The piperidine-based Takemoto catalyst has been successfully employed in a novel asymmetric transfer hydroxymethylation of activated isoindolinones, allowing us to prepare the enantioenriched hydroxymethylated adducts in good to excellent yields (48-96%) and enantiopurities (81:19-97:3 e.r.). To increase the reaction rate without compromising the selectivity, carefully optimized formaldehyde surrogates were employed, providing a convenient source of anhydrous formaldehyde with a base-triggered release. The substrate scope, including 34 entries, showed the considerable generality of the asymmetric transformation, and most entries exhibited complete conversions in 24-48 h. A scale-up experiment and multiple enantioselective downstream transformations were also carried out, suggesting the prospective synthetic utility of the products.
- Publication type
- Journal Article MeSH
Evaluation of circulating tumor cells (CTCs) has demonstrated clinical validity as a prognostic tool based on enumeration, but since the introduction of this tool to the clinic in 2004, further clinical utility and widespread adoption have been limited. However, immense efforts have been undertaken to further the understanding of the mechanisms behind the biology and kinetics of these rare cells, and progress continues toward better applicability in the clinic. This review describes recent advances within the field, with a particular focus on understanding the biological significance of CTCs, and summarizes emerging methods for identifying, isolating, and interrogating the cells that may provide technical advantages allowing for the discovery of more specific clinical applications. Included is an atlas of high-definition images of CTCs from various cancer types, including uncommon CTCs captured only by broadly inclusive nonenrichment techniques.
In the past, selection of intermediate clinical endpoints (ICEs) in prostate cancer (PCa) trials largely depended on qualitative assessments; however, the advancing quality of research necessitates a robust correlation with overall survival (OS). This review summarises the results from several high-quality meta-analyses that explored the validity of ICEs as surrogates for OS. We found strong evidence that metastasis-free survival can serve as an ICE in localized PCa. In advanced disease, valid ICEs were identified only within the context of metastatic hormone-sensitive PCa, including radiological and clinical progression-free survival; however, concerns remain regarding their use owing to the limited generalisability of the data used to validate their surrogacy. PATIENT SUMMARY: Intermediate clinical endpoints can reduce the costs of trials and allow earlier introduction of new treatment methods. This article summarises results from studies verifying the validity of these endpoints as surrogates for overall survival.
- MeSH
- Humans MeSH
- Survival Rate MeSH
- Prostatic Neoplasms * mortality therapy pathology MeSH
- Endpoint Determination MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Fibrate therapy results in elevation of plasma total homocysteine (tHcy), which is known to induce oxidative stress and endothelial dysfunction. We aimed to establish whether fibrate-induced elevation of tHcy has also similar consequences and whether they may be prevented by folate co-administration. Eighteen subjects with hypercholesterolemia were included in an open, prospective, cross-over study. We compared intra-individually the effect of fenofibrate on tHcy, oxidative stress and endothelial dysfunction surrogates, in monotherapy and when combined with 10 mg of folate. These effects were also compared with fluvastatin monotherapy. Fenofibrate in monotherapy significantly decreased LDL cholesterol, increased the tHcy by 39.5 %, while oxidized LDL (oxLDL), malondialdehyde (MDA), von Willebrand factors (vWf) and thrombomodulin (TMD) remained unchanged. When fibrate was co-administered with folate, the tHcy remained on the initial post-diet level, while both the total and oxLDL as well as MDA, vWf and TMD decreased. In contrast to fenofibrate monotherapy, fluvastatin (80 mg) had a similar effect as combined therapy with fenofibrate and folate, while tHcy remained uninfluenced. In conclusion, fenofibrate decreases the LDL cholesterol, but in contrast to fluvastatin, has no significant antioxidative and endothelium-protective potential, probably due to a concomitant increase of tHcy. These effects may be improved by co-administration of folate.
- MeSH
- Endothelium, Vascular cytology enzymology physiopathology MeSH
- Fenofibrate administration & dosage pharmacokinetics MeSH
- Financing, Government MeSH
- Hyperhomocysteinemia enzymology etiology MeSH
- Folic Acid administration & dosage pharmacokinetics MeSH
- Humans MeSH
- Lipoproteins biosynthesis metabolism adverse effects MeSH
- Oxidative Stress genetics drug effects MeSH
- Lipid Peroxidation genetics drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Comparative Study MeSH
- MeSH
- Brachial Artery pathology MeSH
- Endothelium, Vascular pathology ultrasonography MeSH
- Adult MeSH
- Humans MeSH
- Reproducibility of Results MeSH
- Blood Flow Velocity physiology MeSH
- Ultrasonography methods MeSH
- Vasodilation physiology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Comparative Study MeSH
The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.
- MeSH
- Acetylcholinesterase metabolism MeSH
- Butyrylcholinesterase metabolism MeSH
- Quinolinium Compounds chemical synthesis chemistry pharmacology MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Pyridinium Compounds chemical synthesis chemistry pharmacology MeSH
- Recombinant Proteins metabolism MeSH
- Molecular Docking Simulation MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Náhradní mateřství (NM) je procedura, kdy asistovanou reprodukci, těhotenství a porod podstoupí žena s cílem vzdát se narozeného dítěte a rodičovská práva a povinnosti převést na někoho jiného, předem domluveného. Složitost procedury s sebou přináší mnoho právních problémů; hlavními jsou určení právního rodičovství, vymahatelnost dohod uzavřených před porodem dítěte či před zahájením léčby, kompenzace nákladů, registrace novorozence, cesty hledání náhradní matky, právo dítěte znát své rodiče. Náš článek je reakcí na článek Náhradní mateřství v právní praxi, uveřejněný v Časopise zdravotnického práva a bioetiky (2015, Vol. 5, No. 2), reagujeme především na problematiku hledání náhradní matky.
Surrogate motherhood (SM) is a procedure, when a woman undergoes assisted reproduction, pregnancy and childbirth in order to give up her child and transfer parental rights and obligations someone else, who she previously agreed with. The complexity of the procedure entails many legal problems; the most important are the determination of legal parenthood, enforceability of agreements concluded before the child's birth or before commencement of treatment, compensation of costs, registration of the newborn, the search for a surrogate mother, the right of the child to know her/his parents. Our article is a response to the article Surrogate motherhood in Legal Practice, published in JMLB (2015, Vol. 5, No. 2), and we mainly address the issue of seeking a surrogate mother.
- Keywords
- surogátní mateřství,
- MeSH
- Reproductive Techniques, Assisted MeSH
- Humans MeSH
- Gestational Carriers MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Pregnancy MeSH
- Publication type
- Review MeSH
Objective. The aim of this study was to investigate the feasibility of online monitoring of irradiation time (IRT) and scan time for FLASH proton radiotherapy using a pixelated semiconductor detector.Approach. Measurements of the time structure of FLASH irradiations were performed using fast, pixelated spectral detectors based on the Timepix3 (TPX3) chips with two architectures: AdvaPIX-TPX3 and Minipix-TPX3. The latter has a fraction of its sensor coated with a material to increase sensitivity to neutrons. With little or no dead time and an ability to resolve events that are closely spaced in time (tens of nanoseconds), both detectors can accurately determine IRTs as long as pulse pile-up is avoided. To avoid pulse pile-up, the detectors were placed well beyond the Bragg peak or at a large scattering angle. Prompt gamma rays and secondary neutrons were registered in the detectors' sensors and IRTs were calculated based on timestamps of the first charge carriers (beam-on) and the last charge carriers (beam-off). In addition, scan times inx,y, and diagonal directions were measured. The experiment was carried out for various setups: (i) a single spot, (ii) a small animal field, (iii) a patient field, and (iv) an experiment using an anthropomorphic phantom to demonstratein vivoonline monitoring of IRT. All measurements were compared to vendor log files.Main results. Differences between measurements and log files for a single spot, a small animal field, and a patient field were within 1%, 0.3% and 1%, respectively.In vivomonitoring of IRTs (95-270 ms) was accurate within 0.1% for AdvaPIX-TPX3 and within 6.1% for Minipix-TPX3. The scan times inx,y, and diagonal directions were 4.0, 3.4, and 4.0 ms, respectively.Significance. Overall, the AdvaPIX-TPX3 can measure FLASH IRTs within 1% accuracy, indicating that prompt gamma rays are a good surrogate for primary protons. The Minipix-TPX3 showed a somewhat higher discrepancy, likely due to the late arrival of thermal neutrons to the detector sensor and lower readout speed. The scan times (3.4 ± 0.05 ms) in the 60 mm distance ofy-direction were slightly less than (4.0 ± 0.06 ms) in the 24 mm distance ofx-direction, confirming the much faster scanning speed of the Y magnets than that of X. Diagonal scan speed was limited by the slower X magnets.
- MeSH
- Neutrons MeSH
- Proton Therapy * methods MeSH
- Protons MeSH
- Radiometry * methods MeSH
- Gamma Rays MeSH
- Publication type
- Journal Article MeSH
Cíl studie: Přinést podklady pro debatu o kritériích výběru náhradní matky, pokud by procedura měla být v ČR právně regulována. Typ studie: Kvalitativní obsahová analýza dokumentů. Název a sídlo pracoviště: Zdravotně sociální fakulta, Jihočeská univerzita, České Budějovice; AK Prudil a spol., s.r.o., Brno. Metodika: Využito bylo několik zdrojů dat: 1. Právní dokumenty několika evropských států, v nichž je náhradní mateřství regulováno zákonem: UK, NL, Řecko, Portugalsko. 2. Webové stránky agentur, které náhradní mateřství zprostředkovávají; analyzovali jsme jich 23. Výsledky: Nejčastěji zmiňovaným kritériem pro výběr náhradní matky byl její rodičovský status a gynekologická anamnéza. Dále se požadavky týkaly věku, zdravotního stavu (vylučuje se psychiatrická diagnóza), životního stylu. Méně časté byly požadavky na BMI, občanství, příbuznost se žadateli, rodinný stav, bezúhonnost, finanční stabilitu, počty podstoupených procedur. Dále se požadují obtížně zajistitelné charakteristiky, například ochota k proceduře či podpora rodiny. Závěr: Kritéria formulovaná SAR ČGPS ČLS jsou velmi kvalifikovaná, zohledňují složitost procedury. Doporučujeme zvážit horní věkovou hranici a počty procedur, které může absolvovat jedna adeptka (doporučujeme jedinou). Zásadní osobou bude psycholog – psychodiagnostik. Doporučujeme začít vyjednávat s odbornými psychologickými společnostmi o jeho požadované kvalifikaci. Dále doporučujeme akceptovat tuto proceduru pouze pro páry s trvalým pobytem v ČR.
Objective: Provide background to the debate on the criteria for selecting a surrogate mother, if the procedure should be regulated in the Czech Republic. Design: Qualitative content analysis of documents. Setting: Faculty of Health and Social Studies, University of South Bohemia, České Budějovice; AK Prudil et al., Brno. Methods: Several sources of data have been used: 1. Legal documents of several European countries where surrogate motherhood is regulated by law: UK, NL, Greece, Portugal. 2. The websites of agencies that mediate surrogate motherhood; analysed number: 23. Results: The most frequently mentioned criterion for selection a surrogate mother was her parental status and gynecological history. Further, the requirements related to age, state of health (exclusion of psychiatric diagnosis), lifestyle. Less often, BMI requirements, citizenship, relationship with the applicant, marital status, impeccability, financial stability, number of procedures underwent. In addition, difficult-to-assess features, such as willingness to process or family support, are required. Conclusion: The criteria formulated by the SAR ČGPS ČLS are highly qualified, taking into account the complexity of the procedure. We recommend to reconsider the upper age limit and the number of procedures that an adept can pass (we recommend one). The psychologist should be qualified in psychodiagnostics. We recommend starting negotiations with professional psychological societies about his required qualifications. We also recommend accepting this procedure only for couples residing in the Czech Republic.
