Lung cancer immunotherapy

Karcinom pluća jedan je od vodećih uzroka smrti u svijetu. Dijeli se na rak pluća malih stanica i rak pluća ne-malih stanica. Osim po histološkim karakteristikama, ova dva tipa dijele se i po karakterističnim molekularnim biljezima, najzastupljeniji je EGFR. Imunosni sustav ima bitnu ulogu u protutumorskom odgovoru, ali može biti i odgovoran za rast i proliferaciju karcinoma pluća. Receptori kontrolnih točaka su citotoksični T-limfocitni antigen 4 (CTLA-4) i receptor programirane stanične smrti-1 (PD-1) koji suprimiraju aktivaciju, proliferaciju i funkciju stanica T čime pospješuju proliferaciju tumora. Razvijaju se imunoterapije koje ciljano djeluju na stanice imunosnog sustava kako bi se pojačao protutumorski odgovor. Imunoterapija primjenom imunosnih inhibitora kontrolnih točaka, poput ipilimumaba i nivolumaba, pokazala se uspješnom u usporedbi s imunoterapijom primjenom cjepiva. Za razliku od klasičnih metoda liječenja, poput kemoterapije, imunoterapija napada ciljne stanice bez oštećivanja zdravih stanica. Kombinirana terapija uključuje imunoterapiju zajedno s kemoterapijom, ciljanim sredstavima i drugim inhibitorima imunosnog kontrolnog tijeka. Takav pristup ima povećani antitumorski odgovor kroz sinergistički učinak lijekova, kao i primjena krio-imunoterapije. Potrebna je dublja karakterizacija međureakcija između imunosnih i tumorskih stanica, te utvrđivanje pouzdanih prediktivnih biomarkera i potpuno razumijevanje mehanizama uključenih u razvoj stečene rezistencije s ciljem poboljšanja selekcije odgovarajućih pacijenta i ukupne terapijske učinkovitosti.Lung cancer is one of the leading causes of death in the world. It is part of small cell lung cancer and non-small cell lung cancer. Except for histological characteristics, these two types are also divided by characteristic molecular markers, the most common being EGFR. The immune system plays an important role in the antibody response but can also be responsible for the growth and proliferation of lung cancer. Control points receptors are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) receptor suppressing T cell activation, proliferation, and function, thereby enhancing tumor proliferation. Immunotherapy targets the immune system cells in order to enhance the anti-tumor response. Immunotherapy using immune checkpoint inhibitors, such as ipilimumab and nivolumab, has been shown to be successful in comparison with immunotherapy using a vaccine. Unlike classic treatment methods, such as chemotherapy, immunotherapy attacks target cells without damaging healthy cells. Combined therapy includes immunotherapy together with chemotherapy, targeting agents and other immune control flow inhibitors. Such an approach has an increased anticancer response through synergistic drug effects as well as the use of cryo-immunotherapy. Deeper characterization of interactions between immune and tumor cells is required, as well as the determination of reliable predictive biomarkers and a complete understanding of the mechanisms involved in the development of acquired resistance with the aim of improving the selection of appropriate patients and overall therapeutic efficacy

Lung cancer immunotherapy

Karcinom pluća jedan je od vodećih uzroka smrti u svijetu. Dijeli se na rak pluća malih stanica i rak pluća ne-malih stanica. Osim po histološkim karakteristikama, ova dva tipa dijele se i po karakterističnim molekularnim biljezima, najzastupljeniji je EGFR. Imunosni sustav ima bitnu ulogu u protutumorskom odgovoru, ali može biti i odgovoran za rast i proliferaciju karcinoma pluća. Receptori kontrolnih točaka su citotoksični T-limfocitni antigen 4 (CTLA-4) i receptor programirane stanične smrti-1 (PD-1) koji suprimiraju aktivaciju, proliferaciju i funkciju stanica T čime pospješuju proliferaciju tumora. Razvijaju se imunoterapije koje ciljano djeluju na stanice imunosnog sustava kako bi se pojačao protutumorski odgovor. Imunoterapija primjenom imunosnih inhibitora kontrolnih točaka, poput ipilimumaba i nivolumaba, pokazala se uspješnom u usporedbi s imunoterapijom primjenom cjepiva. Za razliku od klasičnih metoda liječenja, poput kemoterapije, imunoterapija napada ciljne stanice bez oštećivanja zdravih stanica. Kombinirana terapija uključuje imunoterapiju zajedno s kemoterapijom, ciljanim sredstavima i drugim inhibitorima imunosnog kontrolnog tijeka. Takav pristup ima povećani antitumorski odgovor kroz sinergistički učinak lijekova, kao i primjena krio-imunoterapije. Potrebna je dublja karakterizacija međureakcija između imunosnih i tumorskih stanica, te utvrđivanje pouzdanih prediktivnih biomarkera i potpuno razumijevanje mehanizama uključenih u razvoj stečene rezistencije s ciljem poboljšanja selekcije odgovarajućih pacijenta i ukupne terapijske učinkovitosti.Lung cancer is one of the leading causes of death in the world. It is part of small cell lung cancer and non-small cell lung cancer. Except for histological characteristics, these two types are also divided by characteristic molecular markers, the most common being EGFR. The immune system plays an important role in the antibody response but can also be responsible for the growth and proliferation of lung cancer. Control points receptors are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) receptor suppressing T cell activation, proliferation, and function, thereby enhancing tumor proliferation. Immunotherapy targets the immune system cells in order to enhance the anti-tumor response. Immunotherapy using immune checkpoint inhibitors, such as ipilimumab and nivolumab, has been shown to be successful in comparison with immunotherapy using a vaccine. Unlike classic treatment methods, such as chemotherapy, immunotherapy attacks target cells without damaging healthy cells. Combined therapy includes immunotherapy together with chemotherapy, targeting agents and other immune control flow inhibitors. Such an approach has an increased anticancer response through synergistic drug effects as well as the use of cryo-immunotherapy. Deeper characterization of interactions between immune and tumor cells is required, as well as the determination of reliable predictive biomarkers and a complete understanding of the mechanisms involved in the development of acquired resistance with the aim of improving the selection of appropriate patients and overall therapeutic efficacy

Lung cancer immunotherapy

Karcinom pluća jedan je od vodećih uzroka smrti u svijetu. Dijeli se na rak pluća malih stanica i rak pluća ne-malih stanica. Osim po histološkim karakteristikama, ova dva tipa dijele se i po karakterističnim molekularnim biljezima, najzastupljeniji je EGFR. Imunosni sustav ima bitnu ulogu u protutumorskom odgovoru, ali može biti i odgovoran za rast i proliferaciju karcinoma pluća. Receptori kontrolnih točaka su citotoksični T-limfocitni antigen 4 (CTLA-4) i receptor programirane stanične smrti-1 (PD-1) koji suprimiraju aktivaciju, proliferaciju i funkciju stanica T čime pospješuju proliferaciju tumora. Razvijaju se imunoterapije koje ciljano djeluju na stanice imunosnog sustava kako bi se pojačao protutumorski odgovor. Imunoterapija primjenom imunosnih inhibitora kontrolnih točaka, poput ipilimumaba i nivolumaba, pokazala se uspješnom u usporedbi s imunoterapijom primjenom cjepiva. Za razliku od klasičnih metoda liječenja, poput kemoterapije, imunoterapija napada ciljne stanice bez oštećivanja zdravih stanica. Kombinirana terapija uključuje imunoterapiju zajedno s kemoterapijom, ciljanim sredstavima i drugim inhibitorima imunosnog kontrolnog tijeka. Takav pristup ima povećani antitumorski odgovor kroz sinergistički učinak lijekova, kao i primjena krio-imunoterapije. Potrebna je dublja karakterizacija međureakcija između imunosnih i tumorskih stanica, te utvrđivanje pouzdanih prediktivnih biomarkera i potpuno razumijevanje mehanizama uključenih u razvoj stečene rezistencije s ciljem poboljšanja selekcije odgovarajućih pacijenta i ukupne terapijske učinkovitosti.Lung cancer is one of the leading causes of death in the world. It is part of small cell lung cancer and non-small cell lung cancer. Except for histological characteristics, these two types are also divided by characteristic molecular markers, the most common being EGFR. The immune system plays an important role in the antibody response but can also be responsible for the growth and proliferation of lung cancer. Control points receptors are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) receptor suppressing T cell activation, proliferation, and function, thereby enhancing tumor proliferation. Immunotherapy targets the immune system cells in order to enhance the anti-tumor response. Immunotherapy using immune checkpoint inhibitors, such as ipilimumab and nivolumab, has been shown to be successful in comparison with immunotherapy using a vaccine. Unlike classic treatment methods, such as chemotherapy, immunotherapy attacks target cells without damaging healthy cells. Combined therapy includes immunotherapy together with chemotherapy, targeting agents and other immune control flow inhibitors. Such an approach has an increased anticancer response through synergistic drug effects as well as the use of cryo-immunotherapy. Deeper characterization of interactions between immune and tumor cells is required, as well as the determination of reliable predictive biomarkers and a complete understanding of the mechanisms involved in the development of acquired resistance with the aim of improving the selection of appropriate patients and overall therapeutic efficacy

Machine learning for pan-cancer classification based on RNA sequencing data

Despite recent improvements in cancer diagnostics, 2%-5% of all malignancies are still cancers of unknown primary (CUP), for which the tissue-of-origin (TOO) cannot be determined at the time of presentation. Since the primary site of cancer leads to the choice of optimal treatment, CUP patients pose a significant clinical challenge with limited treatment options. Data produced by large-scale cancer genomics initiatives, which aim to determine the genomic, epigenomic, and transcriptomic characteristics of a large number of individual patients of multiple cancer types, have led to the introduction of various methods that use machine learning to predict the TOO of cancer patients. In this review, we assess the reproducibility, interpretability, and robustness of results obtained by 20 recent studies that utilize different machine learning methods for TOO prediction based on RNA sequencing data, including their reported performance on independent data sets and identification of important features. Our review investigates the strengths and weaknesses of different methods, checks the correspondence of their results, and identifies potential issues with datasets used for model training and testing, assessing their potential usefulness in a clinical setting and suggesting future improvements

Computational analysis of MT retrotransposons in mouse strains C57BL/6J and PWK/Phj

Retrotranspozoni MT pripadaju klasi LTR retrotranspozona, specifičnih za glodavce. Cjeloviti MT elementi sadrže dva duga terminalna ponavljanja (engl. long terminal repeat, LTR) i internu sekvencu. Zbog ektopične rekombinacije, izrezuje se interna sekvenca cjelovitog MT elementa stvarajući samostalni LTR. Standardna anotacija retrotranspozona radi se programom RepeatMasker, čiji je glavni nedostatak precizna anotacija cjelovitih elemenata. Cilj ovog diplomskog rada bio je poboljšati već postojeću anotaciju cjelovitih MT elemenata dobivenih upotrebom programa RepeatMasker i identificirati homologne MT elemente između klasičnog C57BL/6J i divljeg PWK/PhJ mišjeg soja. Razvijena računalna metoda anotacije cjelovitih MT elemenata usredotočena je na filtriranje njihovih očuvanih duljina LTR-ova i rezultirala je većim brojem anotiranih cjelovitih MT elemenata u C57BL/6J genomu za razliku od PWK/PhJ genoma. Filogenetski mlađi i jedini aktivni cjeloviti MT elementi, MTA i MTB, imali su više novih specifičnih elemenata kod C57BL/6J soja, koji su se pojavili nakon razdvajanja sojeva, dok su stariji MT elementi očuvani među mišjim sojevima. Integracije očuvanih i specifičnih MT elemenata kod sojeva većinom su u intronima protein-kodirajućih gena. Identificirani novi specifični elementi C57BL/6J soja integrirani su u egzone gena olfaktornih receptora te mogu pridonijeti fenotipskim razlikama između mišjih sojeva C57BL/6J i PWK/PhJ.Rodent-specific MT retrotransposons belong to a class of LTR retrotransposons. Full-length MT elements contain two long terminal repeats (LTRs) and an internal sequence. Due to ectopic recombination, the internal sequence of full-length MT elements is excised producing a solo LTR. The standard annotation of retrotransposons is done with RepeatMasker program which one of the major drawbacks is the precise annotation of full-length elements. The goal of this thesis was to improve the RepeatMasker annotation of MT elements and to identify homologous between a classical mouse strain C57BL/6J and a wild-derived mouse strain PWK/PhJ. The developed computational method focuses on the conserved length of their LTRs and has resulted in a larger number of annotated full-length MT elements in in the mouse strain C57BL/6J. Phylogenetically younger and still active annotated full-length MT elements, MTA and MTB, had more new C57BL/6J-strains specific elements that have emerged after the separations of the strains. On the other hand, older MT elements were more conserved among strains. Conserved and strain-specific MT element integrations into genes mostly occurred in introns of protein-coding genes. Identified new C57BL/6J-strains specific elements integrated into exons of olfactory receptor genes, may contribute to phenotypic differences between mouse strains C57BL/6J and PWK/PhJ

Computational analysis of MT retrotransposons in mouse strains C57BL/6J and PWK/Phj

Retrotranspozoni MT pripadaju klasi LTR retrotranspozona, specifičnih za glodavce. Cjeloviti MT elementi sadrže dva duga terminalna ponavljanja (engl. long terminal repeat, LTR) i internu sekvencu. Zbog ektopične rekombinacije, izrezuje se interna sekvenca cjelovitog MT elementa stvarajući samostalni LTR. Standardna anotacija retrotranspozona radi se programom RepeatMasker, čiji je glavni nedostatak precizna anotacija cjelovitih elemenata. Cilj ovog diplomskog rada bio je poboljšati već postojeću anotaciju cjelovitih MT elemenata dobivenih upotrebom programa RepeatMasker i identificirati homologne MT elemente između klasičnog C57BL/6J i divljeg PWK/PhJ mišjeg soja. Razvijena računalna metoda anotacije cjelovitih MT elemenata usredotočena je na filtriranje njihovih očuvanih duljina LTR-ova i rezultirala je većim brojem anotiranih cjelovitih MT elemenata u C57BL/6J genomu za razliku od PWK/PhJ genoma. Filogenetski mlađi i jedini aktivni cjeloviti MT elementi, MTA i MTB, imali su više novih specifičnih elemenata kod C57BL/6J soja, koji su se pojavili nakon razdvajanja sojeva, dok su stariji MT elementi očuvani među mišjim sojevima. Integracije očuvanih i specifičnih MT elemenata kod sojeva većinom su u intronima protein-kodirajućih gena. Identificirani novi specifični elementi C57BL/6J soja integrirani su u egzone gena olfaktornih receptora te mogu pridonijeti fenotipskim razlikama između mišjih sojeva C57BL/6J i PWK/PhJ.Rodent-specific MT retrotransposons belong to a class of LTR retrotransposons. Full-length MT elements contain two long terminal repeats (LTRs) and an internal sequence. Due to ectopic recombination, the internal sequence of full-length MT elements is excised producing a solo LTR. The standard annotation of retrotransposons is done with RepeatMasker program which one of the major drawbacks is the precise annotation of full-length elements. The goal of this thesis was to improve the RepeatMasker annotation of MT elements and to identify homologous between a classical mouse strain C57BL/6J and a wild-derived mouse strain PWK/PhJ. The developed computational method focuses on the conserved length of their LTRs and has resulted in a larger number of annotated full-length MT elements in in the mouse strain C57BL/6J. Phylogenetically younger and still active annotated full-length MT elements, MTA and MTB, had more new C57BL/6J-strains specific elements that have emerged after the separations of the strains. On the other hand, older MT elements were more conserved among strains. Conserved and strain-specific MT element integrations into genes mostly occurred in introns of protein-coding genes. Identified new C57BL/6J-strains specific elements integrated into exons of olfactory receptor genes, may contribute to phenotypic differences between mouse strains C57BL/6J and PWK/PhJ

Computational analysis of MT retrotransposons in mouse strains C57BL/6J and PWK/Phj

Retrotranspozoni MT pripadaju klasi LTR retrotranspozona, specifičnih za glodavce. Cjeloviti MT elementi sadrže dva duga terminalna ponavljanja (engl. long terminal repeat, LTR) i internu sekvencu. Zbog ektopične rekombinacije, izrezuje se interna sekvenca cjelovitog MT elementa stvarajući samostalni LTR. Standardna anotacija retrotranspozona radi se programom RepeatMasker, čiji je glavni nedostatak precizna anotacija cjelovitih elemenata. Cilj ovog diplomskog rada bio je poboljšati već postojeću anotaciju cjelovitih MT elemenata dobivenih upotrebom programa RepeatMasker i identificirati homologne MT elemente između klasičnog C57BL/6J i divljeg PWK/PhJ mišjeg soja. Razvijena računalna metoda anotacije cjelovitih MT elemenata usredotočena je na filtriranje njihovih očuvanih duljina LTR-ova i rezultirala je većim brojem anotiranih cjelovitih MT elemenata u C57BL/6J genomu za razliku od PWK/PhJ genoma. Filogenetski mlađi i jedini aktivni cjeloviti MT elementi, MTA i MTB, imali su više novih specifičnih elemenata kod C57BL/6J soja, koji su se pojavili nakon razdvajanja sojeva, dok su stariji MT elementi očuvani među mišjim sojevima. Integracije očuvanih i specifičnih MT elemenata kod sojeva većinom su u intronima protein-kodirajućih gena. Identificirani novi specifični elementi C57BL/6J soja integrirani su u egzone gena olfaktornih receptora te mogu pridonijeti fenotipskim razlikama između mišjih sojeva C57BL/6J i PWK/PhJ.Rodent-specific MT retrotransposons belong to a class of LTR retrotransposons. Full-length MT elements contain two long terminal repeats (LTRs) and an internal sequence. Due to ectopic recombination, the internal sequence of full-length MT elements is excised producing a solo LTR. The standard annotation of retrotransposons is done with RepeatMasker program which one of the major drawbacks is the precise annotation of full-length elements. The goal of this thesis was to improve the RepeatMasker annotation of MT elements and to identify homologous between a classical mouse strain C57BL/6J and a wild-derived mouse strain PWK/PhJ. The developed computational method focuses on the conserved length of their LTRs and has resulted in a larger number of annotated full-length MT elements in in the mouse strain C57BL/6J. Phylogenetically younger and still active annotated full-length MT elements, MTA and MTB, had more new C57BL/6J-strains specific elements that have emerged after the separations of the strains. On the other hand, older MT elements were more conserved among strains. Conserved and strain-specific MT element integrations into genes mostly occurred in introns of protein-coding genes. Identified new C57BL/6J-strains specific elements integrated into exons of olfactory receptor genes, may contribute to phenotypic differences between mouse strains C57BL/6J and PWK/PhJ

Adherence to Mediterranean Diet in Croatia: Lessons Learned Today for a Brighter Tomorrow

Non-communicable diseases (NCD) and lifestyle, particularly diet, have a close relationship. Based on the recent statistics, Croatian men and women lead in European overweight lists, which implies pessimistic prognosis in terms of incidence and prevalence of NCDs in the future. One of the possible solutions to overcome weight problems is turn to traditional balanced and sustainable diets, such as the Mediterranean diet. In this study, we assessed adherence towards Mediterranean diet using a validated questionnaire in an online survey and associated adherence scores with several demographic and anthropometric data. Based on the results of a validated Mediterranean Diet Adherence Screener (N = 3326), we assessed the adherence score to be 7.6 ± 2.5. The score tended to depend on sex, residence, age, education, income, and body mass index (BMI); indeed, women, residents of a coastal part of the country, older volunteers, those possessing a higher education degree, those with higher income, and those with lower BMI were associated with higher scores. As income was one of the significant findings related to higher adherence scores, we developed a dietary plan complying with Mediterranean diet principles that, on average, costed less than the average traditional balanced diet menu. Taken together, this study brought new findings regarding target groups who need to be encouraged to make lifestyle changes, and highlighted the first steps on how to make them

Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses

Abstract The molecular mechanisms underlying the transition from nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) are incompletely understood. During the development of NAFLD, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that the lack of PLIN5 decreases hepatic injury, indicating a protective role in NAFLD pathology. To better understand the role of PLIN5 in liver disease, we established mouse models of NAFLD and NAFLD-induced HCC, in which wild-type and Plin5 null mice were exposed to a single dose of acetone or 7,12-dimethylbenz[a]anthracene (DMBA) in acetone, followed by a 30-week high-fat diet supplemented with glucose/fructose. In the NAFLD model, RNA-seq revealed significant changes in genes related to lipid metabolism and immune response. At the intermediate level, pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) were blunted in Plin5-deficient mice (Plin5 −/−) compared to wild-type mice (WT). In the NAFLD-HCC model, only WT mice developed liver tumors, while Plin5 −/− mice were resistant to tumorigenesis. Furthermore, only 32 differentially expressed genes associated with NALFD progession were identified in Plin5 null mice. The markers of mitochondrial function and immune response, such as the peroxisome proliferator‐activated receptor-γ, coactivator 1‐α (PGC-1α) and phosphorylated STAT3, were decreased. Lipidomic analysis revealed differential levels of some sphingomyelins between WT and Plin5 −/− mice. Interestingly, these changes were not detected in the HCC model, indicating a possible shift in the metabolism of sphingomelins during carcinogenesis