Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors—CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (T_regs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.

Clonal expansion of CD4⁺CD28^- T cells is a characteristic finding in patients with rheumatoid arthritis (RA). Expanded CD4⁺ clonotypes are present in the peripheral blood, infiltrate into the joints, and persist for years. CD4⁺CD28^- T cells are oligoclonal lymphocytes that are rare in healthy individuals but are found in high percentages in patients with chronic inflammatory diseases. The size of the peripheral blood CD4⁺CD28^- T-cell compartment was determined in 42 patients with RA and 24 healthy subjects by two-color FACS analysis. The frequency of CD4⁺CD28^- T cells was significantly higher in RA patients than in healthy subjects. Additionally, the number of these cells was significantly higher in patients with extra-articular manifestations and advanced joint destruction than in patients with limited joint manifestations. The results suggest that the frequency of CD4⁺CD28^- T cells may be a marker correlating with extra-articular manifestations and joint involvement.

Rheumatoid arthritis (RA) is a multifactorial disease, the pathogenesis of which involves immunological, genetic and environmental factors. P-glycoprotein (P-gp) encoded by the MDR1 gene, is an important transporter for many drugs, xenobiotics and cytokines and may be associated with many immunological processes and apoptosis. The activity of P-gp is genetically determined. Naturally occurring MDR1 polymorphisms have been described and correlated with potential clinical effects. Several mutations in the MDR1 gene have been recognized, but only some of them are associated with P-gp expression. The C3435T polymorphism was found to correlate with the activity of P-glycoprotein. The aim of the study was to evaluate the C3435T MDR1 polymorphism in patients with rheumatoid arthritis and to investigate a possible correlation with disease susceptibility, activity and severity. The study was carried out in 92 patients with rheumatoid arthritis and 97 healthy subjects as a control group. The C3435T polymorphism was determined using the PCR-RFLP method. The distribution of C3435TT MDR1 genotypes in RA patients did not differ significantly from that in a control group and was as follows: 3435CC in 25 (26.9%) subjects, 3435CT in 50 (53.8%) and 3435TT in 17 (18.3%). The probability of remission of RA symptoms after therapy with methotrexate and glucocorticosteroids however, was 2.89-fold greater in patients with the 3435TT genotype compared to patients with the genotypes 3435CC and 3435CT. The risk of having an active form of rheumatoid arthritis resistant to therapy with disease-modifying antirheumatic drugs in patients with 3435CC and 3435CT genotypes was 2.89 times greater than in homozygous 3435TT subjects. We suggest that the C3435T MDR1 polymorphism is not an important genetic risk factor for RA susceptibility, but that this polymorphism may have an influence on the activity of the disease and its response to therapy with disease-modifying antirheumatic drugs.

Objectives – The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. Materials and methods – A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 – patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 – patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMT^L as well as high activity ones, i.e. MAOB allele G and COMT^H, were determined using PCR-RFLP method. Results – No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMT^L/L homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). Conclusion – The results of the study suggest that patients with COMT^L/L genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Objectives Pantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. Methods Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. Results Carriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration–time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λ_z) by 83.3%, prolongation of terminal half-life (t_½) by 572%, a rise in area under the concentration–time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg⋅h/L vs 3.00 ± 1.02 mg⋅h/L, p < 0.05) and C_max (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h). Conclusion These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.