During metastasis, cancer cells navigate through harsh conditions, including various mechanical forces in the bloodstream, highlighting the need to understand the impact of mechanical and shear stresses on cancer cells. To overcome the current methodological limitations of such research, here we present a new device that replicates similar conditions by applying shear stress on cultured cells. The device provides a less complex, easily accessible alternative to traditional fluidics while generating fluid shear stress values comparable to those in human veins and capillaries. The device allows analyses of large cell numbers in standard cell culture flasks and incubators. Using this device to explore the shear stress-induced responses of various human cell lines, we discovered a previously unknown, reversible pre-cytokinetic block occurring in cells that lose anchorage during mitosis and are kept under constant shear stress. Notably, some cancer cell lines appear to bypass this unorthodox cell-cycle block, suggesting its role as a safety checkpoint to restrict the proliferation of cancer cells in the bloodstream and their overall spreading potential. These findings provide new insights into the diverse responses of normal and cancer cells to shear stress and highlight the potential of our technology for research on circulating tumor cells and metastatic spread.
- MeSH
- lidé MeSH
- mechanický stres * MeSH
- mitóza MeSH
- nádorové buněčné linie MeSH
- nádorové cirkulující buňky patologie MeSH
- nádory patologie MeSH
- pevnost ve smyku MeSH
- proliferace buněk MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The study aimed to analyze the effect of respiratory muscle endurance training (RMT) on performance and respiratory function in professional road cyclists during the off-season period. METHODS: Twenty professional road cyclists from the Czech Republic were divided into the control (CON) (N.=10) and the RMT (N.=10) groups. Cyclists from the RMT group accomplished 30 sessions over 10 weeks. Performance in the incremental cycling test and respiratory capacity via test were assessed before and after 10 weeks in both groups. The comparison between and within the groups was performed, together with effect size and delta % (P<0.05). RESULTS: Significant effects on respiratory function during the exercise, on lung volume utilization at 90% of VO
- MeSH
- cyklistika fyziologie MeSH
- dechová cvičení metody MeSH
- dýchací svaly fyziologie MeSH
- dýchání MeSH
- fyzická vytrvalost * fyziologie MeSH
- lidé MeSH
- roční období MeSH
- vytrvalostní trénink * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Doporučené postupy klinické péče o nosiče patogenních variant v klinicky relevantních genech predisponujících ke vzniku Lynchova syndromu a karcinomu kolorekta definují kroky primární a sekundární prevence, která by měla být osobám ve vysokém riziku vzniku dědičných nádorů v ČR poskytnuta. Tvorba doporučených postupů byla organizována pracovní skupinou onkogenetiky Společnosti lékařské genetiky a genomiky při České lékařské společnosti J. E. Purkyně ve spolupráci se zástupci onkologie, onkogynekologie a gastroenterologie. Doporučené postupy vycházejí z aktuálních doporučení National Comprehensive Cancer Network (NCCN), Evropské společnosti pro klinickou onkologii (ESMO) a zohledňují kapacitní možnosti našeho zdravotnictví.
The guidelines for clinical practice for carriers of pathogenic variants in clinically relevant genes predisposing to Lynch syndrome and colorectal cancer define the steps of primary and secondary prevention that should be provided to the individuals at high risk of developing hereditary cancer in the Czech Republic. The drafting of the guidelines was organized by the Oncogenetics Working Group of the Society for Medical Genetics and Genomics of J. E. Purkyně Czech Medical Society, in cooperation with representatives of oncology, oncogynecology, and gastroenterology. The guidelines are based on the current recommendations of the National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO) and take into account the capacity of the Czech healthcare system.
- MeSH
- adhezní molekula epiteliálních buněk genetika MeSH
- dědičné nepolypózní kolorektální nádory genetika MeSH
- genetická predispozice k nemoci * genetika MeSH
- kolorektální nádory * genetika MeSH
- mismatch repair endonukleáza PMS2 genetika MeSH
- MutL homolog 1 genetika MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- zárodečné mutace genetika MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. RESULTS: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. CONCLUSION: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * genetika MeSH
- nádory vaječníků * genetika MeSH
- oprava DNA genetika MeSH
- protein FANCG * genetika MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
ConspectusMagnetic resonance techniques represent a fundamental class of spectroscopic methods used in physics, chemistry, biology, and medicine. Electron paramagnetic resonance (EPR) is an extremely powerful technique for characterizing systems with an open-shell electronic nature, whereas nuclear magnetic resonance (NMR) has traditionally been used to investigate diamagnetic (closed-shell) systems. However, these two techniques are tightly connected by the electron-nucleus hyperfine interaction operating in paramagnetic (open-shell) systems. Hyperfine interaction of the nuclear spin with unpaired electron(s) induces large temperature-dependent shifts of nuclear resonance frequencies that are designated as hyperfine NMR shifts (δHF).Three fundamental physical mechanisms shape the total hyperfine interaction: Fermi-contact, paramagnetic spin-orbit, and spin-dipolar. The corresponding hyperfine NMR contributions can be interpreted in terms of through-bond and through-space effects. In this Account, we provide an elemental theory behind the hyperfine interaction and NMR shifts and describe recent progress in understanding the structural and electronic principles underlying individual hyperfine terms.The Fermi-contact (FC) mechanism reflects the propagation of electron-spin density throughout the molecule and is proportional to the spin density at the nuclear position. As the imbalance in spin density can be thought of as originating at the paramagnetic metal center and being propagated to the observed nucleus via chemical bonds, FC is an excellent indicator of the bond character. The paramagnetic spin-orbit (PSO) mechanism originates in the orbital current density generated by the spin-orbit coupling interaction at the metal center. The PSO mechanism of the ligand NMR shift then reflects the transmission of the spin polarization through bonds, similar to the FC mechanism, but it also makes a substantial through-space contribution in long-range situations. In contrast, the spin-dipolar (SD) mechanism is relatively unimportant at short-range with significant spin polarization on the spectator atom. The PSO and SD mechanisms combine at long-range to form the so-called pseudocontact shift, traditionally used as a structural and dynamics probe in paramagnetic NMR (pNMR). Note that the PSO and SD terms both contribute to the isotropic NMR shift only at the relativistic spin-orbit level of theory.We demonstrate the advantages of calculating and analyzing the NMR shifts at relativistic two- and four-component levels of theory and present analytical tools and approaches based on perturbation theory. We show that paramagnetic NMR effects can be interpreted by spin-delocalization and spin-polarization mechanisms related to chemical bond concepts of electron conjugation in π-space and hyperconjugation in σ-space in the framework of the molecular orbital (MO) theory. Further, we discuss the effects of environment (supramolecular interactions, solvent, and crystal packing) and demonstrate applications of hyperfine shifts in determining the structure of paramagnetic Ru(III) compounds and their supramolecular host-guest complexes with macrocycles.In conclusion, we provide a short overview of possible pNMR applications in the analysis of spectra and electronic structure and perspectives in this field for a general chemical audience.
- Publikační typ
- časopisecké články MeSH
Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.
- MeSH
- checkpoint kinasa 2 * genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * genetika MeSH
- introny * genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * genetika MeSH
- nádory vaječníků genetika MeSH
- prekurzory RNA genetika MeSH
- sestřih RNA * genetika MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Německo MeSH
Male breast cancer (mBC) is a rare cancer diagnosis that constitutes less than 1 % of all breast cancer cases globally. Genetic factors play an important role in the mBC risk. Germline pathogenic variants (PVs) in cancer predisposition genes could be identified in about 15 % of cases. We performed germline genetic testing in 248 Czech mBC patients and 3,626 non-cancer male controls using next-generation sequencing by the CZECANCA panel (226 genes). We identified 46/248 (18.5 %) carriers of PVs in the established mBC predisposition genes, primarily in BRCA2 (N = 34), less frequently in BRCA1 (N = 7) and PALB2 (N = 5). The presence of a PV in these genes significantly increased the mBC risk (OR 44.04; 5.82; and 8.26, respectively). Additionally, we identified 16 carriers of PVs in candidate mBC genes, but only PVs in CHEK2 were significantly associated with increased mBC risk (OR = 4.98). The significance of 26 germline alterations in 23/192 additionally analysed genes remained uncertain. The carriers of PVs in BRCA1 and CHEK2 were significantly younger (55.8 and 52.6 years, respectively) than non-carriers (64.8 years), and all carriers of PVs in the established genes had more frequently grade G3 tumours and positive family cancer history. Our study underscores the critical role of BRCA2 in mBC predisposition while also highlighting the potential contributions of additional genes that warrant further investigation. Moreover, it supports and justifies universal genetic testing for all mBC patients to generally improve early cancer detection and tailored treatment.
- MeSH
- checkpoint kinasa 2 genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genetické testování MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu u mužů * genetika MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- senioři MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
4., přepracované a doplněné vydání xiii, 558 stran : ilustrace (převážně barevné), mapy ; 26 cm
Monografie si klade za cíl informovat odbornou veřejnost o nejnovějších teoretických i klinických poznatcích v prudce se rozvíjejícím oboru klinické onkologie. V novém vydání byla přepracována a rozšířena preklinická část knihy – pokrývá všechny oblasti molekulární onkologie, které je zapotřebí znát pro hlubší pochopení příčin vzniku, šíření nádorů i jejich odpovědi na protinádorovou léčbu. Samostatné kapitoly jsou věnovány tkáňové homeostáze a jejím poruchám v tumorogenezi, mechanismům kancerogeneze, poruchám intracelulární signalizace, poruchám nádorového mikroprostředí, procesu angiogeneze a metastazování. Kniha též reaguje na pokrok v oblasti nádorové imunoterapie. Teoretická část knihy dále obsahuje významné farmakologické kapitoly, které čtenáře seznámí s problematikou eliminace protinádorových léků a s významem lékových interakcí i s metodikou klinických studií.Ve druhé části se čtenář setká s rešeršním zpracováním diagnostiky a léčby základních diagnóz, které syntetizuje poznatky klinické a radiační onkologie, a umožňuje tak lékaři provést po přečtení krátkého textu kvalifikované rozhodnutí u konkrétního nemocného. Orientace v knize je usnadněna logickým řazením jednotlivých diagnóz ve shodě s aktuální verzí Mezinárodní klasifikace nemocí. TNM klasifikace je u všech diagnóz uvedena samozřejmě ta nejnovější, osmá.Ve třetí části knihy jsou zpracována doporučení k provádění podpůrné léčby klinicky nejvýznamnějších nežádoucích účinků a častých symptomů doprovázejících onkologická onemocnění (bolest, nevolnost a zvracení, poruchy kostního metabolismu, anémie, febrilní neutropenie, kardiotoxicita, nefrotoxicita a urotoxicita či kožní toxicita). Nově přibyla také kapitola o terapii maligního ascitu.Je pomocníkem především onkologům, internistům a chirurgům, kteří se denně setkávají s pacienty se zhoubnými nádory, v jejichž diagnostice a léčbě musí provádět řadu zásadních komplikovaných rozhodnutí.
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- onkologie
- MeSH
- analýza přežití MeSH
- digitální technologie MeSH
- ekonomika a organizace zdravotní péče * MeSH
- lékařská informatika MeSH
- lékařská onkologie * organizace a řízení MeSH
- lidé MeSH
- mezioborová komunikace MeSH
- nádory mortalita MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
- Geografické názvy
- Švédsko MeSH
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.
- Publikační typ
- časopisecké články MeSH
