Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma

Ipilimumab, a fully human monoclonal antibody, which blocks cytotoxic T-lymphocyte antigen-4, has demonstrated an improvement in overall survival in 2 phase III trials of patients with advanced melanoma. To gain an understanding of its mechanism of action, the effects of ipilimumab on T-cell populations and on humoral immune responses were studied in patients with advanced melanoma from 2 phase II trials. Antibody levels against 5 tumor antigens were assessed at baseline and up to 12 weeks after ipilimumab treatment. Serologic reactivity to the cancer-testis antigen NY-ESO-1 increased by at least 5-fold at week 12 of treatment in 10% to 13% of patients. Increased antibody levels were also observed to the tumor antigens Melan-A, MAGE-A4, SSX2, and p53. Immunocompetence was evaluated with tetanus boosters administered before ipilimumab and pneumococcal and influenza vaccines given 5 days after ipilimumab treatment. At week 7, most patients who received ipilimumab and vaccine showed greater humoral responses relative to baseline titers. For peripheral T-cell populations, statistically significant increases in the percent of activated (HLA-DR) CD4 and CD8 T cells with concomitant decreases in naive CD4 and CD8 T cells were observed after ipilimumab treatment. These changes were evident by week 4 of treatment. Increases were also observed in central memory, effector memory, and activated ICOS CD4 T cells, but not in ICOS CD8 T cells or in FoxP3 CD4 regulatory T cells. These results suggest that ipilimumab can enhance immune responses mediated by different T-cell populations, and humoral immunity, in melanoma patients.     

Factors associated with non-completion in a double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression

High rates of attrition have been reported in randomized controlled trials of patients with severe psychiatric illness, including psychotic depression (MDpsy). The purpose of this study is to examine factors associated with overall attrition and with subtypes of attrition in the Study of the Pharmacotherapy of Psychotic Depression (STOP-PD). Secondary analysis of data collected in a multi-site, randomized, placebo-controlled trial. Clinical services of academic hospitals. Participants comprised 259 persons with MDpsy, aged 18-93 years. The intervention consisted of the random allocation to 12 weeks of treatment of either olanzapine plus sertraline or olanzapine plus placebo. Demographic and clinical variables associated with overall non-completion and sub-types of non-completion of randomized treatment. One hundred and seventeen (45.2%) subjects did not complete 12 weeks of randomized treatment. In a logistic regression analysis, inpatient entry status, olanzapine monotherapy, and higher cumulative medical burden were statistically significant independent predictors of overall non-completion. In a multinomial logistic regression model that examined predictors of subtypes of non-completion, subjects who entered the study as an inpatient were less likely to complete because of inadequate efficacy as determined by the investigator, and older subjects were less likely to complete because of poorer tolerability. Subjects who were assigned to olanzapine monotherapy, younger subjects, and subjects who entered the study as inpatients were less likely to complete because of reasons other than efficacy or tolerability. Understanding factors that contribute to premature discontinuation in studies of MDpsy, and to the specific reasons for attrition, has the potential to improve the management of this disorder, as well as improve the design of future clinical trials of MDpsy.     

Monitorowanie kinetyki zmian wczesnego chimeryzmu hematopoetycznego i charakterystyka wszczepienia molekularnego za pomocą metody STR-PCR u pacjentów poddanych alloHSCT

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a curative treatment for proportion of patients suffering from malignant and non-malignant hematological disorders. Successful transplantation is a process that requires the engraftment of pluripotent hematopoietic stem cells which can re-establish normal hemopoesis and immune system. Distinguishing between donor and host origin of bone marrow and blood cells is crucial for monitoring of engraftment process. One of the most useful tools for engraftment monitoring is the assessment of hematopoietic chimerism after alloSCT that describes the percentage of donor hematopoietic in a transplant recipient.Thirty eight adult patients after alloHSCT were included into the study. In total 43 allogeneic stem cell transplantations were performed. Hematopoietic chimerism was assessed by STR-PCR technique. The analysis of early chimerism were performed starting from 2^nd to 14th day on every 2 days than to 28 days weekly and on day +30 after alloHSCT.Early hematopoietic chimerism assessment demonstrated that the kinetics of chimerism in patients after alloSCT was compatible with linear trend (R²=0.996) and in patients after alloNMSCT was compatible with logarithmic trend (R²=0.959). The hematopoietic chimerism level was higher in alloSCT on day 2 the difference was statistically significant (p=0.0048).Molecular engraftment preceded hematological engraftment in patients after either myeloablative or non-myeloablative conditioning regiments (alloSCT patients p=1.44×10^?12, alloNMSCT p=2.12×10^?6).Earlier ME was observed in patients after alloHSCT and alloSCT who received more than 3×10⁶ CD34+ cells/kg (alloSCT p=0.0013, alloHSCT p=0.021). The difference was statistically significant.     

The effect of deletion of the edema factor on Bacillus anthracis pathogenicity in guinea pigs and rabbits

Bacillus anthracis secretes three major components, which assemble into two bipartite toxins: lethal toxin (LT), composed of lethal factor (LF) and protective antigen (PA) and edema toxin (ET), composed of edema factor (EF) and PA. EF is a potent calmodulin-dependent adenylate cyclase, which is internalized into the target cell following PA binding. Once inside the cell, EF elevates cAMP levels, interrupting intracellular signaling. Effects of ET were demonstrated on monocytes, neutrophils and T-cells. In an earlier work we demonstrated that a deletion of LF in a fully virulent strain had no effect in guinea pigs and a significant, but not major, effect in the rabbit model. These results suggested that EF might play an important role in the development of infection and mortality following exposure to B. anthracis spores. To evaluate the role of EF in B. anthracis pathogenicity we deleted the cya gene, which encodes the EF protein, in the fully virulent Vollum strain. The Δcya mutant was fully virulent in the guinea pig model as determined by LD₅₀ experiments. In the rabbit model, when infected subcutaneously, the absence of EF had no effect on the virulence of the mutant. However an increase of two orders of magnitude in the LD₅₀ was demonstrated when the rabbits were infected by intranasal instillation accompanied with partial mortality and increased mean time to death.These results argue that in the guinea pig model the presence of one of the toxins, ET or LT is sufficient for the development of the infection. In the rabbit model ET plays a role in respiratory infection, most probably mediating the early steps of host colonization.     

Baclofen intoxication: a “fun drug” causing deep coma and nonconvulsive status epilepticus—a case report and review of the literature

The number of reports on baclofen intoxication has increased in recent years. We report a 15-year-old boy who was referred in a state of deep coma (Glasgow Coma Scale?=?3). On clinical examination, he showed sinus bradycardia with normal blood pressure. On admission to the hospital, he presented intermittent short episodes of generalized tonic-clonic seizures. While results of imaging procedures and initial toxicological screening (including standard HPLC analysis and urine test) were negative, a nonconvulsive status epilepticus was diagnosed by electroencephalography (EEG). Identification of baclofen as causative agent was possible after the boy's father reported abusive baclofen intake. Subsequent toxicological target analysis of blood and urine samples confirmed the excessive intake of baclofen and showed a typical elimination pattern with a secondary release. Following 112?h of mechanical ventilation, the boy rapidly regained consciousness and recovered normal neurological behavior. Conclusions: The present case demonstrates the importance of considering baclofen overdosage in cases of severe coma in combination with an abnormal EEG pattern and sinus bradycardia with normal blood pressure levels, in particular as the substance is popular in internet reports promoting baclofen as a rather harmless "fun drug." Furthermore, it underlines the difficulty to identify baclofen as a causative agent without anamnestic information. Nevertheless, by reviewing existing literature on oral baclofen overdosage, it is possible to picture a nearly specific pattern of clinical symptoms in baclofen intoxication.     

DNA/Ad5 vaccination with SIV epitopes induced epitope-specific CD4⁺ T cells, but few subdominant epitope-specific CD8⁺ T cells

The goals of a T cell-based vaccine for HIV are to reduce viral peak and setpoint and prevent transmission. While it has been relatively straightforward to induce CD8⁺ T cell responses against immunodominant T cell epitopes, it has been more difficult to broaden the vaccine-induced CD8⁺ T cell response against subdominant T cell epitopes. Additionally, vaccine regimens to induce CD4⁺ T cell responses have been studied only in limited settings. In this study, we sought to elicit CD8⁺ T cells against subdominant epitopes and CD4⁺ T cells using various novel and well-established vaccine strategies. We vaccinated three Mamu-A*01⁺ animals with five Mamu-A*01-restricted subdominant SIV-specific CD8⁺ T cell epitopes. All three vaccinated animals made high frequency responses against the Mamu-A*01-restricted Env TL9 epitope with one animal making a low frequency CD8⁺ T cell response against the Pol LV10 epitope. We also induced SIV-specific CD4⁺ T cells against several MHC class II DRBw*606-restricted epitopes. Electroporated DNA with pIL-12 followed by a rAd5 boost was the most immunogenic vaccine strategy. We induced responses against all three Mamu-DRB*w606-restricted CD4 epitopes in the vaccine after the DNA prime. Ad5 vaccination further boosted these responses. Although we successfully elicited several robust epitope-specific CD4⁺ T cell responses, vaccination with subdominant MHC class I epitopes elicited few detectable CD8⁺ T cell responses. Broadening the CD8⁺ T cell response against subdominant MHC class I epitopes was, therefore, more difficult than we initially anticipated.