A modified epitope identified for generation and monitoring of PSA-specific T cells in patients on early phases of PSA-based immunotherapeutic protocols

Efficacy of vaccination in cancer patients on immunotherapeutic protocols can be difficult to evaluate. The aim of this study was therefore to identify a single natural or modified epitope in prostate-specific antigen (PSA) with the ability to generate high levels of PSA-specific T cells to facilitate monitoring in patients after vaccination against prostate cancer. To the best of our knowledge, this study describes for the first time the peptide specificity of T cells stimulated by endogenously processed PSA antigen. The peptide specificity of HLA-A*0201-restricted CD8⁺ T cells against human and rhesus PSA was investigated both in vivo after DNA vaccination in HLA-A*0201-transgenic mice and in vitro after repetitive stimulation of human T cells with DNA-transfected human dendritic cells (DCs). One of seven native PSA peptides, psa53–61, was able to activate high levels of PSA-specific CD8⁺ T cells in HLA-A*0201-transgenic mice after PSA DNA vaccination. Psa53–61 was also the only peptide that induced human T cells to produce IFNγ after stimulation with PSA transfected DCs, however not in all donors. Therefore, plasmids encoding modified epitopes in predicted HLA-A*0201 sequences were constructed. One of these modified PSA plasmids consistently induced IFNγ producing CD8⁺ T cells to the corresponding modified peptide as well as to the corresponding native peptide, in all murine and human T cell cultures. This study demonstrates a novel concept of introducing a modified epitope within a self-tumor antigen, with the purpose of eliciting a reliable T cell response from the non-tolerized immune repertoire, to facilitate monitoring of vaccine efficacy in cancer patients on immunotherapeutic protocols. The purpose of such a modified epitope is thus not to induce therapeutically relevant T cells but rather to, in case of weak or divergent T cell responses to self antigens/peptides, help answer questions about efficacy of vaccine delivery and about the possibility to induce immune responses in the selected and often immunosuppressed cancer patients.     

DJ‐1 is a Parkinson's disease susceptibility gene in southern Italy

De Marco EV, Annesi G, Tarantino P, Nicoletti G, Civitelli D, Messina D, Annesi F, Arabia G, Salsone M, Condino F, Novellino F, Provenzano G, Rocca FE, Colica C, Morelli M, Scornaienchi V, Greco V, Giofrè L, Quattrone A. DJ‐1 is a Parkinson's disease susceptibility gene in southern Italy. Mutations in the gene DJ‐1 have been shown to be a rare cause of early‐onset Parkinson's disease (EOPD). Since DJ‐1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ‐1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single‐nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36–3.08). When we considered a three‐marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ‐1 gene confer risk to sporadic PD in southern Italy.     

Changes in the Power Levels of Cortical EEG Rhythms in Cats during Training Using Acoustic Feedback Signals

Chronic experiments on two conscious cats were performed to study the dynamics of the ratios of spectral power levels of beta and theta rhythms and neuron activity in the dopaminergic system of the ventral tegmentum during EEG feedback sessions. Training was performed using a model in which the level of sound signals presented to the animals decreased as the spectral power ratios of the EEG beta and theta rhythms recorded in the frontal leads increased. In a control series, the changes in the sound signal level were independent of the ongoing EEG. These experiments showed that the ratio of the spectral power levels of the beta and theta rhythms changed during feedback sessions, with increases in the spectral power of the beta rhythm and decreases in the spectral power of the theta rhythm. These changes were accompanied by increases in the activity of presumptive dopaminergic neurons in the ventral tegmentum.     

Study of morphometric parameters of podocyte foot processes in impaired calcium balance

Study of morphometric parameters of podocyte foot processes showed that the increase of parathyroid hormone blood level causes dilatation of podocyte foot processes resulting from accumulation of calcium in the cells. Influence of the hormone on filtration processes in glomeruli as a result of its effect on podocytes is discussed.     

Genotype of the cystic fibrosis population of the Hunter Region of New South Wales

Objective : To determine the genotype of patients attending the cystic fibrosis clinic at John Hunter Hospital, Newcastle, Australia.
Methodology : Seventy-five of the 76 patients attending the clinic over a 6 month period had blood collected for genetic analysis of 17 of the cystic fibrosis (CF) gene mutations.
Results : Sixty-one per cent of the patients were homozygous for the ΔF508 mutation and all except one child had at least one ΔF508 mutation.
Discussion : Nearly 80% of the CF genes were the ΔF508 mutation. This prevalence suggests that the obligatory false negative rate of a newborn screening programme for CF based on a combination of immunoreactive trypsin and the ΔF508 gene may be as low as 4-5%.     

Orthotopic reconstruction of urinary bladder by intestinal flaps

The technique of complete or partial replacement of the urinary bladder (UB) with iliac segment is discussed and principles of creation of small intestinal reservoir are validated. The authors are satisfied with the results of 17 operations for microcystis and to repair UB after radical cysto(prostat)ectomy for UB cancer. Orthotopic reconstruction of the UB is proposed as a new therapeutic standard in UB cancer and microcystis.     

Activity of angiotensin-converting enzyme in the blood and tear of patients with diabetic retinopathy

There have recently been data on the important role of the renin-angiotensin system (RAS) in the pathogenesis of diabetes mellitus and its complications; however, the relationship of systemic and local RAS to the development of diabetic retinopathy (DR) remains little studied. This study determined the activity of angiotensin-converting enzyme (ACE), the key enzyme of RAS in the blood and tear of patients with DR. There was an increase in the blood activity of ACE and a decrease in its lacrimal activity as compared with their normal levels. A relationship was found between the activity of ACE in the blood and tear, on one hand, and the stage of DR, the type of diabetes mellitus, its severity and compensation, and the presence of nephropathy in a patient, on the other.     

Morphological aspects of diagnosis of acute opiate poisoning

Clinical anatomical analysis, forensic chemical, morphological, bacteriological, and immunological investigations of material from 62 subjects dead from acute poisoning with opiates before hospitalization (31 cases) and in hospital (31 cases) were carried out. Organ and tissue lesions typical of opiate poisoning were detected. The outcome of acute poisoning with opiates is largely determined by severe dystrophic and inflammatory processes in organs and tissues, typical of narcomaniacs.     

Otomycoses in the Kuznetsk region and organization of medical services for this group of population

In the Kuzbass region the author examined 238 patients, aged 15 to 80 years, with persistent otitis or inflammatory pathologies of the ears that could not be cured by routine therapy. As a result, in 90 patients (37.8%) otomycosis was diagnosed. Mycosis of the external acoustic meatus was identified in 43 patients (55 mycotic ears or 52.4%), fungal otitis media was found in 21 patients (22 ears or 20.9%), and mycosis of the postoperative cavity was detected in 26 patients (28 mycotic cavities or 26.7%). The following fungi occurred most frequently: Aspergillus niger (75.2%), Candida albicans (6.7%), and Penicillium flavum March (3.8%). In the presence of fungi the bacterial growth was less significant, thus indicating the predominant role of fungi during otomycosis. Nitrofungin and clotrimazol in combination with 1% decamine ointment were effectively used in the treatment. A good antipruritic drug was 7% chloracetophose ointment. Out of 90 patients complete regression was recorded in 84 cases, with 6 patients having relapses.     

Effect of a drug isolated from the heart on the bioenergetics of cardiomyocytes in hypoxia and ischemia]

It has been established that cordialin inhibits selectively succinic acid oxidation and intensifies the exudation of a NADH2 substrate which is energetically more advantageous, and in this way has a favorable effect on energy metabolism, evidence of which is increase of the ATP content in the myocardium. Cordialin correction of the biologic energy of cardiomyocytes in hypoxia and ischemia prevents the accumulation of lipid drops in the cells of the peri-infarction zone, which reflects the high intensity of the processes of fatty acids beta-oxidation. As a result of this glycolysis activation is unnecessary (which is confirmed by high glycogen content, both of a qualitative and quantitative character, in the myocardium and low concentrations of glucose and lactate in the blood) and, consequently, the sequelae of acidosis are prevented.