Effectiveness of infliximab biosimilars in the treatment of moderate to severe chronic plaque psoriasis: experience of real-world data from the register of the program "Treatment of moderate and severe forms of plaque psoriasis (B.47)" of the National Health Fund in Poland.

Introduction: Infliximab (IFX) is a monoclonal antibody that binds to and neutralizes TNF-α. IFX (Remicade) was approved by the U.S. Food and Drug Administration in 2006 for the treatment of severe plaque psoriasis. In 2013 two infliximab biosimilars: Remsima and Inflectra were also registered. The introduction of biosimilar drugs is associated with a significant reduction in treatment costs. Aim: To evaluate the efficacy of treatment with biosimilar IFX with non-medical switch option in patients with plaque psoriasis under the drug program "Treatment of moderate and severe plaque psoriasis" of the Ministry of Health in Poland. Material and methods: The group of 91 adult patients with moderate to severe plaque psoriasis, unresponsive or with contraindications to the standard treatment were qualified to the drug program (in 2016-2018). Efficacy of treatment with biosimilar IFX was evaluated using the Psoriasis Area and Severity Index, body surface area and Dermatology Life Quality Index scoring performed at week 0, 14, 46 and 94. Results: The mean change in PASI, DLQI, and BSA scores at week 14 was 89.92%, 93.75% and 90.91%, respectively. By week 14, 83.52% of patients achieved PASI75, 49.45% PASI ≥ 90 and 26.37% PASI100. At week 46, 84.62% of patients achieved PASI75, 54.95% PASI ≥ 90, and 21.98% PASI100. At week 94 of therapy, 80.22% of patients achieved PASI75, 48.35% PASI ≥ 90, and 18.68% PASI100. At week 94 of therapy, PASI100 was maintained by 37.5% of patients who achieved PASI100 at week 14. Conclusions: 94-week therapy with biosimilar infliximab results in high and sustained clinical efficacy in patients with moderate to severe psoriasis.

Comparative effectiveness of adalimumab versus ustekinumab in the treatment of severe chronic plaque psoriasis: The results based on data from the program "treatment of moderate and severe forms of plaque psoriasis (B.47)" of the National Health Fund in Poland.

Biological agents: TNF-α inhibitors, IL-12, and IL-23 blockers, IL-17 inhibitors are used in the treatment of plaque psoriasis. Adalimumab (ADA) is an antibody that binds to TNF-α. Ustekinumab (UST) blocks IL-12 and IL-23. The data obtained from medical records is of exceptional value. The aim of the study was to evaluate the efficacy of ADA and UST during a single 40-week period of biological treatment of patients under the drug program "Treatment of moderate and severe form of plaque psoriasis." The group of 620 adult patients with moderate to severe form of plaque psoriasis, who were unresponsive or had contraindications to the standard treatment were qualified to the drug program. In the evaluated group, 50.64% patients were treated with UST, 49.36% with ADA. The efficacy of treatment was assessed during weeks 0, 4, 16, 28, and 40. At week 16th, PASI75 reached 80.72% patients in ADA treated group, PASI ≥90 54.88%, PASI100 19.6% of patients. In the UST group (week 16th) PASI75 reached 70.38%, PASI90 44.26%, PASI100 15.6% of patients. At week 28th PASI90 and PASI100 were more pronounced in the ADA group than in UST. In addition, the total percentage of PASI improvement was significantly higher in the ADA group (p = 0.0006). The percentage of PASI improvement in week 40 was statistically higher in ADA group compared to UST (p = 0.015). Compared to UST, ADA was clinically more effective during a 40-week observation. Patients receiving ADA achieved PASI75, PASI90, and PASI100 more frequently and faster than those treated with UST. Additionally, ADA improved the quality of life of psoriatic patients more substantially compared to UST.

[Concomitance of depressive disorders and enduring personality change after catastrophic experience in repression victims in the years 1940-1956]. / Wspólwystepowanie zaburzen depresyjnych i zespolu trwalej zmiany osobowosci po katastrofach u osób represjonowanych w latach 1940-1956.

AIM: The aim of the research project was to assess the incidence of depressive disorders and enduring personality change in the victims of the WWII combatants and repression victims in the years 1940-1956. MATERIALS AND METHODS: The study group consists of 57 members of combatant organizations in the Lodz Voivodeship. Two groups are discerned. Group one comprises individuals with depressive disorders and group two is made up of individuals without depressive disorders. The Beck Depression Inventory and Medical Socio-demographic Questionnaire were applied. RESULTS: The group one (with depressive disorders) is characterized by a high incidence of mental disorders whereas the group two (without the disorders) demonstrates a high prevalence of psychosomatic disorders. Mental disorders related to enduring personality change following exposure to catastrophic stress are more common in the group with depressive disorders. CONCLUSIONS: The researchers wish to point to the need of thorough examination of various combatants and repression victims since the symptoms of enduring personality change following a catastrophic experience as well as after depression may coincide.

The impact of synthetic analogs of histidine on copper(II) and nickel(II) coordination properties to an albumin-like peptide. Possible leads towards new metallodrugs.

The purpose of our research was to obtain peptidomimetics possessing Cu(II) and Ni(II) binding properties, which would be useful for biomedical applications. In this context we used potentiometry, UV-VIS and CD spectroscopies to characterize the Cu(II) and Ni(II) binding properties of pentapeptide analogs of the N-terminal sequence of histatin 5. The peptides investigated had a general sequence DSXAK-am (am stands for C-terminal amide), with X including His and its three synthetic analogs, (4-thiazolyl)-L-alanine (1), (2-pyridyl)-L-alanine (2), and (pyrazol-1-yl)-L-alanine (3). The heterocyclic nitrogens present in these analogs were significantly more acidic than that of the His imidazole. We found that DSXAK-am peptides were able to bind Cu(II) and Ni(II) and form 4N complexes in a cooperative fashion, with similar affinities. These results indicate that acidic heterocyclic amino acids provide a viable alternative for histidine in peptidomimetics designed for metal ion binding.

Dual catalytic role of the metal ion in nickel-assisted peptide bond hydrolysis.

In our previous research we demonstrated the sequence specific peptide bond hydrolysis of the R1-(Ser/Thr)-Xaa-His-Zaa-R2 in the presence of Ni(II) ions. The molecular mechanism of this reaction includes an N-O acyl shift of the R1 group from the Ser/Thr amine to the side chain hydroxyl group of this amino acid. The proposed role of the Ni(II) ion is to establish favorable geometry of the reacting groups. In this work we aimed to find out whether the crucial step of this reaction--the formation of the intermediate ester--is reversible. For this purpose we synthesized the test peptide Ac-QAASSHEQA-am, isolated and purified its intermediate ester under acidic conditions, and reacted it, alone, or in the presence of Ni(II) or Cu(II) ions at pH 8.2. We found that in the absence of either metal ion the ester was quickly and quantitatively (irreversibly) rearranged to the original peptide. Such reaction was prevented by either metal ion. Using Cu(II) ions as CD spectroscopic probe we showed that the metal binding structures of the ester and the final amine are practically identical. Molecular calculations of Ni(II) complexes indicated the presence of steric strain in the substrate, distorting the complex structure from planarity, and the absence of steric strain in the reaction products. These results demonstrated the dual catalytic role of the Ni(II) ion in this mechanism. Ni(II) facilitates the acyl shift by setting the peptide geometry, and prevents the reversal of the acyl shift, by stabilizing subsequent reaction products.

Sequence-specific Ni(II)-dependent peptide bond hydrolysis for protein engineering: active sequence optimization.

In previous studies we showed that Ni(II) ions can hydrolytically cleave a peptide bond preceding Ser/Thr in peptides of a general sequence RN-(Ser/Thr)-Xaa-His-Zaa-RC, where RN and RC are any peptide sequences. A peptide library screening, assisted by accurate measurements of reaction kinetics for selected peptides, demonstrated the preference for bulky and aromatic residues at variable positions Xaa and Zaa [A. Krezel, E. Kopera, A.M. Protas, A. Wyslouch-Cieszynska, J. Poznanski, W. Bal, J. Am. Chem. Soc., 132 (2010) 3355-3366]. In this work we used a similar strategy to find out whether the next residue downstream to Zaa may influence the reaction rate. Using an Ac-Gly-Ala-Ser-Arg-His-Zaa-Baa-Arg-Leu-NH2 library, with Zaa and Baa positions containing all common amino acids except of Cys, we found a very strong preference for aromatic residues in both variable positions. This finding significantly limits the range of useful Xaa, Zaa and Baa substitutions, thus facilitating the search for optimal sequences for protein engineering applications [E. Kopera, A. Belczyk-Ciesielska, W. Bal, PLoS One 7 (2012) e36350].

Effect of D-amino acid substitutions on Ni(II)-assisted peptide bond hydrolysis.

Previously we demonstrated the sequence-specific hydrolysis of the R1-(Ser/Thr)-peptide bond in Ni(II) complexes of peptides with a general R1-(Ser/Thr)-Xaa-His-Zaa-R2 sequence (R1 and R2 being any sequences) (Kopera, E.; Krezel, A.; Protas, A. M.; Belczyk, A.; Bonna, A.; Wyslouch-Cieszynska, A.; Poznanski, J.; Bal, W. Inorg. Chem. 2010, 49, 6636). In order to refine our understanding of the mechanism of this reaction and to find ways to accelerate it, we undertook a systematic study of effects of d-amino acid substitutions in the template Ac-Gly-Ala-Ser-Arg-His-Trp-Lys-Phe-Leu-NH2 peptide on the hydrolysis rate constants. We found that all stereochemical alterations made around the Ni(II) chelate plane resulted in the decrease of the reaction rate. However, the Ni(II) coordination, a prerequisite to the reaction, was not compromised by these substitutions. We demonstrated that the reaction is only possible when either the side chain of the crucial Ser (or Thr) residue is on the same part of the chelate plane as the next residue in the sequence (Arg), or the side chain of the residue following His (Trp) resides on the opposite side of the plane. The rate of reaction is the fastest when both these conditions are fulfilled. Another novel effect is the strong dependence of the rate of the acyl shift step on the character of the leaving group.

AlkB dioxygenase preferentially repairs protonated substrates: specificity against exocyclic adducts and molecular mechanism of action.

Efficient repair by Escherichia coli AlkB dioxygenase of exocyclic DNA adducts 3,N(4)-ethenocytosine, 1,N(6)-ethenoadenine, 3,N(4)-α-hydroxyethanocytosine, and reported here for the first time 3,N(4)-α-hydroxypropanocytosine requires higher Fe(II) concentration than the reference 3-methylcytosine. The pH optimum for the repair follows the order of pK(a) values for protonation of the adduct, suggesting that positively charged substrates favorably interact with the negatively charged carboxylic group of Asp-135 side chain in the enzyme active center. This interaction is supported by molecular modeling, indicating that 1,N(6)-ethenoadenine and 3,N(4)-ethenocytosine are bound to AlkB more favorably in their protonated cationic forms. An analysis of the pattern of intermolecular interactions that stabilize the location of the ligand points to a role of Asp-135 in recognition of the adduct in its protonated form. Moreover, ab initio calculations also underline the role of substrate protonation in lowering the free energy barrier of the transition state of epoxidation of the etheno adducts studied. The observed time courses of repair of mixtures of stereoisomers of 3,N(4)-α-hydroxyethanocytosine or 3,N(4)-α-hydroxypropanocytosine are unequivocally two-exponential curves, indicating that the respective isomers are repaired by AlkB with different efficiencies. Molecular modeling of these adducts bound by AlkB allowed evaluation of the participation of their possible conformational states in the enzymatic reaction.

Backbone dynamics of TFE-induced native-like fold of region 4 of Escherichia coli RNA polymerase sigma70 subunit.

Folding of a recombinant protein rECsigma(70) (4) comprising domain 4 of E. coli RNA polymerase sigma(70) subunit, upon addition of 2,2,2-trifluoroethanol (TFE) to its aqueous solution, was monitored by heteronuclear NMR spectroscopy. The TFE-induced migration of resonance signals in a series of (15)N-HSQC spectra displayed sequence-dependent heterogeneity. A common trend of uniform upfield shift in both (1)H and (15)N dimensions, indicative of generation of helical structures, breaks down for some residues almost cooperatively at 10-15% TFE (v/v), pointing to the buildup of non-helical regions separating the initially induced helices. The preferences of residues to assume either helical or non-helical conformation are correlated with the location in the sequence rather than with their type. CSI descriptors and (15)N relaxation data obtained for the protein at 10% TFE allowed characterization of the stability of the pre-folded state of rECsigma(70) (4). By all the criteria applied, three highly populated alpha-helical regions separated by much more flexible residues forming a loop and a turn in the DNA-binding HLHTH motif were identified. The location of the secondary structure elements along the protein sequence coincides with those found in homologous proteins, and with the helix nucleation regions determined in unfolded rECsigma(70) (4) at low pH. The bimodal distribution of the (15)N relaxation parameters enabled identification of residues forming a framework of the folded protein strictly corresponding to the HLHTH motif, bracketed by unfolded terminal regions. Thus, in respect to rECsigma(70) (4) in aqueous solution TFE acts not only as a strong helix inducer, but also as a folding agent.