Impaired fibroblast growth factor receptor (FGFR) signaling is associated with many human conditions, including growth disorders, degenerative diseases, and cancer. Current FGFR therapeutics are based on chemical inhibitors of FGFR tyrosine kinase activity (TKIs). However, FGFR TKIs are limited in their target specificity as they generally inhibit all FGFRs and other receptor tyrosine kinases. In the search for specific inhibitors of human FGFR1, we identified VZ23, a DNA aptamer that binds to FGFR1b and FGFR1c with a KD of 55 nM and 162 nM, respectively, but not to the other FGFR variants (FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4). In cells, VZ23 inhibited the activation of downstream FGFR1 signaling and FGFR1-mediated regulation of cellular senescence, proliferation, and extracellular matrix homeostasis. Consistent with the specificity toward FGFR1 observed in vitro, VZ23 did not inhibit FGFR2-4 signaling in cells. We show that the VZ23 inhibits FGFR1 signaling in the presence of cognate fibroblast growth factor (FGF) ligands and its inhibitory activity is linked to its capacity to form unusual G-quadruplex structure. Our data suggest that targeting FGFR1 with DNA aptamers could be an effective alternative to TKIs for treating impaired FGFR1 signaling in human craniosynostoses.
- Publication type
- Journal Article MeSH
OBJECTIVES: This study aims to explore the lasting effects of stress experienced by pregnant women during World War II (WWII) on body and head measurements of their adult daughters. METHODS: The research sample consists of 336 female university students born in Poland between 1925 and 1951. The data include body measurements and socioeconomic information (parental occupation and number of siblings) acquired from questionnaires collected between the 1950s and 1970s. Student's t-test, Mann-Whitney test and Analysis of Variance were used to analyze differences in body measurements between groups of women born before and during the war, as well as the possible influences of socioeconomic variables. RESULTS: The mean measurements of body height, symphysion height, and waist circumference were lower in women conceived and born during the war compared to those born in the pre-war period. In contrast, the mean measurements of biacromial (shoulder) width, trunk length, and three head dimensions were higher in women conceived and born during the war. Additionally, the number of siblings appeared to be a significant factor that may have influenced the body measurements of women in both groups. For instance, a higher number of living siblings, particularly sisters, was associated with reduced body dimensions, such as body height and waist circumference, while a greater number of deceased siblings was linked to an increase in certain body dimensions. CONCLUSION: The results suggest that war-related prenatal conditions may have influenced the postnatal growth and development of women conceived and born during the war. Notably, the direction of these changes varied, which indicates that the growth response to the war-related conditions was a complex adaptation, reflecting both positive and negative changes in different body parts, rather than a uniform pattern of growth suppression.
- MeSH
- World War II * MeSH
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Stress, Psychological MeSH
- Socioeconomic Factors MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Poland MeSH
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.
- MeSH
- Autophagy * genetics MeSH
- White People genetics MeSH
- Carcinoma, Pancreatic Ductal * genetics pathology MeSH
- Forkhead Transcription Factors MeSH
- Genetic Predisposition to Disease * MeSH
- Hepatocyte Nuclear Factor 3-alpha genetics metabolism MeSH
- Polymorphism, Single Nucleotide * MeSH
- Cohort Studies MeSH
- Humans MeSH
- Biomarkers, Tumor * genetics MeSH
- Tumor Suppressor Proteins * genetics MeSH
- Pancreatic Neoplasms * genetics pathology MeSH
- Case-Control Studies MeSH
- Transcription Factors genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
The soil microbiota exhibits an important function in the ecosystem, and its response to climate change is of paramount importance for sustainable agroecosystems. The macronutrients, micronutrients, and additional constituents vital for the growth of plants are cycled biogeochemically under the regulation of the soil microbiome. Identifying and forecasting the effect of climate change on soil microbiomes and ecosystem services is the need of the hour to address one of the biggest global challenges of the present time. The impact of climate change on the structure and function of the soil microbiota is a major concern, explained by one or more sustainability factors around resilience, reluctance, and rework. However, the past research has revealed that microbial interventions have the potential to regenerate soils and improve crop resilience to climate change factors. The methods used therein include using soil microbes' innate capacity for carbon sequestration, rhizomediation, bio-fertilization, enzyme-mediated breakdown, phyto-stimulation, biocontrol of plant pathogens, antibiosis, inducing the antioxidative defense pathways, induced systemic resistance response (ISR), and releasing volatile organic compounds (VOCs) in the host plant. Microbial phytohormones have a major role in altering root shape in response to exposure to drought, salt, severe temperatures, and heavy metal toxicity and also have an impact on the metabolism of endogenous growth regulators in plant tissue. However, shelf life due to the short lifespan and storage time of microbial formulations is still a major challenge, and efforts should be made to evaluate their effectiveness in crop growth based on climate change. This review focuses on the influence of climate change on soil physico-chemical status, climate change adaptation by the soil microbiome, and its future implications.
The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.
- Publication type
- Journal Article MeSH
- Review MeSH
Existence syndromu časného normoglykemického zhoršení byla dlouhou dobu předmětem sporů. V současné době je tento syndrom široce akceptován pod zkratkou EWDR. Jeho podstatou je rychlá kompenzace subkompenzovaného až dekompenzovaného diabetu, která vede k progresi diabetické retinopatie. Významnou roli v jeho patogenezi hrají vysoké hladiny růstového faktoru. V kazuistice upozorňujeme na současný přístup v prevenci této závažné komplikace.
The existence of normoglycaemic re-entry phenomenon has long been a matter of controversy. Currently, this syndrome is widely accepted under the acronym EWDR. Its essence is rapid compensation of subcompensated to decompensated diabetes, which leads to progression of diabetic retinopathy. High levels of growth factor play a significant role in its pathogenesis. In the case report, we draw attention to the current approach to the prevention of this serious complication.
Blokáda receptoru pro lidský epidermáiní růstový faktor 2 (human epidermal growth factor receptor 2, HER2, ErbB2) se dostává do popředí léčby napříč onkologickými diagnózami. Nejvíce dat máme k dispozici u HER pozitivních tumorů prsu, kde jsou tyto přípravky používány nejdéle v podobě monokionáiních protilátek (trastuzumab, pertuzumab), tyrosinkinázových inhibitorů (lapatinib, neratinib, tukatinib) nebo novějších konjugátů (trastuzumab emtansin). Anti-HER2 terapii můžeme využít až u 20 % pacientů s adenokarcinomem žaludku, nové přípravky by mohly možnosti této léčby ještě zvýšit. Jednou z takových látek, která si svými výsledky buduje pozici v léčebných schématech adenokarcinomu žaludku, je trastuzumab deruxtekan.
Human epidermal growth factor receptor 2 (HER2, ErbB2) blockade is at the forefront of treatment across cancer diagnoses. Most data are available for HER-positive breast tumors, where these agents have been used for the longest time in the form of monoclonal antibodies (trastuzumab, pertuzumab), tyrosine kinase inhibitors (Lapatinib, neratinib, tucatinib) or newer conjugates (trastuzumab emtansine). Anti-HER2 therapy can be used in up to 20% of patients with gastric adenocarcinoma; new agents could increase the potential of this treatment. Trastuzumab deruxtecan is one such agent that is building its position in gastric adenocarcinoma treatment regimens.
Akromegália je raritné endokrinologické ochorenie charakterizované nadprodukciou rastového hormónu (RH), najčastej- šie na podklade adenómu hypofýzy s následnou zvýšenou produkciou inzulínu podobného rastového faktora 1 (IGF-1) v pečeni. Účinky RH a IGF-1 na metabolizmus glukózy sú antagonistické; RH vyvoláva inzulínovú rezistenciu, zatiaľ čo IGF-1 zvyšuje inzulínovú citlivosť. Avšak inzulín-antagonizujúci účinok RH prevyšuje inzulín-senzitizujúci účinok IGF-1 v cieľových tkanivách, čo vedie k vzniku diabetes mellitus (DM) pri akromegálii. Sekundárny DM je častou komplikáciou u pacientov s akromegáliou. DM môže byť prvým prejavom ochorenia, pretože hyperglykémia spôsobená inzulínovou rezistenciou býva často významná. Diagnostika a liečba DM u pacientov s akromegáliou je komplexná a vyžaduje multidisciplinárny prístup, ktorý zahŕňa endokrinológov, diabetológov a ďalších špecialistov. Účinná kontrola akromegálie prostredníctvom chirurgického zákroku, farmakoterapie alebo rádioterapie môže zlepšiť glukózovú homeostázu a znížiť riziko komplikácií spojených s DM. Uvedený prehľadový článok sa zaoberá patofyziologickými a klinickými zvláštnosťami DM u pacientov s akromegáliou, ako aj potenciálnymi účinkami špecifickej liečby akromegálie na glukózovú homeostázu.
Acromegaly is a rare endocrine disorder characterized by the overproduction of growth hormone (GH), most commonly due to a pituitary adenoma, leading to increased production of insulin-like growth factor 1 (IGF-1) in the liver. The effects of GH and IGF-1 on glucose metabolism are antagonistic; GH induces insulin resistance, while IGF-1 enhances insulin sensitivity. However, the insulin-antagonizing effect of GH outweighs the insulin-sensitizing effect of IGF-1 in target tissues, leading to the development of diabetes mellitus (DM) in acromegaly.Secondary DM is a frequent complication in patients with acromegaly. In fact, DM may be the first manifestation of the disease, because hyperglycemia caused by insulin resistance is often significant. The diagnosis and management of DM in patients with acromegaly are complex and require a multidisciplinary approach involving endocrinologists, diabetologists, and other specialists. Effective control of acromegaly through surgery, pharmacotherapy, or radiotherapy can improve glucose homeostasis and reduce the risk of complications associated with DM. This review article discusses the pathophysiological and clinical characteristics of DM in patients with acromegaly, as well as the potential effects of specific acromegaly treatments on glucose homeostasis.
Úvod: Dosud stále platí, že pozdní záchyt onemocnění karcinomem vaječníku je zásadní příčina jeho špatné prognózy. Zatím nebyl identifikován žádný dostatečně senzitivní a zároveň specifický marker ani kombinace markerů a zobrazovacích metod, které by jednoznačně umožňovaly záchyt časných, potenciálně dobře kurabilních stadií a dále prebiopticky diferencovaly skupinu ultrazvukově špatně odlišitelných benigní lézí od maligních tumorů. V designu retrospektivní studie byly zkoumány hladiny sérového vaskulárního endoteliálního faktoru D (VEGF-D). VEGF-D má vztah k nádorem indukované angiogenezi, lymfangiogenezi a remodelaci cév s efektem facilitace metastazování a zlepšené distribuce kyslíku a živin pro nádorovou tkáň. Na druhou stranu lymfatická síť slouží jako bariéra proti nádorové diseminaci a je to transportní systém pro imunitně činné elementy v potlačování nádorového bujení. Cílem studie bylo prověřit, zda existuje rozdíl v hladinách sérového VEGF-D ve skupině pacientek s maligními tumory, s benigními lézemi vaječníku a u zdravých kontrol bez patologického nálezu na adnexech. Metody: Retrospektivně bylo zhodnoceno 162 sér odebraných předoperačně a uchovaných procesem mrazení v biobance v letech 2022–2023. Testovaný soubor byl stratifikován na základě histopatologického výsledku vyšetření adnex na skupinu maligních tumorů (n = 54), skupinu benigních lézí (n = 47) a skupinu zdravých kontrol (n = 61). Ke statistickému vyhodnocení parametrů byly použity metody deskriptivní statistické analýzy. Pro porovnání sérových hladin VEGF-D byly použity neparametrické testy. Všechny analýzy byly uvažovány na hladině významnosti 5 %. Sérový VEGF-D byl analyzován metodou ELISA Quantikine® Human VEGF D R&D Systems a hodnoty byly odečteny spektrofotometricky na readeru TECAN. Výsledky: Výsledek srovnání deskriptivních statistických parametrů je ve vyšetřovaném souboru statisticky významný (p = 0,00067) pro rozdíl mezi hodnotami sérového VEGF-D v souboru benigních lézí a maligních tumorů. Dále existuje statisticky významný rozdíl mezi hodnotami pacientek s maligními tumory a mezi zdravými kontrolami (p = 0,0008). Mezi hodnotami u pacientek s benigními lézemi a u zdravých kontrol nebyl nalezen statisticky významný rozdíl (p = 0,4308). Ve srovnání s konvenčním markerem CA125 korelovala patologicky zvýšená hladina sérového CA125 s nízkou hodnotou sérového VEGF-D u pacientek s maligními tumory. Stejná shoda panovala ve srovnání s markerem HE4: vysoké sérové hladiny HE4 byly ve skupině pacientek s maligním tumorem doprovázeny nízkou hladinou VEGF-D, navíc v bodovém grafickém zobrazení se jasně stratifikovala skupina pacientek s maligními tumory od skupiny benigních lézí a zdravých kontrol. Závěr: S ohledem na získané výsledky má vyšetřování sérové hladiny VEGF-D potenciál diagnostického testu s přínosem ke stratifikaci obtížně prebiopticky diferencovatelných adnextumorů.
Introduction: Until now, it is still true that late detection of ovarian cancer is a major cause of its poor prognosis. So far, no sufficiently sensitive and specific marker or combination of markers and imaging methods has been identified that would unambiguously allow the detection of early potentially highly-curable stages and furthermore prebioptically differentiate a group of poorly distinguishable benign lesions from malignant tumours on ultrasound. In a retrospective study design, serum levels of vascular endothelial growth factor D (VEGF-D) were investigated. VEGF-D is related to tumour-induced angiogenesis, lymphangiogenesis, and vascular remodelling with the effect of facilitating metastasis and improved oxygen and nutrient distribution into tumour tissue. On the other hand, the lymphatic network serves as a barrier against tumour dissemination and is a transport system for immune-active elements in suppressing tumorigenesis. The aim of this study was to investigate that there is a difference in serum VEGF-D levels in a group of patients with malignant tumours, benign ovarian lesions, and healthy controls without pathological findings in the adnexa. Methods: 162 sera collected preoperatively and preserved by a freezing process in a biobank in 2022–2023 were retrospectively evaluated. The test set was stratified on the basis of histopathological results of the adnexal examination into the malignant tumour group (N = 54), benign lesion group (N = 47), and healthy control group (N = 61). Descriptive statistical analysis methods were used for the statistical evaluation of the parameters. Nonparametric tests were used to compare serum VEGF-D levels. All analyses were considered at a significance level of 5%. Serum VEGF-D was analysed by ELISA Quantikine® Human VEGF D R&D Systems and values were read spectrophotometrically on a TECAN reader. Results: The result of the comparison of descriptive statistical parameters was statistically significant (P = 0.00067) for the difference between serum VEGF-D levels in the set of benign lesions and malignant tumours. Furthermore, there was a statistically significant difference between the values of patients with malignant tumours and healthy controls (P = 0.0008). No statistically significant difference was found between the values of patients with benign lesions and healthy controls (P = 0.4308). Compared to the conventional marker CA125, pathologically elevated serum CA125 levels correlated with low serum VEGF-D levels in patients with malignant tumours. The same concordance was observed in comparison with the HE4 marker: high serum HE4 levels were accompanied by low VEGF-D levels in the group of patients with malignant tumours; moreover, the dot plot clearly stratified the group of patients with malignant tumours from the group of benign lesions and healthy controls. Conclusion: In view of the results obtained, the investigation of serum VEGF-D levels has the potential of a diagnostic test with a contribution to the stratification of the difficult of prebioptically differentiating adnexal tumours.
Background: Lung cancer is the leading cause of cancer-related deaths globally, with epidermal growth factor receptor (EGFR) mutations present in approximately 17-39% of non-small cell lung cancer (NSCLC) cases. Osimertinib, a third-generation oral EGFR tyrosine kinase inhibitor (EGFR-TKI), has become a cornerstone in the treatment of EGFR-mutated NSCLC. However, the full scope of its potentially life-threatening adverse effects, particularly cardiomyopathy, remains underexplored. Methods: This retrospective study was conducted using data from a multi-center registry of NSCLC patients with EGFR mutations treated with first-line osimertinib therapy between December 2018 and April 2024. Osimertinib-related cardiotoxicity was defined as a composite of reduced ejection fraction (EF) and cardiac death. Results: The study cohort consisted of 17 patients, and most of the patients had a history of smoking. Cardiac toxicity onset varied from 1 to 28 months following osimertinib initiation, with 70.59% of the patients experiencing symptoms within the first 6 months of treatment. Fourteen patients showed some degree of symptom improvement and EF recovery, although most did not return to baseline EF levels. Comorbidities, including heart failure, hypertension, and dyslipidemia, were prevalent across the cohort. Conclusions: While osimertinib remains an effective treatment for EGFR-mutated NSCLC, its associated cardiac toxicity, particularly in patients with pre-existing conditions, presents a significant challenge. Close monitoring, early intervention, and individualized management strategies are critical in mitigating these risks. Patients with mild cardiac toxicity may be suitable for rechallenge, while those with more severe or persistent toxicity should generally be excluded from further osimertinib treatment.
- Publication type
- Journal Article MeSH
