Prognostic Factors Influencing the Effect of Chemotherapy in Cervical and Ovarian Cancer

První část práce: Prognostické faktory ovlivňující efekt chemoterapie u ovariálních karcinomů ÚVOD: Membránové transportéry (jako ABC, SLC a ATPázy) se podílejí na karcinogenezi a rozvoji chemorezistence, ale jejich význam pro prognózu epiteliálního karcinomu vaječníků (EOC) je stále málo známý. METODY: Hodnotili jsme profil genové exprese 39 ABC a 12 SLC transportérů a 3 ATPáz ve tkáních EOC a zabývali jsme se jejich významem pro prognózu a klinický průběh pacientek s EOC. Byla odhadnuta relativní exprese genů v souboru primárních EOC (n=57) a v kontrolních ovariálních tkáních (n=14) a porovnána s klinickými údaji a přežitím pacientek. Získané údaje byly validovány na nezávislém souboru pacientek (n=60). VÝSLEDKY: Šest ABC genů a gen SLC22A18 byly v karcinomech ve srovnání s kontrolami významně nadměrně exprimovány, zatímco exprese 12 genů ABC, 5 genů SLC, ATP7A a ATP11B byla snížena. Exprese genů ABCA12, ABCC3, ABCC6, ABCD3, ABCG1 a SLC22A5 byla vyšší u high-grade serózního karcinomu ve srovnání s ostatními podtypy. Exprese genu ABCA2 významně souvisela s grade EOC u obou souborů pacientek. Pozoruhodné je, že úroveň genové exprese ABCA9, ABCA10, ABCC9 a SLC16A14 významně souvisela s PFS v pilotních i validačních souborech. Hladina ABCG2 souvisela s PFS v souhrnném souboru pacientek. ZÁVĚR: Geny...First part of the thesis: Prognostic factors influencing the effect of chemotherapy in ovarian cancer INTRODUCTION: Membrane transporter proteins (for example ABC, SLC and ATPases) take part in oncogenesis and the formation of chemoresistance, however the interpretation of their importance in ovarian cancer prognosis is still limited. METHODS: Gene expression profiling was performed on 39 ABC and 12 SLC transporters and 3 ATPases in epithelial ovarian cancer (EOC) tissues and the results were assessed with respect to prognosis and clinical presentation of EOC patients. In a cohort of tissues with primary EOC (n = 57) and control tissues (n = 14) we assessed relative expression of genes and compared it with the clinical and survival information. The data was verified on a separate cohort (n = 60). RESULTS: 6 ABC genes and the SLC22A18 gene were considerably over-expressed in the cancer tissues in comparison with control tissues and the expression of 12 ABC genes, 5 SLC genes, ATP7A, ATP11B was reduced. The expression of ABCA12, ABCC3, ABCC6, ABCD3, ABCG1, SLC22A5 genes was greater in HGSC in comparison with other types. Expression of ABCA2 was considerably related to tumour grade in both cohorts. Particularly, the expression levels of ABCA9, ABCA10, ABCC9 and SLC16A14 were considerably related to...Gynekologicko - porodnická klinikaLékařská fakulta v PlzniFaculty of Medicine in Pilse

Effect of dexamethasone in patients with ARDS and COVID-19 (REMED trial)—study protocol for a prospective, multi-centre, open-label, parallel-group, randomized controlled trial

BACKGROUND: Since December 2019, SARS-CoV-2 virus has infected millions of people worldwide. In patients with COVID-19 pneumonia in need of oxygen therapy or mechanical ventilation, dexamethasone 6 mg per day is currently recommended. However, the dose of 6 mg of dexamethasone is currently being reappraised and may miss important therapeutic potential or may prevent potential deleterious effects of higher doses of corticosteroids. METHODS: REMED is a prospective, open-label, randomised controlled trial testing the superiority of dexamethasone 20 mg (dexamethasone 20 mg on days 1-5, followed by dexamethasone 10 mg on days 6-10) vs 6 mg administered once daily intravenously for 10 days in adult patients with moderate or severe ARDS due to confirmed COVID-19. Three hundred participants will be enrolled and followed up for 360 days after randomization. Patients will be randomised in a 1:1 ratio into one of the two treatment arms. The following stratification factors will be applied: age, Charlson Comorbidity Index, CRP levels and trial centre. The primary endpoint is the number of ventilator-free days (VFDs) at 28 days after randomisation. The secondary endpoints are mortality from any cause at 60 days after randomisation; dynamics of the inflammatory marker, change in WHO Clinical Progression Scale at day 14; and adverse events related to corticosteroids and independence at 90 days after randomisation assessed by the Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days. The study will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. DISCUSSION: We aim to compare two different doses of dexamethasone in patients with moderate to severe ARDS undergoing mechanical ventilation regarding efficacy and safety. TRIAL REGISTRATION: EudraCT No. 2020-005887-70. ClinicalTrials.gov NCT04663555. Registered on December 11, 2020

Subspecialty training in Europe:a report by the European Network of Young Gynaecological Oncologists

Backgroun

Aorto-ventricular tunnel

Aorto-ventricular tunnel is a congenital, extracardiac channel which connects the ascending aorta above the sinutubular junction to the cavity of the left, or (less commonly) right ventricle. The exact incidence is unknown, estimates ranging from 0.5% of fetal cardiac malformations to less than 0.1% of congenitally malformed hearts in clinico-pathological series. Approximately 130 cases have been reported in the literature, about twice as many cases in males as in females. Associated defects, usually involving the proximal coronary arteries, or the aortic or pulmonary valves, are present in nearly half the cases. Occasional patients present with an asymptomatic heart murmur and cardiac enlargement, but most suffer heart failure in the first year of life. The etiology of aorto-ventricular tunnel is uncertain. It appears to result from a combination of maldevelopment of the cushions which give rise to the pulmonary and aortic roots, and abnormal separation of these structures. Echocardiography is the diagnostic investigation of choice. Antenatal diagnosis by fetal echocardiography is reliable after 18 weeks gestation. Aorto-ventricular tunnel must be distinguished from other lesions which cause rapid run-off of blood from the aorta and produce cardiac failure. Optimal management of symptomatic aorto-ventricular tunnel consists of diagnosis by echocardiography, complimented with cardiac catheterization as needed to elucidate coronary arterial origins or associated defects, and prompt surgical repair. Observation of the exceedingly rare, asymptomatic patient with a small tunnel may be justified by occasional spontaneous closure. All patients require life-long follow-up for recurrence of the tunnel, aortic valve incompetence, left ventricular function, and aneurysmal enlargement of the ascending aorta

Leukemias in CR - Epidemiologic Characteristics and Incidence and Mortality Trends

This final thesis deals with four main types of leukemia (AML, ALL, CML, CLL). Their etiology, pathogenesis, clinical symptoms, diagnostics and treatment are described in detail in the first chapter. Second chapter deals with the main purpose of this thesis, which is the description of epidemiological characteristics and incidence and mortality trends of leukemia in Czech Republic. Czech statistical data is compared with world statistics. Leukemia is malignant blood diseases, which accounts for 3% of all malignant tumors. Over the past 30 years there has been an increase in leukemia incidence and mortality in Czech Republic by approximately 50%. This is in accordance with the same development in the world. By the year 2015 we expect these values to increase further by 10%. The highest incidence of leukemia occurs in countries with high living and economic prosperity. In 1997 there was recorded a decrease in the rate of mortality increase. This is due to modern diagnostics and therapy and the possibilities of allogenic and autologous bone marrow transplantation

Prognostic Factors Influencing the Effect of Chemotherapy in Cervical and Ovarian Cancer

First part of the thesis: Prognostic factors influencing the effect of chemotherapy in ovarian cancer INTRODUCTION: Membrane transporter proteins (for example ABC, SLC and ATPases) take part in oncogenesis and the formation of chemoresistance, however the interpretation of their importance in ovarian cancer prognosis is still limited. METHODS: Gene expression profiling was performed on 39 ABC and 12 SLC transporters and 3 ATPases in epithelial ovarian cancer (EOC) tissues and the results were assessed with respect to prognosis and clinical presentation of EOC patients. In a cohort of tissues with primary EOC (n = 57) and control tissues (n = 14) we assessed relative expression of genes and compared it with the clinical and survival information. The data was verified on a separate cohort (n = 60). RESULTS: 6 ABC genes and the SLC22A18 gene were considerably over-expressed in the cancer tissues in comparison with control tissues and the expression of 12 ABC genes, 5 SLC genes, ATP7A, ATP11B was reduced. The expression of ABCA12, ABCC3, ABCC6, ABCD3, ABCG1, SLC22A5 genes was greater in HGSC in comparison with other types. Expression of ABCA2 was considerably related to tumour grade in both cohorts. Particularly, the expression levels of ABCA9, ABCA10, ABCC9 and SLC16A14 were considerably related to..

Detekce rotační symetrie ve 3D pomocí kandidátů zrcadlové symetrie a parametrizace rotace založené na kvaternionech

Vlastnost symetrie ve 3D objektech je užitečná v různých aplikacích jako zarovnání objektů, komprese, symetrická editace nebo rekonstrukce neúplných objektů. Její robustní a efektivní detekce je však náročný úkol. Dva nejčastěji se vyskytující typy symetrie jsou pravděpodobně zrcadlová a rotační symetrie. Zatímco metod pro detekci zrcadlové symetrie existuje poměrně dost, nezdá se, že by tomu tak bylo u detekce rotační symetrie. V tomto článku je navrženo použití přibližných zrcadlových symetrií k odvození přijatelných rotačních symetrií, které lze integrovat s různými přístupy pro detekci zrcadlové symetrie. Jeden takový specifický přístup, založený na maximalizaci dané míry symetrie, je zvolen a kombinován s touto myšlenkou. Dále je navržena modifikace maximalizačního kroku pro rotace pomocí jednoduché, ale účinné, kvaternionové parametrizace transformace rotace, která se zdá být v oblasti detekce symetrie nová. Výsledky potvrzují, že tato kombinace poskytuje robustní a efektivní řešení pro nalezení rotační symetrie v 3D množině bodů a zvládne data s přibližnou symetrií, vstup poškozený šumem nebo dokonce částečná data.The property of symmetry in 3D objects is helpful in various applications such as object alignment, compression, symmetrical editing or reconstruction of incomplete objects. However, its robust and efficient detection is a challenging task. The two most commonly occurring types of symmetry are probably reflectional and rotational symmetry. While reflectional symmetry detection methods are quite plentiful, this does not seem to be the case with rotational symmetry detection. In this paper a use of approximate reflectional symmetries to derive plausible approximate rotational symmetries is proposed that can be integrated with multiple different approaches for reflectional symmetry detection. One such specific approach, based on maximizing a given symmetry measure, is chosen and combined with this idea. A modification of the maximization step for rotations is further proposed using a simple, yet efficient, quaternion-based parameterization of the rotation transformation which seems novel in the field of symmetry detection. The results confirm that this combination provides a robust and efficient solution for finding rotational symmetry in a 3D point set and can handle approximate symmetry, noisy input or even partial data

Detekce rotační symetrie ve 3D pomocí kandidátů zrcadlové symetrie a parametrizace rotace založené na kvaternionech

Vlastnost symetrie ve 3D objektech je užitečná v různých aplikacích jako zarovnání objektů, komprese, symetrická editace nebo rekonstrukce neúplných objektů. Její robustní a efektivní detekce je však náročný úkol. Dva nejčastěji se vyskytující typy symetrie jsou pravděpodobně zrcadlová a rotační symetrie. Zatímco metod pro detekci zrcadlové symetrie existuje poměrně dost, nezdá se, že by tomu tak bylo u detekce rotační symetrie. V tomto článku je navrženo použití přibližných zrcadlových symetrií k odvození přijatelných rotačních symetrií, které lze integrovat s různými přístupy pro detekci zrcadlové symetrie. Jeden takový specifický přístup, založený na maximalizaci dané míry symetrie, je zvolen a kombinován s touto myšlenkou. Dále je navržena modifikace maximalizačního kroku pro rotace pomocí jednoduché, ale účinné, kvaternionové parametrizace transformace rotace, která se zdá být v oblasti detekce symetrie nová. Výsledky potvrzují, že tato kombinace poskytuje robustní a efektivní řešení pro nalezení rotační symetrie v 3D množině bodů a zvládne data s přibližnou symetrií, vstup poškozený šumem nebo dokonce částečná data.The property of symmetry in 3D objects is helpful in various applications such as object alignment, compression, symmetrical editing or reconstruction of incomplete objects. However, its robust and efficient detection is a challenging task. The two most commonly occurring types of symmetry are probably reflectional and rotational symmetry. While reflectional symmetry detection methods are quite plentiful, this does not seem to be the case with rotational symmetry detection. In this paper a use of approximate reflectional symmetries to derive plausible approximate rotational symmetries is proposed that can be integrated with multiple different approaches for reflectional symmetry detection. One such specific approach, based on maximizing a given symmetry measure, is chosen and combined with this idea. A modification of the maximization step for rotations is further proposed using a simple, yet efficient, quaternion-based parameterization of the rotation transformation which seems novel in the field of symmetry detection. The results confirm that this combination provides a robust and efficient solution for finding rotational symmetry in a 3D point set and can handle approximate symmetry, noisy input or even partial data

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers

DataSheet_1_Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy.pdf

Epithelial ovarian carcinoma (EOC) is known for high mortality due to diagnosis at advanced stages and frequent therapy resistance. Previous findings suggested that the DNA repair system is involved in the therapeutic response of cancer patients and DNA repair genes are promising targets for novel therapies. This study aimed to address complex inter-relations among gene expression levels, methylation profiles, and somatic mutations in DNA repair genes and EOC prognosis and therapy resistance status. We found significant associations of DUT expression with the presence of peritoneal metastases in EOC patients. The high-grade serous EOC subtype was enriched with TP53 mutations compared to other subtypes. Furthermore, somatic mutations in XPC and PRKDC were significantly associated with worse overall survival of EOC patients, and higher FAAP20 expression in platinum-resistant than platinum-sensitive patients was observed. We found higher methylation of RAD50 in platinum-resistant than in platinum-sensitive patients. Somatic mutations in BRCA1 and RAD9A were significantly associated with higher RBBP8 methylation in platinum-sensitive compared to platinum-resistant EOC patients. In conclusion, we discovered associations of several candidate genes from the DNA repair pathway with the prognosis and platinum resistance status of EOC patients, which deserve further validation as potential predictive biomarkers.</p