PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

• MeSH
• akrylamidy * MeSH
• aniliny terapeutické užití   MeSH
• erbB receptory genetika   MeSH
• indoly * MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• nádory centrálního nervového systému * diagnostické zobrazování   farmakoterapie   genetika   MeSH
• nádory plic * farmakoterapie   genetika   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   genetika   patologie   MeSH
• pemetrexed terapeutické užití   MeSH
• platina terapeutické užití   MeSH
• pyrimidiny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• akrylamidy * MeSH
• aniliny MeSH
• erbB receptory MeSH
• indoly * MeSH
• inhibitory proteinkinas MeSH
• osimertinib MeSH Prohlížeč
• pemetrexed MeSH
• platina MeSH
• pyrimidiny * MeSH

PURPOSE: The aim of our study was to evaluate if therapeutic success in the first-line of anticancer treatments in patients with NSCLC may predict treatment success in the following lines. METHODS: We analyzed the data of patients with NSCLC stage III/IV from the TULUNG registry separately for chemotherapy, TKIs, ALK inhibitors, and immunotherapy in the first line during the years 2011-2019. "Succesful treatment " was defined as PFS ≥ 6 months, a "good responder " was a patient with ˃50% of "successful treatment " lines. Treatment responses were analyzed separately for each drug group. Descriptive statistics, Fisher exact test, Pearson Chi-Squared test, log-rank test, and univariate/multivariate logistic regression models were used. RESULTS: The first-line TKI therapy was successful in 66.2%, while good responders accounted for 50.7% of the cohort and their rates were similar for all types of TKIs. First-line platinum-based chemotherapy was successful in 43.1% and 48.6% for combinations with pemetrexed and bevacizumab, respectively. Good responders accounted for 29.5% and 25.9%, respectively. In the group of ALK inhibitors, we observed treatment success in 52.3% of cases, while alectinib showed the highest effectiveness (up to 70%). Good responders constituted 50% of the group. In the first-line immunotherapy group, survival benefit was observed in 52.3%, and good responders constituted 52.3% of the cohort. CONCLUSION: We concluded that the treatment success in first-line therapies in patients with NSCLC may predict survival benefits in the subsequent lines, particularly in EGFR- or ALK-positive disease and immunotherapy-treated patients.

• Klíčová slova
• Anticancer treatment, Effectiveness, Non-small cell lung cancer, Overall survival, Progression-free survival,
• MeSH
• bevacizumab terapeutické užití   MeSH
• erbB receptory MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory plic * MeSH
• nemalobuněčný karcinom plic * MeSH
• pemetrexed terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bevacizumab MeSH
• erbB receptory MeSH
• inhibitory proteinkinas MeSH
• pemetrexed MeSH

There is only limited data on cytomegalovirus (CMV) prophylaxis with high-dose (HD) aciclovir after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We performed a retrospective analysis on a total of 179 patients who underwent their allo-HSCT with HD-aciclovir prophylaxis at our center. A clinically significant CMV infection (cs-CMVi) was observed in 56 (31%) cases with a median time of 49 (range 25-147) days after HSCT. A significantly higher CMV infection rate was observed in seropositive recipients with a seronegative donor (74%) compared to seropositive recipients with a seropositive donor, and seronegative recipients with seropositive and seronegative donors (24%, 18%, 7% respectively; p < 0.001). The CMV serostatus was the only significant risk factor for CMV infection in our analysis. CMV disease developed in three patients with CMV-related death in two cases. During HD-aciclovir prophylaxis, we did not observe any medical condition attributable to HD-aciclovir's adverse effects. Compared to published results, we observed a low incidence of cs-CMVi with HD-aciclovir prophylaxis in several patient subgroups, especially in seropositive recipients with a seropositive donor. With respect to the determined threshold, HD-aciclovir prophylaxis seems to have good efficacy in an intermediate cs-CMVi risk patients, but prospective randomized trials would be needed for definite conclusions.

• MeSH
• acyklovir terapeutické užití   MeSH
• antivirové látky terapeutické užití   MeSH
• cytomegalovirové infekce * etiologie   prevence a kontrola   farmakoterapie   MeSH
• Cytomegalovirus MeSH
• lidé MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acyklovir MeSH
• antivirové látky MeSH

Guanine quadruplexes (GQs) are non-canonical nucleic acid structures involved in many biological processes. GQs formed in single-stranded regions often need to be unwound by cellular machinery, so their mechanochemical properties are important. Here, we performed steered molecular dynamics simulations of human telomeric GQs to study their unfolding. We examined four pulling regimes, including a very slow setup with pulling velocity and force load accessible to high-speed atomic force microscopy. We identified multiple factors affecting the unfolding mechanism, i.e.,: (i) the more the direction of force was perpendicular to the GQ channel axis (determined by GQ topology), the more the base unzipping mechanism happened, (ii) the more parallel the direction of force was, GQ opening and cross-like GQs were more likely to occur, (iii) strand slippage mechanism was possible for GQs with an all-anti pattern in a strand, and (iv) slower pulling velocity led to richer structural dynamics with sampling of more intermediates and partial refolding events. We also identified that a GQ may eventually unfold after a force drop under forces smaller than those that the GQ withstood before the drop. Finally, we found out that different unfolding intermediates could have very similar chain end-to-end distances, which reveals some limitations of structural interpretations of single-molecule spectroscopic data.

• MeSH
• G-kvadruplexy * MeSH
• guanin * chemie   MeSH
• lidé MeSH
• mechanické jevy MeSH
• simulace molekulární dynamiky MeSH
• telomery MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• guanin * MeSH

Guanine-quadruplex structures (G4) are unusual nucleic acid conformations formed by guanine-rich DNA and RNA sequences and known to control gene expression mechanisms, from transcription to protein synthesis. So far, a number of molecules that recognize G4 have been developed for potential therapeutic applications in human pathologies, including cancer and infectious diseases. These molecules are called G4 ligands. When the biological effects of G4 ligands are studied, the analysis is often limited to nucleic acid targets. However, recent evidence indicates that G4 ligands may target other cellular components and compartments such as lysosomes and mitochondria. Here, we summarize our current knowledge of the regulation of lysosome by G4 ligands, underlying their potential functional impact on lysosome biology and autophagic flux, as well as on the transcriptional regulation of lysosomal genes. We outline the consequences of these effects on cell fate decisions and we systematically analyzed G4-prone sequences within the promoter of 435 lysosome-related genes. Finally, we propose some hypotheses about the mechanisms involved in the regulation of lysosomes by G4 ligands.

• Klíčová slova
• Autophagy, TFEB, guanine-quadruplex, lysosome membrane permeabilization, transcriptional regulation,
• MeSH
• autofagie * MeSH
• DNA metabolismus   MeSH
• G-kvadruplexy * MeSH
• guanin MeSH
• lidé MeSH
• ligandy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• guanin MeSH
• ligandy MeSH

SIGNIFICANCE STATEMENT: Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches. BACKGROUND: The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined. METHODS: This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia. RESULTS: The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia. CONCLUSION: Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .

• MeSH
• antivirové látky škodlivé účinky   MeSH
• cytomegalovirové infekce * epidemiologie   MeSH
• Cytomegalovirus genetika   MeSH
• lidé MeSH
• neutropenie * chemicky indukované   komplikace   MeSH
• příjemce transplantátu MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• valganciklovir škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antivirové látky MeSH
• valganciklovir MeSH

OBJECTIVE: To obtain information on the serum concentrations of acyclovir and its metabolite in routine health care with respect to the renal function. METHODS: This prospective study analyzed data from 27 patients receiving acyclovir intravenously between June 2019 and October 2021. Patients were divided into two subgroups according to the estimated glomerular filtration rate. Serum concentrations of acyclovir and its metabolite 9-(carboxymethoxymethyl) guanine were mainly analyzed on day 5 after the initiation of treatment before the morning dose (trough concentration) and 30 min after the end of the infusion (peak concentration). RESULTS: Trough acyclovir concentrations ranged from 0.8 to 7.6 mg/L and peak concentrations from 6.3 to 25.7 mg/L, and trough metabolite concentrations ranged from 0.12 to 2.30 mg/L and peak concentrations from 0.47 to 2.70 mg/L, respectively. The ratio of trough metabolite and acyclovir concentrations ranged from 0.07 to 0.63 and the ratio of peak concentrations from 0.03 to 0.24. Patients in the subgroup with reduced renal function were significantly older, smaller, and of lower body weight and received significantly lower doses of acyclovir. CONCLUSIONS: A 10-fold difference in the weight-adjusted apparent clearance of acyclovir was observed between patients. This wide interindividual variability in acyclovir pharmacokinetics can lead not only to toxicity but also to suboptimal acyclovir concentrations in severe infections. Therefore, therapeutic monitoring of serum concentrations of acyclovir and its metabolite may be important for optimizing pharmacotherapy, especially in patients with severe clinical conditions.

• Klíčová slova
• 9-(carboxymethoxymethyl) guanine, Acyclovir, Concentrations, Monitoring,
• MeSH
• acyklovir * farmakokinetika   MeSH
• antivirové látky MeSH
• guanin * MeSH
• hodnoty glomerulární filtrace MeSH
• lidé MeSH
• prospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acyklovir * MeSH
• antivirové látky MeSH
• guanin * MeSH

G-quadruplex (G4) structures are non-canonical DNA/RNA secondary structures able to form within guanine rich nucleic acids sequences. They are present in several regions of the human genome including gene promoters, untranslated sequences, and telomeres. Due to their biological relevance G4 structures are considered important drug targets, in particular for anticancer therapies, leading to the development of G4 stabilizing small molecules. Telomeric regions have received special attention in this field since they can fold into several distinct intramolecular G-quadruplexes topologies. Herein, we report the synthesis of 2,9-disubstituted-1,10-phenanthroline derivatives and their ability to stabilize different intramolecular telomeric G4 sequences. We evaluated ligand-induced stabilization, selectivity and specificity of ligands using Förster Resonance Energy Transfer (FRET) melting experiments and circular dichroism (CD). In addition, we assessed the cytotoxicity of ligands against two cancer cell lines (A549 and H1299) and one healthy cell line (NHDF).

• Klíčová slova
• 2,9-disubstituted-1,10-phenanthroline derivatives, Biophysical evaluation, G-quadruplex structures, In vitro studies,
• MeSH
• cirkulární dichroismus MeSH
• DNA chemie   MeSH
• fenantroliny MeSH
• G-kvadruplexy * MeSH
• guanin MeSH
• lidé MeSH
• ligandy MeSH
• RNA MeSH
• telomery MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1,10-phenanthroline MeSH Prohlížeč
• DNA MeSH
• fenantroliny MeSH
• guanin MeSH
• ligandy MeSH
• RNA MeSH

Dissociations of DNA trinucleotide codons as gas-phase singly and doubly protonated ions were studied by tandem mass spectrometry using 15N-labeling to resolve identity in the nucleobase loss and backbone cleavages. The monocations showed different distributions of nucleobase loss from the 5'-, middle, and 3'-positions depending on the nucleobase, favoring cytosine over guanine, adenine, and thymine in an ensemble-averaged 62:27:11:<1 ratio. The distribution for the loss of the 5'-, middle, and 3'-nucleobase was 49:18:33, favoring the 5'-nucleobase, but also depending on its nature. The formation of sequence w2+ ions was unambiguously established for all codon mono- and dications. Structures of low-Gibbs-energy protomers and conformers of dAAA+, dGGG+, dCCC+, dTTT+, dACA+, and dATC+ were established by Born-Oppenheimer molecular dynamics and density functional theory calculations. Monocations containing guanine favored classical structures protonated at guanine N7. Structures containing adenine and cytosine produced classical nucleobase-protonated isomers as well as zwitterions in which two protonated bases were combined with a phosphate anion. Protonation at thymine was disfavored. Low threshold energies for nucleobase loss allowed extensive proton migration to occur prior to dissociation. Loss of the nucleobase from monocations was assisted by neighboring group participation in nucleophilic addition or proton abstraction, as well as allosteric proton migrations remote from the reaction center. The optimized structures of diprotonated isomers for dAAA2+ and dACA2+ revealed combinations of classical and zwitterionic structures. The threshold and transition-state energies for nucleobase-ion loss from dications were low, resulting in facile dissociations involving cytosine, guanine, and adenine.

• MeSH
• adenin chemie   MeSH
• cytosin chemie   MeSH
• DNA chemie   MeSH
• fosfáty MeSH
• guanin chemie   MeSH
• kodon MeSH
• podjednotky proteinů MeSH
• protony * MeSH
• thymin * chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenin MeSH
• cytosin MeSH
• DNA MeSH
• fosfáty MeSH
• guanin MeSH
• kodon MeSH
• podjednotky proteinů MeSH
• protony * MeSH
• thymin * MeSH

BACKGROUND AND AIMS: Plant tissue nitrogen (N) and phosphorus (P) and genome traits, such as genome size and guanine-cytosine (GC) content, scale with growth or metabolic rates and are linked to plant ecological strategy spectra. Tissue NP stoichiometry and genome traits are reported to affect plant growth, metabolic rates or ecological strategies in contrasting ways, although the elemental costs for building and maintaining DNA are typically overlooked. METHODS: We formulated stoichiometry- and ecology-based predictions on the relationship between genome size and GC content to tissue N, P and N : P and tested them on a set of 130 herbaceous species from a temperate grassland using ordinary, phylogenetic and quantile regression. KEY RESULTS: Genome size was only negatively linked to plant N and N : P in species with very small genomes. We found no link between genome size and plant P. GC content was negatively linked to plant N and P but we found these significant links consistently in both GC-rich and GC-poor species. Finally, GC content correlated positively with plant N : P but only in species with GC-rich genomes. CONCLUSIONS: Our results provide stronger support for the ecology-based predictions than the stoichiometry-based predictions, and for the links between GC content and plant N and P stoichiometry than for genome size. We argue that the theories of plant metabolic rates and ecological strategies (resource-acquisitive vs. conservative or ruderal vs. stress-tolerator spectra) better explain interspecific genome-NP stoichiometry relationships at the tissue level (although relatively weakly) than the stoichiometric theory based on the elemental costs for building and maintaining DNA.

• Klíčová slova
• GC content, genome size, nitrogen, phosphorus, plant ecological strategies, stoichiogenomics, tissue stoichiometry,
• MeSH
• cytosin metabolismus   MeSH
• délka genomu MeSH
• dusík * metabolismus   MeSH
• fosfor * metabolismus   MeSH
• fylogeneze MeSH
• guanin metabolismus   MeSH
• pastviny MeSH
• rostliny metabolismus   MeSH
• zastoupení bazí MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytosin MeSH
• dusík * MeSH
• fosfor * MeSH
• guanin MeSH