Přehled sumarizuje dostupná dohledatelná fakta o léčbě karcinomu ovaria na území současné České republiky, která pocházejí z archivu pracoviště autorů v listinné podobě a z digitalizovaných časopisů v internetové databázi Medvik. Uvedena je stručná historie využití dosud známých metod onkologické terapie karcinomu ovaria: onkologická chirurgie, radioterapie, konvenční systémová léčba, imunoterapie, cílená terapie.
- Klíčová slova
- Cytembena,
- MeSH
- adjuvantní chemoterapie dějiny metody MeSH
- antitumorózní látky terapeutické užití MeSH
- dějiny 20. století MeSH
- gynekologické chirurgické výkony dějiny metody MeSH
- imunoterapie dějiny metody MeSH
- lidé MeSH
- nádory vaječníků * terapie MeSH
- protokoly protinádorové léčby MeSH
- radioterapie dějiny metody MeSH
- Check Tag
- dějiny 20. století MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
- Geografické názvy
- Československo MeSH
V terapii chronické lymfocytární leukemie (CLL) došlo v posledním desetiletí k zásadním změnám s výrazným zlepšením léčebných výsledků a delším přežitím pacientů s tímto onemocněním. Revoluční změnou byl příchod cílených léků, a to zejména inhibitorů Brutonovy tyrozinkinázy (akalabrutinib, ibrutinib, zanubrutinib) a Bcl2 inhibitorů (venetoklax). Tyto malé molekuly již i v běžné praxi prakticky nahradily chemoterapii, a to nejdříve v relapsech, a v poslední době i v první linii léčby CLL. Mezi hlavní výhody cílené terapie patří lepší tolerance léčby a vysoká účinnost, a to i u skupiny pacientů s prognosticky nepříznivou aberací genu TP53, kteří zpravidla byli refrakterní na chemoterapii. Tento článek shrnuje aktuální možnosti cílené terapie a hlavní trendy vývoje léčby CLL.
The treatment of chronic lymphocytic leukemia (CLL) has undergone profound changes in the last decade with significant improvements in therapeutic outcomes and longer survival of patients with this disease. A major change has been the advent of targeted drugs, especially Bruton's tyrosine kinase inhibitors (acalabrutinib, ibrutinib, zanubrutinib) and Bcl2 inhibitors (venetoclax). These small molecules have already practically replaced chemotherapy in routine practice, first in relapse setting and more recently in first-line treatment of CLL. The main advantages of targeted therapy include better tolerance to treatment and high efficacy, including in the group of patients with prognostically unfavourable TP53 gene aberrations, who were usually refractory to chemotherapy. This article summarizes the current options for targeted therapy and the main trends in CLL treatment.
- Klíčová slova
- akalabrutinib, ibrutinib, idelalisib, venetoklax, zanubrutinib, pirtobrutinib,
- MeSH
- antitumorózní látky terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- cílená molekulární terapie metody MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- proteinkinasa BTK antagonisté a inhibitory MeSH
- protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
Aktuálně dostupná data z klinických studií jednoznačně dokládají benefit cílené terapie oproti chemoimunoterapii v léčbě relabované či refrakterní chronické lymfocytární leukemie (R/R CLL). Jednou z dominantně používaných modalit cílené léčby je kombinace antiCD20 protilátky rituximabu a inhibitoru antiapoptotického proteinu BCL-2 venetoklaxu, jejíž efektivita a bezpečnost byly prokázány v rámci studie Murano. Hlavními výhodami tohoto režimu je časově limitovaná terapie, vysoké procento dosažených dlouhotrvajících léčebných odpovědí a vysoké procento hlubokých remisí na úrovni měřitelné reziduální choroby (MRD). Časově limitovaná terapie také umožňuje diskuzi o možnosti opakování léčby v případě laboratorního či klinického relapsu. Robustní data podporující tento přístup však zatím chybí. Venetoklax navíc dosahuje velmi dobrých výsledků i ve skupině vysoce rizikových pacientů s mutací TP53. Z nežádoucích účinků je třeba jmenovat především syndrom z nádorového rozpadu během ramp-up periody a cytopenie vyskytující se v průběhu léčby. Naše kazuistika dokumentuje případ pacienta s chronickou lymfocytární leukemií, včetně prokázané mutace TP53, u kterého byla ve druhé linii léčby použita kombinace rituximab-venetoklax (R-Ven) s velmi dobrou klinickou odpovědí.
Currently available data from clinical trials clearly demonstrate the benefit of targeted therapy over chemoimmunotherapy in the treatment of relapsed or refractory chronic lymphocytic leukemia (R/R CLL). One of the predominantly used modalities of targeted therapy is the combination of the antiCD20 antibody rituximab and the BCL-2 antiapoptotic protein inhibitor venetoclax, whose efficacy and safety were confirmed in the Murano trial. The main advantages of this regimen are the time-limited therapy, the high percentage of long-lasting treatment responses and the high percentage of deep remissions at the measurable residual disease (MRD) level. In addition, the time-limited therapy allows discussion of the possibility of repeating the treatment in case of laboratory or clinical relapse. However, robust data supporting this approach are still lacking. Venetoclax also achieves very good results in the group of high-risk patients with TP53 mutation. Among the side effects, it is important to mention tumor-lysis syndrome during the ramp-up period and cytopenias occurring in the course of treatment. Our case report documents the case of a patient with chronic lymphocytic leukemia, including a proven TP53 mutation, in whom the rituximab-venetoclax combination (R-Ven) was used as a second-line treatment with a very good clinical response.
- Klíčová slova
- venetoklax,
- MeSH
- antigeny CD20 terapeutické užití MeSH
- chronická lymfatická leukemie * farmakoterapie MeSH
- cílená molekulární terapie metody MeSH
- geny p53 MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- protoonkogenní proteiny c-bcl-2 antagonisté a inhibitory MeSH
- recidiva MeSH
- rituximab terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
Trypanosomatids (Euglenozoa) are a diverse group of unicellular flagellates predominately infecting insects (monoxenous species) or circulating between insects and vertebrates or plants (dixenous species). Monoxenous trypanosomatids harbor a wide range of RNA viruses belonging to the families Narnaviridae, Totiviridae, Qinviridae, Leishbuviridae, and a putative group of tombus-like viruses. Here, we focus on the subfamily Blastocrithidiinae, a previously unexplored divergent group of monoxenous trypanosomatids comprising two related genera: Obscuromonas and Blastocrithidia. Members of the genus Blastocrithidia employ a unique genetic code, in which all three stop codons are repurposed to encode amino acids, with TAA also used to terminate translation. Obscuromonas isolates studied here bear viruses of three families: Narnaviridae, Qinviridae, and Mitoviridae. The latter viral group is documented in trypanosomatid flagellates for the first time. While other known mitoviruses replicate in the mitochondria, those of trypanosomatids appear to reside in the cytoplasm. Although no RNA viruses were detected in Blastocrithidia spp., we identified an endogenous viral element in the genome of B. triatomae indicating its past encounter(s) with tombus-like viruses.
- Publikační typ
- časopisecké články MeSH
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, escape coronavirus disease 2019 therapeutics and vaccines, and jeopardize public health. To combat SARS-CoV-2 antigenic escape, we developed a rapid, high-throughput pipeline to discover monospecific VHH antibodies and iteratively develop VHH-Fc-VHH bispecifics capable of neutralizing emerging SARS-CoV-2 variants. By panning VHH single-domain phage libraries against ancestral or beta spike proteins, we discovered high-affinity VHH antibodies with unique target epitopes. Combining two VHHs into a tetravalent bispecific construct conferred broad neutralization activity against multiple variants and was more resistant to antigenic escape than the monospecific antibody alone. Following the rise of the Omicron variant, a VHH in the original bispecific construct was replaced with another VHH discovered against the Omicron BA.1 receptor binding domain; the resulting bispecific exhibited neutralization against both BA.1 and BA.5 sublineage variants. A heavy chain-only tetravalent VHH-Fc-VHH bispecific platform derived from humanized synthetic libraries held a myriad of unique advantages: (i) synthetic preconstructed libraries minimized risk of liabilities and maximized discovery speed, (ii) VHH scaffolds allowed for a modular "plug-and-play" format that could be rapidly iterated upon as variants of concern arose, (iii) natural dimerization of single VHH-Fc-VHH polypeptides allowed for straightforward bispecific production and purification methods, and (iv) multivalent approaches enhanced avidity boosting effects and neutralization potency, and conferred more robust resistance to antigenic escape than monovalent approaches against specific variants. This iterative platform of rapid VHH discovery combined with modular bispecific design holds promise for long-term viral control efforts.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Limited real-world evidence exists about the burden of atopic dermatitis (AD) in patients receiving systemic or non-systemic therapies in clinical practices. ESSENTIAL AD was an observational study that aimed to fill this information gap. METHODS: ESSENTIAL AD enrolled (September 2021-June 2022) adult patients with physician-confirmed AD that was routinely managed with systemic and non-systemic treatment in a real-world setting from 15 countries in Eastern Europe, the Middle East, and Africa. Primary outcome variables were Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), and Dermatology Life Quality Index (DLQI) assessed during one office visit. RESULTS: A total of 799 enrolled patients fulfilled selection criteria and were included in the study. Patients mean (standard deviation [SD]) age was 36.3 (14.4) years, 457 (57.2%) were female, and the majority of patients were white (647 [81.0%]). Mean (SD) time since AD diagnosis was 17.6 (15.2) years (median 16.5; interquartile range [IQR] 3.3-26.8). The mean (SD) EASI, SCORAD, and DLQI total scores were 11.3 (11.3 [median 8.1; IQR 3.6-15.8]), 37.8 (17.9 [median 35.5; IQR 24.2-49.0]), and 10.6 (7.2 [median 10.0; IQR 5.0-15.0]), respectively. Patients receiving systemic treatment had significantly higher disease burden (mean [SD] EASI 13.3 [13.0]; median [IQR] 9.6 [3.9-17.9]) versus non-systemic treatment (mean [SD] 9.3 [8.7]; median [IQR] 6.8 [3.0-13.2]; P < 0.0001). Results were similar for SCORAD (39.9 [19.6] vs 35.6 [15.7]; median [IQR] 38.6 [24.7-53.1] vs 32.6 [23.9-44.6]; P = 0.0017), and DLQI total scores (11.4 [7.4] vs 9.9 [6.9]; median [IQR] 11.0 [5.0-16.0] vs 9.0 [5.0-14.0]; P = 0.0033, respectively). CONCLUSION: Patients with AD continue to have substantial disease burden despite treatment with systemic therapy, suggesting that a need for effective disease management remains, including effective therapies that improve psychological outcomes and reduce economic burden of AD, in Eastern Europe, the Middle East, and Africa.
- Publikační typ
- časopisecké články MeSH
The diagnosis of malignant melanoma, often an inconspicuous but highly aggressive tumor, is most commonly done by histological examination, while additional diagnostic methods on the level of elements and molecules are constantly being developed. Several studies confirmed differences in the chemical composition of healthy and tumor tissue. Our study presents the potential of the LIBS (Laser-Induced-Breakdown Spectroscopy) technique as a diagnostic tool in malignant melanoma (MM) based on the quantitative changes in elemental composition in cancerous tissue. Our patient group included 17 samples of various types of malignant melanoma and one sample of healthy skin tissue as a control. To achieve a clear perception of results, we have selected two biogenic elements (calcium and magnesium), which showed a dissimilar distribution in cancerous tissue from its healthy surroundings. Moreover, we observed indications of different concentrations of these elements in different subtypes of malignant melanoma, a hypothesis that requires confirmation in a more extensive sample set. The information provided by the LIBS Imaging method could potentially be helpful not only in the diagnostics of tumor tissue but also be beneficial in broadening the knowledge about the tumor itself.
Triggering receptor expressed on myeloid cells 2 (TREM-2), a glycosylated receptor belonging to the immunoglobin superfamily and especially expressed in the myeloid cell lineage, is frequently explained as a reminiscent receptor for both adaptive and innate immunity regulation. TREM-2 is also acknowledged to influence NK cell differentiation via the PI3K and PLCγ signaling pathways, as well as the partial activation or direct inhibition of T cells. Additionally, TREM-2 overexpression is substantially linked to cell-specific functions, such as enhanced phagocytosis, reduced toll-like receptor (TLR)-mediated inflammatory cytokine production, increased transcription of anti-inflammatory cytokines, and reshaped T cell function. Whereas TREM-2-deficient cells exhibit diminished phagocytic function and enhanced proinflammatory cytokines production, proceeding to inflammatory injuries and an immunosuppressive environment for disease progression. Despite the growing literature supporting TREM-2+ cells in various diseases, such as neurodegenerative disorders and cancer, substantial facets of TREM-2-mediated signaling remain inadequately understood relevant to pathophysiology conditions. In this direction, herein, we have summarized the current knowledge on TREM-2 biology and cell-specific TREM-2 expression, particularly in the modulation of pivotal TREM-2-dependent functions under physiopathological conditions. Furthermore, molecular regulation and generic biological relevance of TREM-2 are also discussed, which might provide an alternative approach for preventing or reducing TREM-2-associated deformities. At last, we discussed the TREM-2 function in supporting an immunosuppressive cancer environment and as a potential drug target for cancer immunotherapy. Hence, summarized knowledge of TREM-2 might provide a window to overcome challenges in clinically effective therapies for TREM-2-induced diseases in humans.
- MeSH
- buňky NK imunologie MeSH
- fagocytóza MeSH
- lidé MeSH
- membránové glykoproteiny * metabolismus genetika MeSH
- nádory imunologie metabolismus genetika MeSH
- přirozená imunita MeSH
- receptory imunologické * metabolismus genetika MeSH
- signální transdukce MeSH
- T-lymfocyty imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses. The compounds suppressed RNA hydrolysis by Cap-ENDOs, with IC50 values predominantly in the lower μM range. Molecular docking studies revealed the interactions with metal ions to be essential for the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold activity. Calorimetric analysis uncovered Mn2+ ions to have the highest affinity for sites within the targets, irrespective of aminoacidic variations influencing metal cofactor preferences. Interestingly, spectrophotometric findings unveiled sole dinuclear species formation between the scaffold and Mn2+. Moreover, the complexation of two Mn2+ ions within the viral enzymes appears to be favourable, as indicated by the binding of compound 11 to TOSV Cap-ENDO (Kd = 28 ± 3 μM). Additionally, the tendency of compound 11 to stabilize His+ more than His- Cap-ENDOs suggests exploitable differences in their catalytic pockets relevant to improving specificity. Collectively, our results underscore the isoindolinone scaffold's potential as a strategic starting point for the design of pan-antibunyavirus drugs.
- MeSH
- antivirové látky farmakologie chemie chemická syntéza MeSH
- Bunyaviridae účinky léků metabolismus MeSH
- endonukleasy * metabolismus antagonisté a inhibitory MeSH
- inhibitory enzymů farmakologie chemie chemická syntéza MeSH
- isoindoly chemická syntéza farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Atherosclerosis is a major cause of ischemic stroke, and early detection of advanced atherosclerosis in the carotid artery is important for reducing morbidity and mortality. What is even more important is not only detection of atherosclerosis but early determination whether the patients are at high risk of an event with adverse effects as the size of the plaque does not necessarily reflect its potential to trigger such events. AIM: We studied whether plasma lipidomics profile can be used as a diagnostic tool for stratification of stable or unstable plaques without the need of removing the carotid plaque. METHODS: This study used liquid chromatography high-resolution tandem mass spectrometry lipidomics to characterize lipid profiles in patients' plasma and found that patients with significant and complicated (vulnerable) atherosclerotic plaque had distinct lipid profiles compared to those with insignificant plaques. RESULTS: The lipid classes that were most predictive of vulnerable plaque were lysophosphoethanolamines, fatty acyl esters of hydroxy fatty acids, free fatty acids, plasmalogens, and triacylglycerols. Most of these compounds were found decreased in plasma of patients with unstable plaques which enabled sufficient performance of a statistical model used for patient stratification. CONCLUSIONS: Plasma lipidomes measured by liquid chromatography-mass spectrometry show differences in patients with stable and unstable carotid plaques, therefore these compounds could potentially be used as biomarkers for unstable plaque in future clinical diagnosis.
- MeSH
- aterosklerotický plát * krev MeSH
- biologické markery * krev MeSH
- chromatografie kapalinová MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipidomika * MeSH
- lipidy * krev MeSH
- nemoci arterie carotis * krev diagnóza MeSH
- prediktivní hodnota testů MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spontánní ruptura MeSH
- studie případů a kontrol MeSH
- tandemová hmotnostní spektrometrie * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
