المؤلفون: Albert Grinshpun, Douglas Russo, Wen Ma, Ana Verma, Francisco Hermida-Prado, Shira Sherman, Giorgio Gaglia, Sheheryar Kabraji, Gregory Kirkner, Melissa E. Hughes, Nancy U. Lin, Zachary Sandusky, Agostina Nardone, Cristina Guarducci, Quang-De Nguyen, Sandro Santagata, Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: npj Breast Cancer, Vol 10, Iss 1, Pp 1-12 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2374-4677Test

الوصول الحر: https://doaj.org/article/7c7a103652a4404eac1f649798184d56Test

المؤلفون: Gellért Balázs Karvaly, István Vincze, Michael Noel Neely, István Zátroch, Zsuzsanna Nagy, Ibolya Kocsis, Csaba Kopitkó

المصدر: Pharmaceutics, Vol 16, Iss 3, p 358 (2024)

مصطلحات موضوعية: therapeutic drug monitoring, piperacillin, tazobactam, nonparametric adaptive grid, Bayesian models, pharmacokinetics, Pharmacy and materia medica, RS1-441

الوصف: Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm. Thirty quasi-models were subsequently generated for each model type, and nonparametric maximum a posteriori probability Bayesian estimates were established for each patient. A significant difference in performance was found between one- and two-compartment models. Acceptable agreement was found between predicted and observed piperacillin concentrations, and between the estimates of the random-effect pharmacokinetic variables obtained using the so-called support points of the pop-PK models or the quasi-models as priors. The mean squared errors of the predictions made using the quasi-models were similar to, or even considerably lower than those obtained when employing the pop-PK models. Conclusion: fully artificial nonparametric quasi-models can efficiently augment pop-PK models containing few support points, to make individual pharmacokinetic estimates in the clinical setting.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1999-4923/16/3/358Test; https://doaj.org/toc/1999-4923Test

الوصول الحر: https://doaj.org/article/66c127ee5e374e399f14cccabc4dec79Test

المؤلفون: Zsuzsanna Nagy, Klaudia Barabas, Gergely Kovacs

المصدر: Frontiers in Endocrinology, Vol 14 (2023)

مصطلحات موضوعية: estrogen, neurodegenaration, fertility, classical way, non-classical way, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2023.1144417/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/68e378974cc84764b9fb932cac92e5bbTest

المؤلفون: Zsuzsanna Nagy, Allan Herbison, Andrea Kwakowsky, Gergely Kovacs, Klaudia Barabas

المصدر: Frontiers in Endocrinology, Vol 14 (2023)

مصطلحات موضوعية: estrogen, estrogen receptor, GnRH, neurodegeneration, classical and non-classical actions, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2023.1192671/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/4eee45973de74f65bfd4f79beeee760dTest

المؤلفون: Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: Frontiers in Oncology, Vol 13 (2023)

مصطلحات موضوعية: breast cancer, estrogen receptor, ESR1 fusion, endocrine therapy resistance, SERD, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2023.1155540/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/4cf1136085424b6eac26d3bb1f04eaaeTest

المؤلفون: Miklós Fagyas, Zsolt Fejes, Renáta Sütő, Zsuzsanna Nagy, Borbála Székely, Marianna Pócsi, Gergely Ivády, Edina Bíró, Gabriella Bekő, Attila Nagy, György Kerekes, Zoltán Szentkereszty, Zoltán Papp, Attila Tóth, János Kappelmayer, Béla Nagy, Jr.

المصدر: International Journal of Infectious Diseases, Vol 115, Iss , Pp 8-16 (2022)

مصطلحات موضوعية: SARS-CoV-2, ACE2, inflammation, COVID-19 disease, biomarker, outcome, Infectious and parasitic diseases, RC109-216

الوصف: Objectives: Angiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells. Here we investigated circulating ACE2 activity to predict the severity and mortality of COVID-19. Methods: Serum ACE2 activity was measured in COVID-19 (110 critically ill and 66 severely ill subjects at hospital admission and 106 follow-up samples) and in 32 non-COVID-19 severe sepsis patients. Associations between ACE2, inflammation-dependent biomarkers, pre-existing comorbidities, and clinical outcomes were studied. Results: Initial ACE2 activity was significantly higher in critically ill COVID-19 patients (54.4 [36.7-90.8] mU/L) than in severe COVID-19 (34.5 [25.2-48.7] mU/L; P

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1201971221008766Test; https://doaj.org/toc/1201-9712Test

الوصول الحر: https://doaj.org/article/e66c5aaf070048b0bb2bb110f12d9088Test

المؤلفون: Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: Frontiers in Oncology, Vol 12 (2023)

مصطلحات موضوعية: breast cancer, estrogen receptor, ESR1 fusion, endocrine therapy resistance, SERD, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Breast cancer is the most frequent female malignant tumor, and the leading cause of cancer death in women worldwide. The most common subtype of breast cancer is hormone receptor positive that expresses the estrogen receptor (ER). Targeting ER with endocrine therapy (ET) is the current standard of care for ER positive (ER+) breast cancer, reducing mortality by up to 40% in early- stage disease. However, resistance to ET represents a major clinical challenge for ER+ breast cancer patients leading to disease recurrence or progression of metastatic disease. Salient drivers of ET resistance are missense mutations in the ER gene (ESR1) leading to constitutive transcriptional activity and reduced ET sensitivity. These mutations are particularly prominent and deleterious in metastatic breast cancer (MBC). In addition to activating ESR1 point mutations, emerging evidence imposes that chromosomal translocation involving the ESR1 gene can also drive ET resistance through the formation of chimeric transcription factors with constitutive transcriptional activity. Although these ESR1 gene fusions are relatively rare, they are enriched in ET resistant metastatic disease. This review discusses the characteristics of ER fusion proteins and their association with clinical outcomes in more aggressive and metastatic breast cancer. The structure and classification of ER fusion proteins based on function and clinical significance are also addressed. Finally, this review summarizes the metastatic phenotypes exhibited by the ER fusion proteins and their role in intrinsic ET resistance.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2022.1037531/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/edb23833f08c43a9ad4e7e6461d94908Test

المؤلفون: Márta Vargha, Eszter Róka, Norbert Erdélyi, Kitti Németh, Zsuzsanna Nagy-Kovács, Péter B. Kós, Attila I. Engloner

المصدر: Diversity, Vol 15, Iss 5, p 621 (2023)

مصطلحات موضوعية: riverbank filtration, water treatment, microbial community, metabarcoding, climate change, Biology (General), QH301-705.5

الوصف: In drinking water supply, riverbank filtration (RBF) is an efficient and cost-effective way of eliminating pathogens and micropollutants using a combination of biotic and abiotic processes. Microbial communities in the hyporheic zone both contribute to and are shaped by these processes. Microbial water quality at the point of consumption is in turn influenced by the source water microbiome, water treatment and distribution system. Understanding microbial community shifts from source to tap and the factors behind them is instrumental in maintaining safe drinking water delivery. To this end, microbial communities of an RBF-based drinking water supply system were investigated by metabarcoding in a one-year sampling campaign. Samples were collected from the river, RBF wells, treated water, and a consumer’s tap. Metabarcoding data were analysed in the context of physicochemical and hydrological parameters. Microbial diversity as well as cell count decreased consistently from the surface water to the tap. While Proteobacteria were dominant throughout the water supply system, typical river water microbiome phyla Bacteroidota, Actinobacteria, and Verrucomicrobiota were replaced by Nitrospira, Patescibacteria, Chloroflexi, Acidobacteriota, Methylomicrobilota, and the archaeal phylum Nanoarcheota in well water. Well water communities were differentiated by water chemistry, in wells with high concentration groundwater derived iron, manganese, and sulphate, taxa related to iron and sulphur biogeochemical cycle were predominant, while methane oxidisers characterised the more oxic wells. Chlorine-resistant and filtration-associated taxa (Acidobacteria, Firmicutes, and Bdellovibrionota) emerged after water treatment, and no potentially pathogenic taxa were identified at the point of consumption. River discharge had a distinct impact on well water microbiome indicative of vulnerability to climate change. Low flow conditions were characterised by anaerobic heterotrophic taxa (Woesarchaeales, Aenigmarchaeales, and uncultured bacterial phyla MBNT15 and WOR-1), implying reduced efficiency in the degradation of organic substances. High flow was associated the emergence of typical surface water taxa. Better understanding of microbial diversity in RBF water supply systems contributes to preserving drinking water safety in the future changing environment.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1424-2818/15/5/621Test; https://doaj.org/toc/1424-2818Test

الوصول الحر: https://doaj.org/article/670d89d3a0d74b8faa8e0995a80c2d7dTest

المؤلفون: Klaudia Barabás, Bernadett Makkai, Nelli Farkas, Hanga Réka Horváth, Zsuzsanna Nagy, Kata Váradi, Dóra Zelena

المصدر: Frontiers in Endocrinology, Vol 13 (2022)

مصطلحات موضوعية: COVID-19 vaccines, SARS-Cov-2 infection, COVID-19 pandemic, menstrual cycle, depression, human surveys, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: Observations of women and clinicians indicated that the prevalence of menstrual cycle problems has escalated during the COVID-19 pandemic. However, it was not clear whether the observed menstrual cycle changes were related to vaccination, the disease itself or the COVID-19 pandemic-induced psychological alterations. To systematically analyze this question, we conducted a human online survey in women aged between 18 and 65 in Hungary. The menstrual cycle of 1563 individuals were analyzed in our study in relation to the COVID-19 vaccination, the COVID-19 infection, the pandemic itself and the mental health. We found no association between the COVID-19 vaccination, the vaccine types or the COVID-19 infection and the menstrual cycle changes. We also evaluated the menstrual cycle alterations focusing on three parameters of the menstrual cycle including the cycle length, the menses length and the cycle regularity in three pandemic phases: the pre-peak, the peak and the post-peak period in Hungary. Our finding was that the length of the menstrual cycle did not change in any of the periods. However, the menses length increased, while the regularity of the menstrual cycle decreased significantly during the peak of the COVID-19 pandemic when comparing to the pre- and post-peak periods. In addition, we exhibited that the length and the regularity of the menstrual cycle both correlated with the severity of depression during the post-peak period, therefore we concluded that the reported menstrual cycle abnormalities during the peak of COVID-19 in Hungary might be the result of elevated depressive symptoms.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2022.974788/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/149aee3829474a8ebef7229b7f4b7302Test

المؤلفون: Klaudia Barabás, Gergely Kovács, Viola Vértes, Erzsébet Kövesdi, Péter Faludi, Ildikó Udvarácz, Dániel Pham, Dóra Reglődi, Istvan M. Abraham, Zsuzsanna Nagy

المصدر: Frontiers in Endocrinology, Vol 13 (2022)

مصطلحات موضوعية: PACAP, GnRH, kisspeptin, estrogen receptor α, estrous cycle, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: The hypothalamic gonadotropin-releasing hormone (GnRH)–kisspeptin neuronal network regulates fertility in all mammals. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide isolated from the hypothalamus that is involved in the regulation of several releasing hormones and trop hormones. It is well-known that PACAP influences fertility at central and peripheral levels. However, the effects of PACAP on GnRH and kisspeptin neurons are not well understood. The present study investigated the integrity of the estrous cycle in PACAP-knockout (KO) mice. The number and immunoreactivity of GnRH (GnRH-ir) neurons in wild-type (WT) and PACAP KO female mice were determined using immunohistochemistry. In addition, the number of kisspeptin neurons was measured by counting kisspeptin mRNA-positive cells in the rostral periventricular region of the third ventricle (RP3V) and arcuate nucleus (ARC) using the RNAscope technique. Finally, the mRNA and protein expression of estrogen receptor alpha (ERα) was also examined. Our data showed that the number of complete cycles decreased, and the length of each cycle was longer in PACAP KO mice. Furthermore, the PACAP KO mice experienced longer periods of diestrus and spent significantly less time in estrus. There was no difference in GnRH-ir or number of GnRH neurons. In contrast, the number of kisspeptin neurons was decreased in the ARC, but not in the R3PV, in PACAP KO mice compared to WT littermates. Furthermore, ERα mRNA and protein expression was decreased in the ARC, whereas in the R3PV region, ERα mRNA levels were elevated. Our results demonstrate that embryonic deletion of PACAP significantly changes the structure and presumably the function of the GnRH–kisspeptin neuronal network, influencing fertility.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2022.993228/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/3a91c1dfb90a4b4aa4bc09e1029b9440Test