A neotektonika és a klímaváltozások szerepe a Körös medence késő-pleisztocén-holocén vízhálózatának fejlődésében = Neotectonic and climate control on Late Pleistocene-Holocene drainage pattern development of the Körös basin

A Körös-medence alluviális síkságának területén az egykori folyóhálózat nyomait rekonstruáltuk légifotó-elemzések, űrfelvételek, SRTM adatok és a folyószabályozás előtti természetes vízhálózatot mutató 18. századi topográfiai térképek alapján. Az elemzések azt mutatták, hogy a területen egy északkelet felől érkező nagy, meanderező folyó folyt, míg a déli részen egy fonatos folyó maradványai azonosíthatóak. A különböző mederrajzolatú zónákba 15 folyamatos magvételű sekélyfúrást mélyítettünk, illetve homok- és agyagfejtők szelvényeit is megvizsgáltuk. 32 homokminta optikai lumineszcens kormeghatározása (OSL), illetve 7 minta radiokarbon-vizsgálata alapján megállapítottuk, hogy a vizsgált folyóvízi üledékek a késő-pleniglaciális és a késő-glaciális során rakódtak le. A minták nehézásvány-vizsgálata alapján az egykori meanderező folyó az Ős-Tiszával azonosítható, amely az ÉK-DNy-i csapású Érmellék süllyedéke mentén folyt a késő-pleniglaciálisban. Az ős-Tisza érmelléki lefutását határon túli területek vizsgálata során 11 további OSL koradattal is alátámasztottuk. A fonatos folyó a Fekete- és Fehér-Körösök ősének tekinthető, amely csak a késő-glaciálisban jelent meg a területen. Szeizmikus szelvények újraértelmezése, neotektonikai terepi mérések, valamint a fúrásszelvényekben észlelhető eltérő vastagságviszonyok alapján az Érmellék vidéke 14-16 ezer évvel ezelőttig jelentős mértékben süllyedt, ami a folyófejlődés fő tektonikai meghatározója volt. | The palaeo-drainage network pattern of the Körös Basin was reconstructed on the basis of airborne photo interpretation, analysis of satellite images, SRTM dataset and historical topographic maps from the 18th century. The investigation showed that a large meandering river system was coming from the NE, and a braided river entered the alluvial plain from the SE. Different alluvial units were characterised by sedimentary logs of 15 continuous cored boreholes and several sand- and clay-pit sections. OSL dating of 32 quartz samples and 7 radocarbon datings showed that the sediments have Late Pleniglacial to Late Glacial ages. Transport directions inferred from heavy mineral analyses demonstrate that the large meandering river system can be identified with the palaeo-Tisza, flowing along the NE-SW striking Érmellék depression during the Late Pleniglacial. The former flow path of the palaeo-Tisza was supported by complementary field work performed in Romania, and another 11 OSL dates. The braided river can be regarded as a precursor to the Fekete- and Fehér-Körös rivers which entered the alluvial plain from the southeast during the Late Glacial. A combined interpretation of seismic profiles, neotectonic field measurements and variations in thickness of sediments along the studied profile revealed that there was a remarkable tectonic control on river development, driven by subsidence along the Érmellék depression until 14-16 ky and uplift of the SE-ern part of the catchment area

A COVID–19-járvány hatása a leggyakoribb légzőszervi megbetegedések lefolyására

Bevezetés: A SARS-CoV-2 által okozott fertőzés az elmúlt három évben meghatározta mindennapi életünket, és nem várt terhet rótt az egészségügyi ellátórendszerre, többek között azáltal, hogy komoly kockázati tényezőt jelenthet a már meglévő, különböző légzőszervi megbetegedésekkel küzdő betegek számára is. Célkitűzés: A COVID–19 és a fertőzéskor már fennálló légzőszervi megbetegedések, elsősorban a krónikus obstruk- tív tüdőbetegség (COPD), valamint az asztma összefüggéseinek feltárása. Módszer: Hazai vizsgálatunkban közel 29 000 beteg adatait dolgoztuk fel retrospektíven. Eredmények: Eredményeink alapján elmondható, hogy a COPD mint társbetegség megléte a nemzetközi megállapí- tással egybehangzóan összefüggést mutat a COVID–19-fertőzés súlyosságával, illetve enyhén növeli az intenzív osz- tályos kezelés és a gépi lélegeztetés szükségességének kockázatát a SARS-CoV-2 okozta megbetegedés során. Asztma esetében mindezt nem sikerült kimutatnunk, vagyis sem a SARS-CoV-2-fertőzés súlyosságát, sem az intenzív osztá- lyos kezelés és a gépi lélegeztetés szükségességét nem befolyásolta jelentősen az asztma mint társbetegség megléte. Megbeszélés: Ahogy nemzetközi tanulmányokban is olvasható, a COPD mint társbetegség megléte nem növeli jelentős mértékben a SARS-CoV-2-fertőzés kockázatát. Ugyanakkor kijelenthető, hogy a COPD növeli a COVID–19-pozitív betegek kórházba kerülésének esélyét, és emeli a megbetegedés súlyosabb lefolyásának valószínűségét. Tekintettel a COPD-betegekben a tüdő károsodása során végbemenő szerkezeti átépülésre és rendellenes regenerálódási folyamatokra, e betegek a vírusfertőzés lezajlása után fokozott odafigyelést, valamint személyre szabott rehabilitációt igényelnek. Következtetés: Összességében elmondható, hogy a jövőben a személyre szabott terápiás megközelítés bevezetéséhez elengedhetetlen a különböző COPD-s fenotípusok (valamint egyéb krónikus tüdőbetegségek) és a SARS-CoV-2-fer- tőzés klinikai megnyilvánulásainak mélyreható vizsgálata

Tobacco endgame in the WHO European Region: Feasibility in light of current tobacco control status

INTRODUCTION To assess the feasibility of developing World Health Organization (WHO) European Region countries' goals and measures in line with tobacco endgame objectives, information on the current tobacco control context and capacity is needed. The aim of this study was to assess the implementation of measures in the region. METHODS In this cross-sectional study we used data from the WHO FCTC implementation reports and MPOWER from 2020 in 53 WHO European Region countries. Six domains (i.e. capacity, taxation and price policies, other national key regulations, public awareness raising and communication, tobacco use cessation, and monitoring) were formed. Subsequently, available indicators under these domains were scored and the level of implementation was computed for each country. Mann-Whitney tests were carried out to compare the scores between the group of countries with and without official endgame goals. RESULTS Overall, implementation of the WHO FCTC with the selected indicators at the country level ranged from 28% to 86%, and of MPOWER from 31% to 96%. Full implementation was achieved by 28% of WHO FCTC Parties in the region in taxation and price policies, 12% in public awareness raising and communication, CONCLUSIONS There is unequal implementation of both WHO FCTC and MPOWER measures among WHO European Region countries. MPOWER and WHO FCTC provide all the measures for the necessary first steps, followed by innovativ

HUNCHEST-II contributes to a shift to earlier-stage lung cancer detection: final results of a nationwide screening program

The introduction of low-dose CT (LDCT) altered the landscape of lung cancer (LC) screening and contributed to the reduction of mortality rates worldwide. Here we report the final results of HUNCHEST-II, the largest population-based LDCT screening program in Hungary, including the screening and diagnostic outcomes, and the characteristics of the LC cases.A total of 4215 high-risk individuals aged between 50 and 75 years with a smoking history of at least 25 pack-years were assigned to undergo LDCT screening. Screening outcomes were determined based on the volume, growth, and volume doubling time of pulmonary nodules or masses. The clinical stage distribution of screen-detected cancers was compared with two independent practice-based databases consisting of unscreened LC patients.The percentage of negative and indeterminate tests at baseline were 74.2% and 21.7%, respectively, whereas the prevalence of positive LDCT results was 4.1%. Overall, 76 LC patients were diagnosed throughout the screening rounds (1.8% of total participants), out of which 62 (1.5%) patients were already identified in the first screening round. The overall positive predictive value of a positive test was 58%. Most screen-detected malignancies were stage I LCs (60.7%), and only 16.4% of all cases could be classified as stage IV disease. The percentage of early-stage malignancies was significantly higher among HUNCHEST-II screen-detected individuals than among the LC patients in the National Koranyi Institute of Pulmonology's archive or the Hungarian Cancer Registry (p < 0.001).HUNCHEST-II demonstrates that LDCT screening for LC facilitates early diagnosis, thus arguing in favor of introducing systematic LC screening in Hungary.HUNCHEST-II is the so-far largest population-based low-dose CT screening program in Hungary. A positive test's overall positive predictive value was 58%, and most screen-detected malignancies were early-stage lesions. These results pave the way for expansive systematic screening in the region.• Conducted in 18 medical facilities, HUNCHEST-II is the so far largest population-based low-dose CT screening program in Hungary. • The vast majority of screen-detected malignancies were early-stage lung cancers, and the overall positive predictive value of a positive test was 58%. • HUNCHEST-II facilitates early diagnosis, thus arguing in favor of introducing systematic lung cancer screening in Hungary

A subset of lung cancer cases shows robust signs of homologous recombination deficiency associated genomic mutational signatures

Abstract PARP inhibitors are approved for the treatment of solid tumor types that frequently harbor alterations in the key homologous recombination (HR) genes, BRCA1/2. Other tumor types, such as lung cancer, may also be HR deficient, but the frequency of such cases is less well characterized. Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and their presence can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. We derived various HRD-associated mutational signatures from whole-genome and whole-exome sequencing data in the lung adenocarcinoma and lung squamous carcinoma cases from TCGA, and in a patient of ours with stage IVA lung cancer with exceptionally good response to platinum-based therapy, and in lung cancer cell lines. We found that a subset of the investigated cases, both with and without biallelic loss of BRCA1 or BRCA2, showed robust signs of HR deficiency. The extreme platinum responder case also showed a robust HRD-associated genomic mutational profile. HRD-associated mutational signatures were also associated with PARP inhibitor sensitivity in lung cancer cell lines. Consequently, lung cancer cases with HRD, as identified by diagnostic mutational signatures, may benefit from PARP inhibitor therapy

Detection of Molecular Signatures of Homologous Recombination Deficiency in Bladder Cancer

PURPOSE: PARP inhibitors are approved for use in breast, ovarian, prostate and pancreatic cancer, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as BRCA1/2. However, the frequency of HR deficiency in other solid tumor types, including bladder cancer, is less well characterized. EXPERIMENTAL DESIGN: Specific DNA aberration profiles (mutational signatures) are induced by homologous recombination deficiency (HRD) and the presence of these “genomic scars” can be used to assess the presence or absence of HR deficiency in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole exome and whole genome data, we measured various HR deficiency-associated mutational signatures in bladder cancer. RESULTS: We found that a subset of bladder tumors have evidence of HR deficiency. In addition to a small number of tumors with bi-allelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HR deficiency associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8 which encodes CtIP, a key protein involved in HR. CONCLUSION: A subset of bladder tumors have genomic features suggestive of HR deficiency and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HR deficiency

Comparative expression analysis of immune-related markers in surgically resected lung neuroendocrine neoplasms

Background: Although immunotherapy has led to a paradigm shift in the treatment of lung cancer, the therapeutic approaches for lung neuroendocrine neoplasms (LNENs) are still limited. Our aim was to explore the immunological landscape and the expression of immune checkpoint markers in LNENs. Methods: Surgically removed tumor samples of 26 atypical carcinoid (AC), 30 large cell neuroendocrine carcinoma (LCNEC) and 29 small cell lung cancer (SCLC) patients were included. The immune phenotype of each tumor type was assessed by using a panel of 15 immune-related markers. As these markers are potentially expressed by immune cells and/or tumor cells, they might serve as putative targets for immunotherapy. Expression patterns were measured by immunohistochemistry and correlated with clinicopathological parameters and prognosis. Results: Unsupervised hierarchical clustering revealed distinct immunologic profiles across tumor types. Specifically, AC tumors were characterized by high tumor cell CD40 expression and low levels of immune infiltrates whereas SCLC samples had a high CD47 and Inducible T Cell Costimulator (ICOS) expression in tumor cells and immune cells, respectively. High CD70 and CD137 expression by tumor cells as well as elevated expression of CD27, Lymphocyte Activation Gene 3 (LAG3), and CD40 by immune cells were characteristic for LCNEC samples. Overall, SCLC and LCNEC tumors had a more immunogenic phenotype than AC samples. High tumor cell CD47 and CD40 expressions were associated with impaired and improved survival outcomes, respectively. Conclusions: By providing insights into the widely divergent immunologic profiles of LNENs, our results might serve as a basis for the development of novel immunotherapy-related approaches in these devastating malignancies

Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma

Abstract Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6–4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells