Aptamer BC 007’s Affinity to Specific and Less-Specific Anti-SARS-CoV-2 Neutralizing Antibodies

COVID-19 is a pandemic respiratory disease that is caused by the highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-SARS-CoV-2 antibodies are essential weapons that a patient with COVID-19 has to combat the disease. When now repurposing a drug, namely an aptamer that interacts with SARS-CoV-2 proteins for COVID-19 treatment (BC 007), which is, however, a neutralizer of pathogenic autoantibodies in its original indication, the possibility of also binding and neutralizing anti-SARS-CoV-2 antibodies must be considered. Here, the highly specific virus-neutralizing antibodies have to be distinguished from the ones that also show cross-reactivity to tissues. The last-mentioned could be the origin of the widely reported SARS-CoV-2-induced autoimmunity, which should also become a target of therapy. We, therefore, used enzyme-linked immunosorbent assay (ELISA) technology to assess the binding of well-characterized publicly accessible anti-SARS-CoV-2 antibodies (CV07-209 and CV07-270) with BC 007. Nuclear magnetic resonance spectroscopy, isothermal calorimetric titration, and circular dichroism spectroscopy were additionally used to test the binding of BC 007 to DNA-binding sequence segments of these antibodies. BC 007 did not bind to the highly specific neutralizing anti-SARS-CoV-2 antibody but did bind to the less specific one. This, however, was a lot less compared to an autoantibody of its original indication (14.2%, range 11.0–21.5%). It was also interesting to see that the less-specific anti-SARS-CoV-2 antibody also showed a high background signal in the ELISA (binding on NeutrAvidin-coated or activated but noncoated plastic plate). These initial experiments suggest that the risk of binding and neutralizing highly specific anti-SARS CoV-2 antibodies by BC 007 should be low.     

The influence of the sacrificial agent nature on transformations of the Zn(OH)2/Cd0.3Zn0.7S photocatalyst during hydrogen production under visible light

Photocatalysts based on zinc hydroxide and a solid solution of CdS and ZnS were prepared via the precipitation method and used for photocatalytic hydrogen production from aqueous solutions of inorganic (Na₂S/Na₂SO₃) and organic (ethanol) sacrificial agents. The photocatalysts were tested in cyclic experiments for hydrogen evolution and studied using X-ray diffraction (XRD), UV-Vis diffuse reflectance spectroscopy, high-resolution transmission electron microscopy (HRTEM), energy-dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy (XPS) techniques. Different transformations of the β-Zn(OH)₂ co-catalyst were observed in the presence of inorganic and organic sacrificial agents; namely, ZnS was formed in Na₂S/Na₂SO₃ solution, whereas the formation of ε-Zn(OH)₂ was detected in solution with ethanol. The composite Zn(OH)₂/Cd_1−xZn_xS photocatalysts have great potential in various photocatalysis processes (e.g., hydrogen production, CO₂ reduction, and the oxidation of organic contaminants) under visible light.

The nature of the sacrificial agent affects the transformations of a Zn(OH)₂ co-catalyst during photocatalytic hydrogen production.     

Should We Use N-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses?

Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 +/- 6 years, body weight 74 +/- 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) = 10 + 9 x (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.     

Clinicomorphological characteristics of Sezary's disease and mycosis fungoides

AIM: To try a combined approach to the study of clinicomorphological and immunophenotypical characteristics of primary cutaneous T-cell lymphomas. MATERIAL AND METHODS: Clinical, histological, genotypic and immunophenotypical parameters were studied in 7 patients (4 male and 3 female, mean age 53.1 +/- 7.8%) with Sezary's disease (SD) and 10 patients (6 male, 4 female, mean age 54.0 +/- 4.0 years) with mycosis fungoides (MF) treated in Hematological Research Center in 1998-2004. RESULTS: Six of seven SD patients had SD stage IV with leukemization, Sezary's cells were found in peripheral blood. Bone marrow and lymph nodes involvement was observed in 5 patients. Morphological signs of transformation into lymphosarcoma were detected in three patients. Skin samples of all the patients showed epidermotropism with lymphoid infiltration of the derma and skin appendages. All the patients had clonal rearrangement of T-cell receptor by gamma-chain. Immunophenotyping (IPT) detected T-cell markers CD45RO, CD43, CD3, CD4 on lymphoid cells. IPT of peripheral blood lymphoid cells was typical for SD in 3 patients. Low density of CD4 and CD2, CD4 and CD5, the presence of CD7 were registered in 1 patient each. The disease history was 3.4 +/- 0.7 years. A lethal outcome was related with septic complications after polychemotherapy. MF history in 10 patients was 10.9 +/- 2.1 years. Stages III and IV were diagnosed in 2 of 10 patients. All the patients had typical pathohistological changes. Polymerase chain reaction test detected clone by rearrangement of gamma-chain of T-cell receptor. In 2 patients IPT detected CD4 absence in the presence of CD8 and CD7. The aberrant clone typical for NK-cells was detected in one case. Two patients died of the disease progression after 7 and 20 years of MF. CONCLUSION: Multiple tests help early diagnosis and conduction of optimal therapy for cutaneous T-cell lymphomas.     

Characterization of sleep disturbance in patients with tinnitus

BACKGROUND: Approximately 60 % of patients with tinnitus experience disturbances of the normal sleep pattern. METHODS: Polysomnography was performed on 26 patients with tinnitus and sleep disturbances. RESULTS: In 17 of 26 patients polysomnography revealed a pathological sleep analysis: 10 patients were diagnosed with obstructive sleep apnea syndrome, 4 with insomnia and an increased index of arousals as well as a reduction of deep sleep- and REM-phases. Pathological movements of the legs were seen in 3 cases. Six of 9 patients with a normal sleep during the whole night displayed a prolonged latency period until falling asleep. CONCLUSIONS: Many studies show that sleep disturbances are a factor that strongly predicts decreased tolerance to tinnitus. This and the findings of this study implicate, that somnographic workup is helpful in patients with tinnitus in order to integrate adequate therapy of the sleep disturbance in the concept of tinnitus therapy and to avoid adaptive difficulties to tinnitus.     

Use of thymodepressin for treating autoimmune cytopenia

AIM: To study influence of thymodepressin on the course of autoimmune cytopenia. MATERIAL AND METHODS: Thymodepressin is a new synthetic hemoregulatory dipeptide (gamma-D-Glu-D-Trp). It was used for the treatment of 22 patients with autoimmune cytopenia. RESULTS: Hemoglobin levels were elevated in autoimmune hemolytic anemia and platelet levels were high in idiopathic thrombocytopenic purpura. A thymodepressin course resulted in a fall of total lymphocyte count and activated CD3+CD69+ lymphocytes. CONCLUSION: The above results, safety, absence of toxicity and allergenicity, parenteral and intranasal useability open perspectives for further studies of therapeutic action of thymodepressin as an immunodepressant in autoimmune processes.     

The effects of Streptolysin-O and sodium hyaluronate on the permeability of the round window membrane in guinea pigs--an electrophysiologic study

BACKGROUND: The round window membrane (RWM) acts like a barrier for topically applied substances into the middle ear preventing diffusion into the perilymphatic fluid compartment. MATERIAL AND METHOD: In an animal model, modulation of the permeability of the RWM was attempted using Streptolysin-O (SLO) in various concentrations and sodium hyaluronate. Thereafter, the effect of intratympanically applied Lidocain 2 % on hearing threshold measured by auditory brainstem response was tested for Lidocain 2 % and Lidocain 2 % in combination with SLO or sodium hyaluronate. RESULTS: The results show that both, SLO and sodium hyaluronate, influence the effect of Lidocain 2 % on hearing thresholds as an indirect sign for changes of the permeability of the RWM. However SLO by itself in low concentrations decreased auditory thresholds in some animals while this was never observed with sodium hyaluronate. CONCLUSIONS: Our findings preclude SLO and favor sodium hyaluronate as a modulator of RWM permeability in therapeutic trials.     

Mutant p53: the loaded gun

Alterations in the p53 gene are the most common genetic defects found in tumors so far. Taking into account that p53 is a powerful inducer of cell death it is not surprising that the abolition of its function occurs almost universally during tumor development. There are several features of p53 inactivation in tumors which are quite unique. Firstly, mutations occur at high frequency in the p53 gene, ie, around 50% of human tumors carry p53 mutations. Secondly, mutations are largely of the same type, ie, 87% of them are point missense mutations resulting in a substitution of one amino acid residue. Thirdly, the majority of mutations occur in the DNA binding domain of p53. Finally, mutant p53 proteins accumulate at high levels in tumor cells. Can we take advantage of p53 mutations in tumor cells to selectively kill them? Is this the Achilles heel of tumors that can be exploited for novel non-toxic anticancer therapy? In this review the possible approaches toward reactivation of mutant p53 in tumors will be discussed.