most specific secreted kallikreins in ovarian cancer. These kallikreins may have clinical implications in the differential diagnosis of ovarian carcinoma from benign diseases and other cancer types.