Comparative cytotoxicity of 2,3,9-trimethoxypterocarpan in leukemia cell lines (HL-60, Jurkat,Molt-4, and K562) and human peripheral blood mononuclear cells

The purpose of this study was to investigate the antiproliferative activity of 2,3,9-trimethoxypterocarpan, a known pterocarpan with cytotoxic activity against many tumor cell lines, in a panel of four leukemia cell lines (HL-60, Molt-4, Jurkat, and K562) and on human peripheral blood mononuclear cells (PBMC). The pterocarpan showed IC₅₀ ranging from 0.1 to 0.5 μg/ml at leukemic cells after 72 h of incubation, with K562 being the most resistant cell line. This compound seemed to be selective to tumor cell lines, since at a concentration of 10 μg/ml after 72 h, it only reduced 19% of viable peripheral mononuclear cells.     

Effects of long-term acetyl-L-carnitine administration in rats--II: Protection against the disrupting effect of stress on the acquisition of appetitive behavior.

Long-term acetyl-L-carnitine (ALCAR) administration prevents the development of escape deficit produced by acute exposure to unavoidable stress. However, it does not revert the escape deficit sustained by chronic stress exposure. Rats exposed to chronic stress show a low dopamine (DA) output in the nucleus accumbens shell (NAcS) and do not acquire an appetitive behavior sustained by the earning of vanilla sugar (VS) made contingent on the choice of one of the two divergent arms of a Y-maze (VS-sustained appetitive behavior, VAB), while control rats consistently do. The present study shows that ALCAR treatment in rats exposed to a 7-day stress protocol prevented a decrease in DA output in the NAcS and medial prefrontal cortex (mPFC) of rats, and that it strengthened the DA response to VS consummation in the same two areas. Moreover, rats treated with long-term ALCAR or exposed to chronic stress while treated with ALCAR acquired VAB as efficiently as control rats. Moreover, VAB acquisition in stressed rats treated with ALCAR coincided with the reversal of the deficits in escape and in dopaminergic transmission in the NAcS. Thus, repeated ALCAR treatment preserved the DA response to VS in chronically stressed rats and this effect appeared to be predictive of the rat's competence to acquire VAB.     

A B7-1-transfected human melanoma line stimulates proliferation and cytotoxicity of autologous and allogeneic lymphocytes

B7 co-stimulation is necessary to activate resting T cells upon antigen recognition by the T cell receptor. To see whether expression of B7 may render human melanoma cells able to stimulate T cells, a cloned melanoma line (Me1B6), which did not express B7-1, was transfected with the human B7-1 gene. In proliferation assays, B7-1 transfected cells (Me1B6/B7) showed greater stimulatory activity of allogeneic and autologous peripheral blood lymphocytes (PBL) compared to parental, non-transfected tumor cells. This effect was also seen when allogeneic CD8⁺ and CD4⁺ subpopulations were used as effectors. In these studies, activation of lymphocytes was B7-1-dependent and HLA classes I and II mediated. The higher proliferation correlated with an increased lytic activity by PBL stimulated with B7-1⁺ tumor cells against the untransfected Me1B6. Furthermore, PBL from a metastatic melanoma patient stimulated by Me1B6/B7 developed an higher lytic activity not only against Me1B6 but also against their autologous, B7-1^? tumor. Finally, after Me1B6/B7 stimulation, PBL released interleukin (IL)-2 and interferon-γ, but not IL-4, suggesting a Th1-mediated response. These data support the use of B7-1 transfected melanoma cells in the therapeutic vaccination of melanoma patients.     

Potential of Daclizumab in Solid Organ Transplantation

The central role that the cytokine interleukin-2 (IL-2) and its receptor (IL-2R) play in the induction of the immune response has been recognised for some time. IL-2R consists of 3 chains (alpha, beta and gamma). The alpha-chain (T cell activation antigen or CD25) is expressed only after T-lymphocyte activation. Therefore a monoclonal antibody targeting the alpha-chain can result in selective immunosuppression. The first generation anti-IL-2Ralpha monoclonal antibodies consisted of mouse and rat antibodies that were promising but not totally effective in clinical studies. The immunogenicity, short half-life and inability to recruit host effector functions such as antibody-dependent cell-mediated cytotoxicity associated with the rodent monoclonal antibodies limit their clinical use. Chimerisation or humanisation of these monoclonal antibodies resulted in antibodies with a predominantly human framework that retained the antigen specificity of the original rodent monoclonal antibodies. A fully humanised anti-IL-2R monoclonal antibody, daclizumab, and a chimeric anti-IL-2R monoclonal antibody, basiliximab, have undergone successful phase III pivotal trials in which they were well tolerated and effective in the immunoprophylaxis of patients undergoing renal transplantation. Daclizumab 1 mg/kg every other week for a total of 5 doses in patients administered standard triple immunosuppression who had received grafts from cadaver or living related donors saturated the IL-2Ralpha on circulating lymphocytes for at least 3 months after transplantation. The efficacy and safety of intravenous daclizumab 1 mg/kg prior to transplantation and again at 2, 4, 6 and 8 weeks postoperatively, in conjunction with standard dual or triple immunosuppression, were further assessed in 2 phase III clinical trials. In both trials, biopsy-proven rejection was significantly reduced 6 months after the transplantation. The half-life of daclizumab was 20 days. The addition of daclizumab did not increase the incidence of adverse events, infectious complications or malignancies. Basiliximab 20mg was administered on the day of and on day 4 after transplantation, in conjunction with standard dual immunosuppression, in 2 phase III trials involving cadaver and/or living related transplants. The incidence of biopsy-proven acute rejection at 6 months was significantly reduced with basiliximab. The half-life of basiliximab was 7 days. The drug was not associated with increased risks of adverse events, infectious complications or malignancies. In an ongoing study, patients receiving a maintenance immunosuppression regimen of prednisone, cyclosporin and mycophenolate mofetil were administered daclizumab or placebo. Biopsy-proven rejection was lower in the group receiving daclizumab, and coadministration with mycophenolate mofetil was well tolerated with no pharmacokinetic interactions.     

Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes

Genetic and pharmacological studies have suggested that brain-derived neurotrophic factor (BDNF) may be associated with the pathophysiology of bipolar disorder (BD). The present study investigated serum BDNF levels in manic, depressed, euthymic BD patients and in matched healthy controls, using an enzyme-linked immunosorbent assay (sandwich-ELISA). Serum BDNF levels were decreased in manic (p = 0.019) and depressed (p = 0.027) BD patients, as compared with euthymic patients and controls. Serum BDNF levels were negatively correlated with the severity of manic (r = −0.37, p = 0.005) and depressive (r = −0.30, p = 0.033) symptoms. These findings further support the hypothesis that the BDNF signaling system may play a role in the pathophysiology of BD.     

Recently amplified satellite DNA inCallithrix argentata (Primates,Platyrrhini)

A satellite DNA has been cloned from the neotropical primateCallithrix argentata and designated CarB. The presence of the satellite was assayed in New and Old World primates by blot hybridization: CarB is highly amplified in the genomes of all three species belonging to theC. argentata species group (C. argentata, C. emiliae, C. humeralifer), but is either absent, or present in only minor amounts, in other primates, including the closely related species,C. jacchus. A completely sequenced CarB monomeric unit was 1528 bp in length and mapped to the telomeric C-band-positive regions of manyC. argentata species group chromosomes. Sequence data from eight CarB clones indicated an average difference of 3.5% when base substitutions alone were counted. The hybridization and sequence data suggest that this satellite underwent a period of amplification and dispersal in the genome of a recent ancestor of theC. argentata species group.     

Predictive factors of recurrence in adenocarcinoma of the esophagogastric junction in the multimodal era

IntroductionAdenocarcinoma of the esophagogastric junction (AEGJ) represents a poor prognostic tumor. We evaluated the recurrence pattern and risk factors associated with recurrence in patients undergoing surgical resection by AEJG.MethodsRecurrences were categorized as locoregional, peritoneal, or distant. These three recurrence groups and a non-recurrence group were compared, and overall survival (OS) and disease-free survival (DFS) for each one was obtained.ResultsWe analyzed 188 patients with curative surgical treatment. Recurrence was observed in 72 (38.3%) patients. Locoregional recurrence was observed in 17 (23.6%); 20 (27.8%) peritoneal recurrence and 35 (48.6%) distant metastasis. DFS was 9, 5, and 8 months, and OS was 21.8, 13.2, and 20.8, respectively. Tumors larger than 5 cm are risk factors for peritoneal recurrence (OR:2.88, p = 0.012). Positive lymph nodes were related to distant metastasis (OR:9.15, p = 0.040), and lymphatic invasion for locoregional recurrence (OR:3.81, p = 0.028).ConclusionAEGJ is associated with high rates of early recurrence.     

Quality of life outcomes after minimally invasive repair of pectus excavatum utilizing a new set of metallic bars and stabilizers

Background/PurposeThe aim of the study was to evaluate the postoperative quality of life (QoL) of patients who underwent minimally invasive repair of pectus excavatum (MIRPE) with a newly designed bar and bar stabilizers.MethodsWe conducted a prospective randomized study in which patients were operated either with standard perpendicular stabilizers (control group) or with the newly designed oblique stabilizers (intervention group). All patients were evaluated 6 months after the operation with the Pectus Excavatum Evaluation Questionnaire (PEEQ).ResultsThere were 16 patients in the control group and 14 in the intervention group. Mean age was 17 (SD: 3.3, range 14–27) years. There were no demographic differences between groups. Two patients in the control group and one in the intervention group were repaired with two bars instead of one. There was one reoperation in each group. There was a significant difference between the pre- and postoperative scores, in both groups, in the patient body image domain (control group: 9.5 to 3; p < 0.01; intervention group 10 to 3; p < 0.01), as well as in the psychosocial domain (control group: 13.5 to 24, p < 0.01; intervention group: 15 to 24, p < 0.01). With regards to the patients' perception of physical difficulties before and after MIRPE, the difference between pre- and postoperative scores was greater in the intervention group (8 to 12, p < 0.01) than in the control group (10 to 11, p = 0.04). The mean length of stay was 4.5 and 5 days in the intervention group and the control group, respectively.ConclusionOur study showed that patients who underwent MIRPE with the newly designed bars and stabilizers had non-inferior outcomes than patients reported in the literature who underwent MIRPE with standard bars and stabilizers. We found slightly better outcomes in patients in the intervention group compared to the control group, but larger studies will be needed to confirm if those differences are statistically significant.Level of evidenceII     

Modulation of oral squamous cell carcinoma incidence in rats via diet and a novel calcium channel antagonist

An unexpected dose related increase in oral squamous cell carcinomas was observed in a standard 2-year carcinogenicity study with a novel calcium channel blocker, in which Wistar rats received daily doses of 0, 1.5, 7, 20, or 40 mg/kg of the compound mixed with a standard diet containing fibers from barley. This finding was associated with an increased incidence of severe (destructive) periodontitis and the formation of oro-nasal fistulae at the 2 highest doses. Five assays of the compound for genotoxicity were negative indicating that a genotoxic effect was highly improbable. To investigate the underlying pathogenic mechanisms a second 2-year study in the same strain of rats was initiated and the influence of the diet and/or a possible local irritancy by the drug was assessed. In this second study the compound was administered by oral gavage at daily doses of 0, 7, or 40 mg/kg (later reduced to 20 mg/kg due to systemic intolerance) to rats maintained either on the standard diet or on a low fiber diet assumed to be less aggressive in terms of inducing periodontal lesions. Dose dependent gingival overgrowth (a class-related effect) was observed in the incisor and molar teeth area of all treated groups but was independent of the diet used. No oral tumors were found in the standard diet or low fiber diet controls and all treatment groups fed the low fiber diet, whereas in the high-dose group fed the standard diet a total of 8 oral squamous cell carcinomas were detected in association with an increased incidence of severe periodontitis. These results indicate that the increased incidence of squamous cell carcinomas observed upon chronic administration of the compound is not due to a direct tumorigenic effect of the drug. Tumor formation is attributable to severe periodontal disease favored by the diet and class related gingival overgrowth.