Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas

The goal of multimodality therapy for localized pancreatic cancer is to maximize local-regional disease control and patient survival. In contrast to surgery for other solid tumors, prolonged recovery following pancreaticoduodenectomy may prevent the timely delivery of postoperative adjuvant therapy. Therefore, efforts at The University of Texas, M.D. Anderson Cancer Center have focused on the delivery of chemotherapy and radiation therapy prior to surgery in patients with localized pancreatic cancer. Clinical trials have emphasized the use of altered-fractionation schedules of radiation therapy combined with novel radiation-sensitizing agents. All treatment schemes aim to decrease toxicity and treatment time while improving therapeutic efficacy.     

Alpha interferons--new therapeutic modalities

Interferons are naturally occurring substances. In fact, interferons are intercellular signalling proteins produced by cells in response to various biological and synthetic stimuli. Three major classes of interferons have been identified: interferons alpha, beta and gamma. Interferons originate from natural sources and are products of recombinant technology. Two forms of recombinant alpha-interferons, 2a and 2b, are available. Alpha-interferons are secreted and synthetised by leucocytes and lymphoblasts. The objective herein is to review the current therapeutic implications of alpha-interferons. Interferons alpha have antiviral, anticancer and immunomodulatory activities. Clinical trials have proved interferons alpha to be of special value as adjuvant therapy (first line drugs) for hairy cell leukemia, virus hepatitis B and C and condylomata acuminata. The efficacy of interferons alpha is now also being evaluated in other malignancies and virus diseases. For instance, interferons alpha are an important advanced modality in the management of chronic myelogenous leukemia and can be considered a first-line therapy option in patients who cannot receive or relapse following allogenic bone marrow transplant. Of course, further research is also required to evaluate combination therapies with interferons alpha and other agents. Presently malignancies have the broadest potential in application of interferons alpha therapy. Hairy cell leukemia responds to interferons alpha in up to 90% of patients, Kaposi's sarcoma, which occurs primarily in association with AIDS, benefit in up to 40% of patents, lymphomas respond in about 65% of patients whereas chronic myelogeneous leukemia in more than 80% of patients in early cases. The uses of interferons alpha in infectious diseases (condylomaty acuminata, rhinovirus infection, protozoal, parasitic and fungal intracellular infections) may also be significant. However, the cost of interferons alpha is too high. This makes interferons alpha a second line therapy, but not in patients where it is more effective than alternative treatment. Interferons alpha are cytokines (intercellular signalling proteins) which have antiviral, anticancer and immunomodulatory activities. Interferons alpha therapy represents an important advanced modality in the management of patients with hematological diseases, malignancies, lymphomas, solid malignant tumours and viral infections. Clinical trials have proved interferons alpha to be of special value as first line drugs for hairy cell leukemia, virus hepatitis B and C and condylomata accuminata. Interferons alpha are used as single primary therapy, adjuvant therapy and maintenance therapy. The limiting factor for the application of interferons alpha is the cost of treatment.     

Thapsigargin and receptor-mediated activation of Drosophila TRPL channels stably expressed in a Drosophila S2 cell line

The Drosophila melanogaster genes, transient receptor potential (trp) and transient receptor potential-like (trpl) encode putative plasma membrane cation channels TRP and TRPL, respectively. We have stably co-expressed Drosophila TRPL with a Drosophila muscarinic acetylcholine receptor (DM1) in a Drosophila cell line (S2 cells). Basal Ca2+ levels measured using Fura-2/AM in unstimulated S2-DM1-TRPL cells were low and indistinguishable from untransfected cells, indicating that the TRPL channels were not constitutively active in this expression system. Activation of DM1 receptor in S2-DM1-TRPL cells by 100 microM carbamylcholine induced Ca2+ release from an intracellular Ca2+ pool followed by a Gd(3+)-insensitive Ca2+ influx. Pretreatment of S2-DM1-TRPL cells with 10 microM atropine abolished Gd(3+)-insensitive Ca2+ influx triggered by carbamylcholine, but the response was not blocked by prior incubation with pertussis toxin. TRPL channels could also be reliably activated by bath application of 1 microM thapsigargin for 10 min or 100 nM thapsigargin for 60 min in Ca(2+)-free solution. In some cells, TRPL channels activated by thapsigargin could further be activated by carbamylcholine. The findings suggest that, when stably expressed in the S2 cell line, TRPL may be regulated by two distinct mechanisms: (i) store depletion; and (ii) stimulation of DM1 receptor via pertussis-toxin insensitive G-protein (or the subsequent activation of PLC), but without further requirement for Ca2+ release.     

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects

We calculated the mean energy required to produce an ion pair (W) in methane-, propane- and butane-based tissue-equivalent (TE) gas mixtures from W values in pure constituent gases according to various models for energy partition among gas components. We found an agreement between the experimental and calculated W values in the methane-based TE gas regardless of the model concept. In contrast, only those models which take into account differences in the stopping powers, total ionization cross sections and model constants of gas components give acceptable results for the propane-based TE gas. The calculated W value for high-energy electrons in the isobutane-based TE gas mixture is 25.2 eV for high-energy electrons and 28.0 eV for approximately 5 MeV alpha particles.     

Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin

Acinetobacter baumannii strain A148, a clinical isolate resistant to imipenem (MIC = 32 mg l-1), synthesized two beta-lactamases with pIs 6.3 and > 9.2. The pI 6.3 enzyme hydrolyzed the penicillins, including isoxazoylpenicillins, first-, second- and, to a lesser extent, third-generation cephalosporins. It was inhibited by chloride ions and by the penem beta-lactamase inhibitor BRL 42715. Clavulanate was a weak inhibitor and EDTA did not affect the beta-lactamase activity. This enzyme also hydrolyzed imipenem with a catalytic efficiency (Kcat/Km) of 1500 mM-1 s-1. Moreover, this purified beta-lactamase produced a positive microbiological clover-leaf test with imipenem. Therefore, the pI 6.3 beta-lactamase was considered to be involved in the imipenem resistance of A. baumannii strain A148.     

Altered proton extrusion in cells adapted to growth at low extracellular pH

Coronary vasodilator and hemodynamic profiles of JTV-506, a newly synthesized 2,2-bis-methoxymethyl benzopyran-derivative potassium channel opener, were evaluated in conscious dogs. JTV-506 (2.5-10 microg/kg, i.v.) elicited dose-dependent increases in coronary blood flow (CBF) and heart rate (HR) but only slight changes in mean blood pressure (MBP). Other vasodilators such as levcromakalim, nicorandil, diltiazem, and nitroglycerin, when administered intravenously, elicited increases in CBF and HR and a decrease in MBP. When dosed orally JTV-506 (0.01-0.1 mg/kg), levcromakalim (0.01-0.1 mg/kg), nicorandil (1-10 mg/kg), and nifedipine (3-30 mg/kg) also elicited increases in CBF and HR and a decrease in MBP. JTV-506 caused a marked increase in CBF with slight changes in HR and MBP. In contrast to JTV-506, however, the changes caused by levcromakalim, nicorandil, and nifedipine were accompanied by a marked increase in HR and a marked decrease in MBP. These results suggest that the action of JTV-506 on hemodynamics is different from that of other vasodilators, including reference potassium channel openers, and that the profile of cardiovascular action of JTV-506 may be useful in the treatment of angina pectoris.