BACKGROUND: Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. METHODS: In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. RESULTS: A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups. CONCLUSIONS: Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).

• MeSH
• benzamidy * škodlivé účinky   aplikace a dávkování   MeSH
• bicyklické sloučeniny heterocyklické * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   mortalita   MeSH
• cyklofosfamid * aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby * MeSH
• dospělí MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• pyraziny * škodlivé účinky   aplikace a dávkování   MeSH
• rituximab * aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   škodlivé účinky   MeSH
• vidarabin analogy a deriváty   aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• acalabrutinib MeSH Prohlížeč
• benzamidy * MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• cyklofosfamid * MeSH
• fludarabine MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• obinutuzumab MeSH Prohlížeč
• pyraziny * MeSH
• rituximab * MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč
• vidarabin MeSH

BACKGROUND: Anticoagulation during extracorporeal membrane oxygenation (ECMO) might still lead to severe bleeding complications. Heparin is the most frequently used anticoagulant, but novel drugs could be promising. Argatroban is a new alternative to heparin. To date, no robust studies have confirmed the clear superiority of argatroban (AG) over heparin, although it has some advantages and may be safer. STUDY DESIGN AND METHODS: An observational study was conducted in all adult veno-venous ECMO patients with COVID-19-associated acute respiratory distress syndrome admitted to the University Hospital Ostrava (n = 63). They were anticoagulated with heparin in the first period and with AG in the second period, targeting the same activated partial thromboplastin time (aPTT; 45-60 s). Bleeding complications requiring transfusion and life-threatening bleeding events were evaluated. The primary objective was to compare heparin and AG in terms of bleeding, transfusion requirements and mortality-related bleeding. RESULTS: The total time on ECMO per patient was 16 days with an in-hospital mortality of 55.6%. The red blood cell consumption in the AG group (median 2.7 transfusions/week) was significantly lower than in the heparin group (median 4.2 transfusions/week, p = 0.011). Life-threatening bleeding complications were higher in the heparin group compared to the AG group (35.7% vs. 10.2%, p = 0.035), and mortality-related bleeding complications were also higher in the heparin group (21.4% vs. 2.0%, p = 0.032). DISCUSSION: Argatroban is an interesting alternative to heparin with less bleeding, less need for red blood cell transfusions and improved safety of ECMO with less mortality-related bleeding.

• Klíčová slova
• anticoagulation, argatroban, bleeding, extracorporeal membrane oxygenation (ECMO), heparin,
• MeSH
• antikoagulancia * škodlivé účinky   terapeutické užití   MeSH
• arginin * analogy a deriváty   MeSH
• COVID-19 komplikace   MeSH
• dospělí MeSH
• heparin * škodlivé účinky   MeSH
• krvácení * chemicky indukované   terapie   MeSH
• kyseliny pipekolové * terapeutické užití   aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mimotělní membránová oxygenace * MeSH
• mortalita v nemocnicích MeSH
• SARS-CoV-2 MeSH
• senioři MeSH
• sulfonamidy * MeSH
• syndrom dechové tísně terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antikoagulancia * MeSH
• argatroban MeSH Prohlížeč
• arginin * MeSH
• heparin * MeSH
• kyseliny pipekolové * MeSH
• sulfonamidy * MeSH

OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

• Klíčová slova
• Fontan procedure, congenital, endothelin receptor antagonist, exercise test, heart defects, open label,
• MeSH
• antagonisté endotelinového receptoru terapeutické užití   škodlivé účinky   MeSH
• časové faktory MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• Fontanova operace * škodlivé účinky   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• paliativní péče MeSH
• prospektivní studie MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   MeSH
• spotřeba kyslíku účinky léků   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   MeSH
• tolerance zátěže účinky léků   MeSH
• vrozené srdeční vady chirurgie   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny * MeSH
• sulfonamidy * MeSH

BACKGROUND: The combination of ibrutinib and venetoclax leverages complementary mechanisms of action and has shown promising clinical activity in mantle cell lymphoma (MCL). This study evaluated the efficacy and safety of ibrutinib-venetoclax compared with ibrutinib-placebo in patients with relapsed or refractory MCL. METHODS: SYMPATICO is a multicentre, randomised, double-blind, placebo-controlled, phase 3 study performed at 84 hospitals in Europe, North America, and Asia-Pacific. Eligible patients were adults (aged ≥18 years) with pathologically confirmed relapsed or refractory MCL after one to five previous lines of therapy and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were randomly assigned (1:1) to receive oral ibrutinib 560 mg once daily concurrently with oral venetoclax (5-week ramp-up to 400 mg once daily) or placebo for 2 years, then single-agent ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Randomisation and treatment assignment occurred via interactive response technology using a stratified permuted block scheme (block sizes of 2 and 4) with stratification by ECOG performance status, previous lines of therapy, and tumour lysis syndrome risk category. Patients and investigators were masked to treatment assignment. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03112174, and is closed to enrolment. FINDINGS: Between April 26, 2018, and Aug 28, 2019, 267 patients were enrolled and randomly assigned; 134 to the ibrutinib-venetoclax group and 133 to the ibrutinib-placebo group. 211 (79%) of 267 patients were male and 56 (21%) were female. With a median follow-up of 51·2 months (IQR 48·2-55·3), median progression-free survival was 31·9 months (95% CI 22·8-47·0) in the ibrutinib-venetoclax group and 22·1 months (16·5-29·5) in the ibrutinib-placebo group (hazard ratio 0·65 [95% CI 0·47-0·88]; p=0·0052). The most common grade 3-4 adverse events were neutropenia (42 [31%] of 134 patients in the ibrutinib-venetoclax group vs 14 [11%] of 132 patients in the ibrutinib-placebo group), thrombocytopenia (17 [13%] vs ten [8%]), and pneumonia (16 [12%] vs 14 [11%]). Serious adverse events occurred in 81 (60%) of 134 patients in the ibrutinib-venetoclax group and in 79 (60%) of 132 patients in the ibrutinib-placebo group. Treatment-related deaths occurred in three (2%) of 134 patients in the ibrutinib-venetoclax group (n=1 COVID-19 infection, n=1 cardiac arrest, and n=1 respiratory failure) and in two (2%) of 132 patients in the ibrutinib-placebo group (n=1 cardiac failure and n=1 COVID-19-related pneumonia). INTERPRETATION: The combination of ibrutinib-venetoclax significantly improved progression-free survival compared with ibrutinib-placebo in patients with relapsed or refractory MCL. The safety profile was consistent with known safety profiles of the individual drugs. These findings suggest a positive benefit-risk profile for ibrutinib-venetoclax treatment. FUNDING: Pharmacyclics (an AbbVie Company) and Janssen Research and Development.

• MeSH
• adenin * analogy a deriváty   MeSH
• bicyklické sloučeniny heterocyklické * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   patologie   MeSH
• lymfom z plášťových buněk * farmakoterapie   patologie   mortalita   MeSH
• piperidiny * aplikace a dávkování   MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sulfonamidy * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• adenin * MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• ibrutinib MeSH Prohlížeč
• piperidiny * MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč

INTRODUCTION: Alopecia areata is a common autoimmune disease which results in reversible hair loss. Janus kinase inhibitors are prescribed for severe alopecia areata with encouraging results. There are no studies comparing the efficacy and safety of Janus kinase inhibitors to traditional treatment options, such as topical immunomodulators and traditional immunosuppressants. AIMS: To retrospectively compare the efficacy and safety of baricitinib, an approved Janus kinase inhibitor, to other treatments for severe AA during a 6-month treatment period. MATERIALS/METHODS: We included patients with newly presenting, relapsing or treatment-resistant alopecia areata with Severity of Alopecia Tool (SALT) score ≥ 50, for the period between July 2021 and July 2023. Medical histories were reviewed and possible side effects were recorded. Primary endpoints were SALT ≤ 20 and SALT ≤ 10 after 6 months of treatment. RESULTS: Seventy-five patients (53 females) were divided into three groups: topical immunomodulators (51 patients); baricitinib (19 patients); and a group receiving pulsed intramuscular corticosteroids or traditional immunosuppressants (11 patients). Twenty-one patients received more than one treatment options within 2 years. After 6 months, the baricitinib group showed superior efficacy with 32% and 26% of patients achieving SALT ≤ 20 and SALT ≤ 10, compared to 12% and 9% in both other groups. Baricitinib demonstrated better secondary outcomes (50% and 90% reduction from initial SALT scores). All treatments exhibited mild-to-moderate and expected side effects. Weight gain, which had not been reported in clinical trials for alopecia areata, was observed in three baricitinib-treated patients. CONCLUSION: Baricitinib was superior to traditional treatments for severe alopecia areata after 6 months. Weight gain concerned 16% of patients receiving baricitinib.

• Klíčová slova
• JAK inhibitors, alopecia areata, baricitinib, baricitinib efficacy, baricitinib safety,
• MeSH
• alopecia areata * farmakoterapie   MeSH
• azetidiny * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• dospělí MeSH
• hormony kůry nadledvin terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• imunologické faktory aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• imunosupresiva * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• inhibitory Janus kinas * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• puriny * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• pyrazoly * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• retrospektivní studie MeSH
• stupeň závažnosti nemoci * MeSH
• sulfonamidy * škodlivé účinky   aplikace a dávkování   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• azetidiny * MeSH
• baricitinib MeSH Prohlížeč
• hormony kůry nadledvin MeSH
• imunologické faktory MeSH
• imunosupresiva * MeSH
• inhibitory Janus kinas * MeSH
• puriny * MeSH
• pyrazoly * MeSH
• sulfonamidy * MeSH

OBJECTIVE: Ischemic complications account for significant patient morbidity following aneurysmal subarachnoid hemorrhage (aSAH). The Prevention and Treatment of Vasospasm with Clazosentan (REACT) study was designed to assess the safety and efficacy of clazosentan, an endothelin receptor antagonist, in preventing clinical deterioration due to delayed cerebral ischemia (DCI) in patients with aSAH. METHODS: REACT was a prospective, multicenter, randomized, double-blind, phase 3 study. Eligible patients had aSAH secured by surgical clipping or endovascular coiling, and had presented with thick and diffuse clot on admission CT scan. Patients were randomized (1:1 ratio) to 15 mg/hour intravenous clazosentan or placebo within 96 hours of the aSAH for up to 14 days, in addition to standard of care treatment including oral or intravenous nimodipine. The primary efficacy endpoint was the occurrence of clinical deterioration due to DCI up to 14 days after initiation of the study drug. The main secondary endpoint was the occurrence of clinically relevant cerebral infarction at day 16 after study drug initiation. Other secondary endpoints included clinical outcome assessed on the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) at week 12 post-aSAH. Imaging and clinical endpoints were centrally adjudicated. RESULTS: A total of 409 patients were randomized between February 2019 and May 2022 across 74 international sites. Three patients did not start study treatment and were not included in the analysis set. The occurrence of clinical deterioration due to DCI was 15.8% (32/202 patients) in the clazosentan group and 17.2% (35/204 patients) in the placebo group, and the difference was not statistically significant (relative risk reduction [RRR] 7.2%, 95% CI -42.6% to 39.6%, p = 0.734). A nonsignificant RRR of 34.1% (95% CI -21.3% to 64.2%, p = 0.177) was observed in clinically relevant cerebral infarcts treated with clazosentan (7.4%, 15/202) versus placebo (11.3%, 23/204). Rescue therapy was less frequently needed for patients treated with clazosentan compared to placebo (10.4%, 21/202 vs 18.1%, 37/204; RRR 42.6%, 95% CI 5.4%-65.2%). A nonsignificant relative risk increase of 25.4% (95% CI -10.7% to 76.0%, p = 0.198) was reported in the risk of poor GOSE and mRS scores with clazosentan (24.8%, 50/202) versus placebo (20.1%, 41/204) at week 12 post-aSAH. Treatment-emergent adverse events were similar to those reported previously. CONCLUSIONS: Clazosentan administered for up to 14 days at 15 mg/hour had no significant effect on the occurrence of clinical deterioration due to DCI. Clinical trial registration no.: NCT03585270 (ClinicalTrials.gov) EU clinical trial registration no.: 2018-000241-39 (clinicaltrialsregister.eu).

• Klíčová slova
• aneurysm, cerebral ischemia, cerebral vasospasm, clazosentan, endothelin-1, subarachnoid hemorrhage, vascular disorders,
• MeSH
• dioxany * terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• intrakraniální vazospazmus etiologie   prevence a kontrola   farmakoterapie   diagnostické zobrazování   MeSH
• ischemie mozku * prevence a kontrola   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• pyridiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři MeSH
• subarachnoidální krvácení * komplikace   diagnostické zobrazování   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• tetrazoly * terapeutické užití   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• clazosentan MeSH Prohlížeč
• dioxany * MeSH
• pyridiny * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tetrazoly * MeSH

BACKGROUND: Celosia argentea is a widely recognized plant for its ornamental qualities and therapeutic uses in traditional medicine. As demand for such multipurpose plants grows, enhancing its phenotypic and physiological traits could further expand its commercial potential. Polyploidization, particularly through chemical treatments like oryzalin, offers a method to induce genetic variation and potentially improve desirable traits in plants. RESULTS: Tetraploid (2n = 4×= 36) nodal segments of C. argentea were treated with oryzalin under in vitro conditions, resulting in successful induction of octoploidy (2n = 8×= 72). Flow cytometry and chromosome counting confirmed polyploidization, with the highest induction rate achieved using 40 µM oryzalin for 24 h. Comparative analyses between octoploid and tetraploid plants revealed significant differences in morphological traits, including increased stem and leaf thickness, larger leaf area, inflorescence characteristics and more compact growth in the octoploids. Additionally, octoploids exhibited enhanced chlorophyll content and altered photosynthetic characteristics, along with notable changes in stomatal size and density. Ploidy stability was maintained across generations, ensuring the heritability of the induced traits. CONCLUSIONS: In vitro polyploidization in C. argentea led to significant phenotypic and physiological improvements, demonstrating its potential for application in ornamental horticulture and plant breeding. This research contributes to the understanding of the impact of in vitro polyploidization on plant development, offering insights for the commercial cultivation and enhancement of C. argentea. CLINICAL TRIAL NUMBER: Not applicable.

• Klíčová slova
• Chromosome doubling, Cockscomb, Crop improvement, Offspring stability, Oryzalin, Polyploid induction, Polyploidization,
• MeSH
• Celosia * genetika   MeSH
• chlorofyl metabolismus   MeSH
• dinitrobenzeny farmakologie   MeSH
• fenotyp MeSH
• fotosyntéza * MeSH
• listy rostlin genetika   růst a vývoj   fyziologie   MeSH
• polyploidie * MeSH
• sulfanilamidy MeSH
• tetraploidie * MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• chlorofyl MeSH
• dinitrobenzeny MeSH
• oryzalin MeSH Prohlížeč
• sulfanilamidy MeSH

The presence of pharmaceuticals in nature systems poses a threat to the environment, plants, animals, and, last but not least, human health. Their transport in soils, waters, and sediments plays important roles in the toxicity and bioavailability of pharmaceuticals. The mobility of pharmaceuticals can be affected by their interactions with organic matter and other soil and water constituents. In this study, a model agarose hydrogel enriched by humic acid as a representative of organic matter is used as a transport medium for pharmaceuticals. Sulphapyridine (as a representative of sulphonamide antibiotics) and diclofenac (as a representative of widely used non-steroidal anti-inflammatory drugs) were chosen for experiments in diffusion cells. Pharmaceuticals were passed through the hydrogel from the donor solution to the acceptor compartment and could interact with humic acids incorporated in the hydrogel. The lag time was prolonged if the hydrogel was enriched by humic acids from 134 to 390 s for sulphapyridine and from 323 to 606 s for diclofenac. Similarly, the incorporation of humic acids in the hydrogel resulted in a decrease in the determined diffusion coefficients. The decrease was stronger in the first stage of the experiment when diffusing particles could interact with vacant binding sites.

• Klíčová slova
• diclofenac, humic acid, hydrogel, sulphapyridine, transport,
• MeSH
• difuze MeSH
• diklofenak * chemie   MeSH
• huminové látky * analýza   MeSH
• hydrogely * chemie   MeSH
• léčivé přípravky chemie   MeSH
• sefarosa * chemie   MeSH
• sulfapyridin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• diklofenak * MeSH
• huminové látky * MeSH
• hydrogely * MeSH
• léčivé přípravky MeSH
• sefarosa * MeSH
• sulfapyridin MeSH

The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.

• MeSH
• apoptóza účinky léků   MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   patologie   MeSH
• fosfohydroláza PTEN metabolismus   MeSH
• lidé MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protokoly antitumorózní kombinované chemoterapie * farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 * antagonisté a inhibitory   metabolismus   MeSH
• pyrimidiny * farmakologie   terapeutické užití   MeSH
• pyrroly farmakologie   terapeutické užití   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• xenogenní modely - testy antitumorózní aktivity * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• BCL2 protein, human MeSH Prohlížeč
• bicyklické sloučeniny heterocyklické * MeSH
• capivasertib MeSH Prohlížeč
• fosfohydroláza PTEN MeSH
• protoonkogenní proteiny c-akt * MeSH
• protoonkogenní proteiny c-bcl-2 * MeSH
• pyrimidiny * MeSH
• pyrroly MeSH
• rituximab MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč

The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel N-(heterocyclylphenyl)benzenesulfonamides 6-28. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 cancer cell proliferation. Compound 25 showed binding mode consistent with this hotspot binding region. Compound 25 inhibited the growth of SW480 and HCT116 cancer cells with IC50's of 2 and 0.12 μM, respectively, and was superior to the reference compounds 5 and 5-FU. 25 inhibited the growth of HCT-116 xenografted in BALB/Cnu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, 25 showed a higher metabolic stability than 5. Compound 25 aims to be a promising lead for the development of colorectal cancer anticancer therapies.

• MeSH
• antitumorózní látky * farmakologie   chemická syntéza   chemie   MeSH
• beta-katenin * metabolismus   antagonisté a inhibitory   MeSH
• HCT116 buňky MeSH
• jaterní mikrozomy metabolismus   MeSH
• lidé MeSH
• myši inbrední BALB C * MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• sulfonamidy * farmakologie   chemie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky * MeSH
• beta-katenin * MeSH
• sulfonamidy * MeSH