Lenvatinib plus pembrolizumab significantly improved efficacy versus sunitinib in treatment of advanced renal cell carcinoma (aRCC) in the phase 3 CLEAR study. We report results of an exploratory post hoc analysis of tumor response data based on baseline metastatic characteristics of patients who received lenvatinib plus pembrolizumab versus sunitinib, at the final overall survival analysis time point of CLEAR (cutoff: July 31, 2022). Treatment-naïve adults with aRCC were randomized to: lenvatinib (20 mg PO QD in 21-day cycles) plus pembrolizumab (n = 355; 200 mg IV Q3W); lenvatinib plus everolimus (not reported here); or sunitinib (n = 357; 50 mg PO QD; 4 weeks on/2 weeks off). The most common (lenvatinib plus pembrolizumab; sunitinib, respectively) metastatic site was lung (71.0%; 63.9%), followed by lymph node (45.6%; 43.7%), bone (22.5%; 24.9%), and liver (17.7%; 19.6%). Across treatment arms, ≥65% had two or more metastatic organs/sites involved, >80% of patients had nontarget lesions, and ~45% had baseline sums of diameters of target lesions ≥60 mm. Lenvatinib plus pembrolizumab demonstrated greater progression-free survival, objective response rate, and duration of response versus sunitinib across evaluable subgroups regardless of site or size of baseline metastasis or number of metastatic sites at baseline. Overall survival generally trended to favor lenvatinib plus pembrolizumab versus sunitinib; and tumor shrinkage was greater across sites (lung, lymph node, liver, and bone) for patients in the lenvatinib-plus-pembrolizumab arm versus the sunitinib arm. These results further support lenvatinib plus pembrolizumab as a standard-of-care in patients with aRCC regardless of site or size of baseline metastasis or the number of metastatic sites.

• MeSH
• chinoliny * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• fenylmočovinové sloučeniny * aplikace a dávkování   terapeutické užití   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   terapeutické užití   MeSH
• karcinom z renálních buněk * farmakoterapie   patologie   mortalita   sekundární   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory ledvin * farmakoterapie   patologie   mortalita   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sunitinib * aplikace a dávkování   terapeutické užití   MeSH
• výsledek terapie 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

Chronic intestinal inflammation significantly contributes to the development of colorectal cancer and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics Felix Kopp Kortagere 6 (FKK6), which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane and DSS. FKK6 (2 mg/kg) displayed substantial antitumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, and cyclin D) in the colon. In addition, we carried out a chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6 in vitro. In conclusion, anticancer effects of FKK6 in azoxymethane/DSS-induced CAC, together with FKK6 safety data from in vitro tests and in vivo chronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC. SIGNIFICANCE STATEMENT: Microbial metabolite mimicry proposes that chemical mimics of microbial metabolites that serve to protect hosts against aberrant inflammation in the gut could serve as a new paradigm for the development of drugs targeting inflammatory bowel disease if, like the parent metabolite, is devoid of toxicity but more potent against the microbial metabolite receptor. We identified a chemical mimic of Felix Kopp Kortagere 6, and we propose that Felix Kopp Kortagere 6 is devoid of toxicity yet significantly reduces tumor formation in an azoxymethane-dextran sodium sulfate model of murine colitis-induced colon cancer.

• MeSH
• azoxymethan toxicita   MeSH
• chronická nemoc MeSH
• indoly farmakologie   terapeutické užití   MeSH
• kolitida farmakoterapie   chemicky indukované   metabolismus   patologie   MeSH
• kolorektální nádory * farmakoterapie   metabolismus   patologie   MeSH
• modely nemocí na zvířatech * MeSH
• molekulární mimikry MeSH
• myši inbrední C57BL * MeSH
• myši MeSH
• nádory asociované s kolitidou patologie   farmakoterapie   metabolismus   MeSH
• síran dextranu toxicita   MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Developing bioinspired materials to convert sunlight into electricity efficiently is paramount for sustainable energy production. Fluorescent proteins are promising candidates as photoactive materials due to their high fluorescence quantum yield and absorption extinction coefficients in aqueous media. However, developing artificial bioinspired photosynthetic systems requires a detailed understanding of molecular interactions and energy transfer mechanisms in the required operating conditions. Here, the supramolecular self-assembly and photophysical properties of fluorescent proteins complexed with organic dyes are investigated in aqueous media. Supercharged mGreenLantern protein, mutated to have a charge of +22, is complexed together with anionic zinc phthalocyanines having 4 or 16 carboxylate groups. The structural characterization reveals a strong electrostatic interaction between the moieties, accompanied by partial conformational distortion of the protein structure, yet without compromising the mGreenLantern chromophore integrity as suggested by the lack of emission features related to the neutral form of the chromophore. The self-assembled biohybrid shows a total quenching of protein fluorescence, in favor of an energy transfer process from the protein to the phthalocyanine, as demonstrated by fluorescence lifetime and ultrafast transient absorption measurements. These results provide insight into the rich photophysics of fluorescent protein-dye complexes, anticipating their applicability as water-based photoactive materials.

• MeSH
• anionty chemie   MeSH
• fluorescenční barviva chemie   MeSH
• fluorescenční spektrometrie MeSH
• indoly * chemie   metabolismus   MeSH
• isoindoly MeSH
• luminescentní proteiny * chemie   metabolismus   MeSH
• organokovové sloučeniny * chemie   metabolismus   MeSH
• přenos energie MeSH
• sloučeniny zinku MeSH
• Publikační typ
• časopisecké články MeSH

The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.

• MeSH
• aktivátory chloridových kanálů terapeutické užití   farmakologie   MeSH
• aminofenoly * terapeutické užití   farmakologie   MeSH
• benzodioxoly * terapeutické užití   farmakologie   MeSH
• chinolony * farmakologie   terapeutické užití   MeSH
• cystická fibróza * genetika   farmakoterapie   MeSH
• fixní kombinace léků MeSH
• indoly * farmakologie   MeSH
• lidé MeSH
• organoidy * metabolismus   MeSH
• protein CFTR genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyridiny farmakologie   MeSH
• pyrrolidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva účinky léků   MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Biopriming seeds with beneficial bacteria has potential to enhance seed germination. Therefore, in this investigation, five sulphur-oxidizing bacterial cultures, viz., Pantoea dispersa SOB2, Bacillus velezensis SN06, Bacillus cereus SN20, Bacillus tropicus SN16, and Bacillus megaterium SN11, were evaluated for different plant growth-promoting traits and their impact on Vigna radiata L. (mung bean) and Brassica juncea L. (mustard) seed germination. Among these, three bacterial cultures Pantoea dispersa SOB2, Bacillus velezensis SN06, and Bacillus megaterium SN11 evinced potential for mineral solubilization on solid medium where Pantoea dispersa SOB2 had the maximum solubilization indices-3.06, 5.14, and 2.48 for phosphate, zinc, and potassium respectively. The culture also displayed higher indole acetic acid (113.12 μg/mL), gibberellic acid (162.66 μg/mL), ammonia (5.23 μg/mL), and siderophore (69.53%) production than other bacterial cultures whereas Bacillus cereus SN20 showed maximum exopolysaccharide production (9.26 g/L). Bacterial culture Pantoea dispersa SOB2 significantly ameliorated the germination rate (3.73 no./day) and relative seed germination (208%) of Brassica juncea L., while Bacillus velezensis SN06 and Bacillus cereus SN20 followed with germination rate and relative seed germination of 2.86 no./day and 207%, respectively. Pantoea dispersa SOB2 displayed lowest mean germination time 2.91 days followed by Bacillus megaterium SN11 with 3.19 days. Biopriming with sulphur-oxidizing bacterial cultures, germination parameters of Vigna radiata L. were also markedly improved. Pantoea dispersa SOB2 demonstrated the highest germination rate (6.72 no./day), relative seed germination (115.56%), and minimum mean generation time (1.73 days). Bacillus velezensis SN06 inoculation had a beneficial effect on the seedling growth of Vigna radiata L., whereas Pantoea dispersa SOB2 greatly aided the seedling growth of Brassica juncea L. Results corroborated a prominent positive correlation between seed germination and plant growth-promoting traits. This is the first study on Pantoea dispersa as sulphur oxidizer, displaying plant growth promoting traits and seed germination potential. The potent sulphur-oxidizing bacterial cultures possessing plant growth promoting activities enhanced seed germination under in vitro conditions that could be further explored in field as biofertilizers to enhance the growth and yield of Brassica juncea L. and Vigna radiata L. crop.

• MeSH
• Bacillus * metabolismus   MeSH
• Bacteria * metabolismus   MeSH
• hořčice rodu Brassica * růst a vývoj   mikrobiologie   MeSH
• klíčení * MeSH
• kyseliny indoloctové metabolismus   MeSH
• oxidace-redukce MeSH
• Pantoea metabolismus   MeSH
• regulátory růstu rostlin metabolismus   MeSH
• semena rostlinná * mikrobiologie   růst a vývoj   MeSH
• síra * metabolismus   MeSH
• vigna * růst a vývoj   mikrobiologie   MeSH
• Publikační typ
• časopisecké články MeSH

Hyponatremia is a crucial complication of therapy with thiazide diuretics. This study compares the epidemiological and biochemical profiles and hospital course of patients using hydrochlorothiazide (HCTZ), indapamide (INDA), and chlorthalidone (CTD) admitted with thiazide-associated hyponatremia (TAH). Data were obtained retrospectively from the hospital's digital registries. The epidemiological and biochemical parameters between the HCTZ, INDA, and CTD groups were compared. The correlation between dose and biochemical parameters in each group was performed. The thiazide groups without diuretic co-medication were compared (HCTZ vs. INDA), and the correlation between dose and biochemical parameters in each group was examined. A comparison of the HCTZ (n = 135), INDA (n = 125), and CTD (n = 27) groups identified differences in serum potassium (s-K; p = 0.03). The hyponatremia correction rate was slower in the CTD group at 96 h after admission (p < 0.001). After the exclusion of diuretic co-medication, the HCTZ group (n = 64/135) showed a higher prevalence of ARBs, s-K (both p < 0.001), and a lower median (IQR) equipotent dose (12.5 (o) mg vs. 2.5 (1.2) mg), prevalence of ACE-I (p < 0.001), and eGFR (p = 0.03), when compared to the INDA group (n = 109/125). In conclusion, except for s-K, we observed no significant difference in biochemical and epidemiological profiles between HCTZ, INDA, and CTD. After excluding the influence of other diuretics, we observed higher s-K in the HCTZ group compared to the INDA group, potentially explained by the lower equipotent dose of HCTZ. The CTD group showed a statistically significant trend of slower hyponatremia correction.

• MeSH
• antihypertenziva škodlivé účinky   MeSH
• chlorthalidon * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• diuretika škodlivé účinky   MeSH
• draslík krev   MeSH
• hydrochlorthiazid * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• hypertenze * farmakoterapie   MeSH
• hyponatremie * chemicky indukované   epidemiologie   krev   MeSH
• indapamid * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• inhibitory symportérů pro chlorid sodný škodlivé účinky   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři 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

The study focuses on the effects of fluvastatin on immunomarkers of the M1 and M2 macrophages and its direct role in macrophage (M0) polarization. Moreover, it investigates the dependency of immunomodulatory properties of fluvastatin on the mevalonate pathway. Macrophages (M0, M1, M2), differentiated from human blood monocytes, were treated with fluvastatin. Mevalonate and geranylgeranyl pyrophosphate intermediates were introduced to assess the mevalonate pathway dependence. The immunomarkers were evaluated with qPCR, ELISA, Griess assay, and flow cytometry. Fluvastatin significantly reduces the pro-inflammatory gene expression (NFκB, IL-1β, IL-6, iNOS) in M1 while enhancing the anti-inflammatory markers (Arg-1, TGFβ) in M2 macrophages. The production of the TNFα, IL-1β, and IL-6 cytokines is reduced in M1, and IL-10 production increased in M2 macrophages. Fluvastatin decreases the iNOS activity in M1 macrophages. The intermediates reverse the fluvastatin's effects on anti-inflammatory gene expression by M2 macrophages, cytokine production (by M1 and M2 macrophages), and iNOS activity (by M1 macrophages). Their impact on surface marker expression was somewhat limited. These findings demonstrate that fluvastatin exerts anti-inflammatory effects on polarized macrophages without affecting polarization per se and also highlight the dependency on the mevalonate pathway. This study deepens the understanding of statins' immunomodulatory mechanisms, suggesting potential applications in treating inflammatory diseases.

• MeSH
• antiflogistika * farmakologie   MeSH
• cytokiny metabolismus   MeSH
• fluvastatin * farmakologie   MeSH
• kyselina mevalonová * metabolismus   MeSH
• lidé MeSH
• makrofágy * účinky léků   metabolismus   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

x

x

• MeSH
• antifibrotické látky škodlivé účinky   terapeutické užití   MeSH
• idiopatická plicní fibróza * farmakoterapie   MeSH
• indoly * škodlivé účinky   terapeutické užití   MeSH
• inhibitory tyrosinkinasy škodlivé účinky   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nežádoucí účinky léčiv diagnóza   terapie   MeSH
• Check Tag
• lidé MeSH

Kombinace sumatriptanu s naproxenem sodným v jedné kombinované tabletě (Frimig Duo) přináší relativně novou možnost pro akutní léčbu migrény, zejména u jedinců s nedostatečným efektem krátce působících triptanů. V textu jsou uvedeny teoretické patofyziologické a farmakologické informace s implementací do klinické praxe.

The combination of sumatriptan with sodium naproxen in a single tablet (Frimig Duo) offers a relatively new option for the acute treatment of migraine, particularly in individuals with insufficient efficacy from short-acting triptans. The text presented provides theoretical pathophysiological and pharmacological information with implementation into clinical practice.

• MeSH
• agonisté serotoninového receptoru 5-HT1 MeSH
• antiflogistika nesteroidní MeSH
• fixní kombinace léků MeSH
• hodnocení léčiv MeSH
• lidé MeSH
• migréna * farmakoterapie   patofyziologie   MeSH
• naproxen * farmakokinetika   farmakologie   terapeutické užití   MeSH
• sumatriptan * farmakokinetika   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Etrasimod, nový perorální modulátor sfingosin-1-fosfátových receptorů (S1P), byl schválen pro léčbu středně těžké až těžké ulcerózní kolitidy. Selektivně ovlivňuje receptory S1P1, S1P4 a S1P5, snižuje migraci lymfocytů a zánět ve střevě. Ve studiích prokázal vysokou účinnost, s klinickou remisí u 32 % pacientů v týdnu 52 a s rychlým nástupem účinku. Bezpečnostní profil je příznivý s nízkým výskytem závažných nežádoucích účinků. Etrasimod nabízí novou terapeutickou možnost pro pacienty s nedostatečnou odpovědí na konvenční nebo biologickou léčbu.

Etrasimod, a novel oral modulator of sphingosine-1-phosphate (S1P) receptors, has been approved for the treatment of moderate to severe ulcerative colitis. It selectively targets S1P1, S1P4, and S1P5 receptors, reducing lymphocyte migration and intestinal inflammation. Clinical studies demonstrated high efficacy, with clinical remission achieved in 32% of patients in week 52, and a rapid onset of action. The safety profile is favorable, with a low incidence of serious adverse events. Etrasimod offers a new therapeutic option for patients with inadequate response to conventional or biologic treatments.

• Klíčová slova
• etrasimod,
• MeSH
• acetáty farmakologie   terapeutické užití   MeSH
• indoly farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• ulcerózní kolitida * farmakoterapie   MeSH
• Check Tag
• lidé MeSH