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StreszczenieUzależnienie od alkoholu stanowi problem zarówno medyczny, jak i społeczno-ekonomiczny. Jest zaliczane do chorób o charakterze wieloczynnikowym, czyli takich, za które odpowiadają relacje gen-gen oraz gen-środo-wisko. Wieloośrodkowe badania nad genetycznym podłożem alkoholizmu podkreślają znaczenie genów kodujących enzymy szlaku rozkładu etanolu w organizmie ludzkim, szczególnie dehydrogenazy alkoholowej (ADH) w rozwoju choroby. Z pięciu klas dehydrogenaz alkoholowych związek z uzależnieniem od alkoholu wykazują izoenzymy klasy I i IV. Klasa IV jest szczególnie interesująca ze względu na jej występowanie w górnym odcinku przewodu pokarmowego, głównie w żołądku. Nie wykazano aktywności tego enzymu w wątrobie. Polimorfizm pojedynczych nukleotydów (SNP) genu kodującego tę klasę, czyli ADH7, wpływa na jej aktywność utleniającą etanol w świetle żołądka i tym samym na metabolizm pierwszego przejścia ( FPM) tej substancji. Opublikowane wyniki różnych ośrodków badawczych pokazują, że konkretne zmiany typu SNP w genie ADH7 mają odmienne znaczenie dla ryzyka uzależnienia od alkoholu w zależności od badanej populacji.Słowa kluczowe: ADH7, alkoholizm, metabolizm pierwszego przejścia. AbstractAlcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic background of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabolism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied.

Mitochondrial DNA changes can contribute to both an increased and decreased likelihood of cancer. This process is complex and not fully understood. Polymorphisms and mutations, especially those of the missense type, can affect mitochondrial functions, particularly if the conservative domain of the protein is concerned. This study aimed to identify the possible relationships between brain gliomas and the occurrence of specific mitochondrial DNA polymorphisms and mutations in respiratory complexes III, IV and V. The investigated material included blood and tumour material collected from 30 Caucasian patients diagnosed with WHO grade II, III or IV glioma. The mitochondrial genetic variants were investigated across the mitochondrial genome using next-generation sequencing (MiSeq/FGx system—Illumina). The study investigated, in silico, the effects of missense mutations on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness. The A14793G (MTCYB), A15758G, (MT-CYB), A15218G (MT-CYB), G7444A (MT-CO1) polymorphisms, and the T15663C (MT-CYB) and G8959A (ATP6) mutations were assessed in silico as harmful alterations that could be involved in oncogenesis. The G8959A (E145K) ATP6 missense mutation has not been described in the literature so far. In light of these results, further research into the role of mtDNA changes in brain tumours should be conducted.

Mitochondria are organelles necessary for oxidative phosphorylation. The interest in the role of mitochondria in the process of carcinogenesis results from the fact that a respiratory deficit is found in dividing cells, especially in cells with accelerated proliferation. The study included tumor and blood material from 30 patients diagnosed with glioma grade II, III and IV according to WHO (World Health Organization). DNA was isolated from the collected material and next-generation sequencing was performed on the MiSeqFGx apparatus (Illumina). The study searched for a possible relationship between the occurrence of specific mitochondrial DNA polymorphisms in the respiratory complex I genes and brain gliomas of grade II, III and IV. The impact of missense changes on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness, were assessed in silico along with their belonging to a given mitochondrial subgroup. The A3505G, C3992T, A4024G, T4216C, G5046A, G7444A, T11253C, G12406A and G13604C polymorphisms were assessed as deleterious changes in silico, indicating their association with carcinogenesis.

chaperon protein expressed at high levels in cancer cells and involved in folding or stabilization of client proteins essential for cancer cell growth and survival. Ganetespib (STA-9090) is one of the second-generation HSP90 inhibitors with potent anti-tumor effect on NSCLC cells. In this study, we evaluated the anti-tumor effect of ganetespib in EGFR-TKI sensitive and acquired resistance NSCLC cell lines. Method: We treated 4 EGFR-mutant NSCLC cell lines (HCC827, HCC4006, HCC4011 and PC-9), and 5 experimentally established EGFR-TKI (gefitinib) resistance cell lines with ganetespib. The EGFR-TKI resistant mechanism consisted of EGFR T790M second mutation, MET amplification, epithelial-to-mesenchymal transition (EMT) and cancer stem cell-like properties. We determined cell proliferation by MTS assay and calculated the IC50 values. We also performed Western blotting to investigate downstream signaling pathway alterations. Result: The IC50 values in parental NSCLC cell lines ranged from 1.3nM to 15nM, and those in acquired EGFR-TKI resistance NSCLC cell lines ranged from 0.87nM to 25nM, which suggests potent anti-tumor effect of ganetespib. In addition, this effect was observed regardless of the resistant mechanisms, including EMT. Ganetespib effectively suppressed the expression of downstream pathway molecules in all examined cell lines including acquired EGFR-TKI resistance NSCLC cell lines. Also, ganetespib effectively induced apoptosis in parental and acquired EGFR-TKI resistance NSCLC cell lines with EGFR T790M mutation or MET amplification. Conclusion: Ganetespib exhibited potent anti-tumor effect in acquired EGFR-TKI resistance NSCLC cell lines regardless of the resistant mechanisms, suggesting that ganetespib could be a promising therapeutic option in the treatment of NSCLC with acquired EGFR-TKI resistance.Background: The analysis of EGFR activating mutations and ALK rearrangement is a routine procedure in qualification of NSCLC patients for molecularly targeted therapy. Targeted sequencing, as a type of NGS, allows more comprehensive analysis of low-frequency variations in suppressors and oncogenes that are commonly mutated in solid tumors. In the following study we analyzed a molecular landscape of NSCLC patients harboring EGFR activating mutations who response for EGFR TKIs. Method: The studied group included 19 Caucasian patients (7 male and 12 female, median age 65±12 years, 4 current smokers, 12 non-smokers and 3 formersmokers) with lung adenocarcinoma. 12 (63%) deletions in exon 19, 4 (21%) substitutions Leu858Arg in exon 21, 2 (11%) insertions A763_Y764 in exon 20 and 1 (5%) substitution Thr790Met in exon 20 of EGFR gene were detected using real-time PCR technique. Four non-smoking patients (median age 65±12 years) with lung adenocarcinoma and wild-type (wt) of EGFR gene were a control group. The DNA for the analysis was isolated from FFPE tissue or cellblocks and the mutational landscape was evaluated using Illumina's TruSight Tumor 26 panel on miSeq platform (Illumina, USA). Result: The targeted s...