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
- Quinolines * administration & dosage therapeutic use MeSH
- Adult MeSH
- Phenylurea Compounds * administration & dosage therapeutic use MeSH
- Antibodies, Monoclonal, Humanized * administration & dosage therapeutic use MeSH
- Carcinoma, Renal Cell * drug therapy pathology mortality secondary MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Kidney Neoplasms * drug therapy pathology mortality MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Sunitinib * administration & dosage therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
INTRODUCTION: It is hypothesized that systemically administered antibiotics penetrate wound sites more effectively during negative pressure wound therapy (NPWT). However, there is a lack of clinical data from patients who receive NPWT for deep sternal wound infection (DSWI) after open-heart surgery. Here, we evaluated vancomycin penetration into exudate in this patient group. PATIENTS AND METHODS: For this prospective observational study, we enrolled 10 consecutive patients treated with NPWT for post-sternotomy DSWI. On the first sampling day, serum and exudate samples were synchronously collected at 0 (pre-dose), 0.5, 1, 2, 3 and 6 h after vancomycin administration. On the following three consecutive days, additional samples were collected, only before vancomycin administration. RESULTS: The ratio of average vancomycin concentration in wound exudate to in serum was higher for free (unbound) (1.51 ± 0.53) than for total (bound + unbound) (0.91 ± 0.29) concentration (p = 0.049). The percentage of free vancomycin was higher in wound exudate than serum (0.79 ± 0.19 vs. 0.46 ± 0.16; p = 0.04). Good vancomycin wound penetration was maintained on the following three days (vancomycin trough exudate-to-serum concentration ratio > 1). The total hospital stay was significantly longer in patients with DSWI (46 ± 11.6 days) versus without DSWI (14 ± 11.7 days) (p < 0.001). There was no in-hospital or 90-day mortality. Two patients experienced late DSWI recurrence. All-cause mortality was 4.8% during a median follow-up of 2.5 years. CONCLUSION: Vancomycin effectively penetrates wound exudate in patients receiving NPWT for DSWI after open-heart surgery.The protocol for this study was registered at ClinicalTrials.gov on July 16, 2024 (NCT06506032).
- MeSH
- Anti-Bacterial Agents * pharmacokinetics administration & dosage MeSH
- Exudates and Transudates metabolism microbiology MeSH
- Surgical Wound Infection * MeSH
- Cardiac Surgical Procedures * adverse effects MeSH
- Middle Aged MeSH
- Humans MeSH
- Prospective Studies MeSH
- Aged MeSH
- Sternotomy * adverse effects MeSH
- Sternum surgery MeSH
- Negative-Pressure Wound Therapy * methods MeSH
- Vancomycin * administration & dosage pharmacokinetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
Lipids from microorganisms, and especially lipids from Archaea, are used as taxonomic markers. Unfortunately, knowledge is very limited due to the uncultivability of most Archaea, which greatly reduces the importance of the diversity of lipids and their ecological role. One possible solution is to use lipidomic analysis. Six radioactive sources were investigated, two of which are surface (Wettinquelle and Radonka) and four deep from the Svornost mine (Agricola, Behounek, C1, and Curie). A total of 15 core lipids and 82 intact polar lipids were identified from the membranes of microorganisms in six radioactive springs. Using shotgun lipidomics, typical Archaea lipids were identified in spring water, namely dialkyl glycerol tetraethers, archaeol, hydroxyarchaeol and dihydroxyarchaeol. Diverse groups of polar heads were formed in archaeal IPLs, whose polar heads are formed mainly by hexose, deoxyhexose, and phosphoglycerol. The analysis was performed using shotgun lipidomics and the structure of all molecular species was confirmed by tandem mass spectrometry. After acid hydrolysis, a mixture of polar compounds was obtained from the polar head. Further analysis by GC-MS confirmed that the carbohydrates were glucose and rhamnose. Analysis by HPLC-MS of diastereoisomers of 2-(polyhydroxyalkyl)-3-(O-tolylthiocarbamoyl)thiazolidine-4(R)-carboxylates revealed that both L-rhamnose and D-glucose are present in spring samples only in varying amounts. The glycoside composition depends on the type of spring, that is, Wettinquelle and Radonka springs are basically shallow groundwater, while the samples from the Svornost mine are deep groundwater and do not contain glycosides with rhamnose. This method enables quick screening for characteristic Archaea lipids, allowing decisions on whether to pursue further analyses, such as metagenomic analysis, to directly confirm the presence of Archaea.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor Mpro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the WT glutamine at the P1 position with isoleucine retains Mpro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter assay suitable for compound library screening and evaluation in HEK293T cells. This assay can detect both overall Mpro inhibition and the fraction of uncleaved precursor form of Mpro through separable fluorescent signals. We observed that inhibitory compounds preferentially block mature Mpro. Bofutrelvir and a novel compound designed in-house showed the lowest selectivity between precursor and mature Mpro, indicating that inhibition of both forms may be possible. Additionally, we observed positive modulation of precursor activity at low concentrations of inhibitors. Our findings help expand understanding of the SARS-CoV-2 viral life cycle and may facilitate development of strategies to target precursor form of Mpro for inhibition or premature activation of Mpro.
- MeSH
- Antiviral Agents * pharmacology chemistry MeSH
- COVID-19 Drug Treatment MeSH
- HEK293 Cells MeSH
- Protease Inhibitors pharmacology chemistry MeSH
- Coronavirus 3C Proteases * metabolism antagonists & inhibitors chemistry genetics MeSH
- Humans MeSH
- Mutation MeSH
- Drug Discovery * methods MeSH
- Proteolysis MeSH
- SARS-CoV-2 * enzymology drug effects metabolism genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND CONTEXT: Spondylodiscitis management presents significant clinical challenges, particularly in critically ill patients, where the risks and benefits of surgical intervention must be carefully balanced. The optimal timing of surgery in this context remains a subject of debate. PURPOSE: This study aims to evaluate the effectiveness of early surgery versus delayed surgery or conservative management in critically ill patients with de novo pyogenic spondylodiscitis. STUDY DESIGN/SETTING: This is an international, multicenter retrospective cohort study involving 24 centers, primarily in Europe. PATIENT SAMPLE: The study included 192 critically ill patients (65.63% male) with a median age of 69 years, all severely affected by pyogenic spondylodiscitis characterized by an initial CRP level >200 mg/l or the presence of two out of four Systemic Inflammatory Response Syndrome criteria upon admission. OUTCOME MEASURES: The primary outcome was 30-day mortality. Secondary outcomes included length of ICU stay, length of hospital stay, and relapse rates of spondylodiscitis. METHODS: Patients were divided into three groups: early surgery (within three days of admission), delayed surgery (after three days of admission), and conservative therapy. Propensity score matching and multivariate regression analyses were performed to adjust for baseline differences and assess the impact of treatment modalities on mortality and other clinical outcomes. RESULTS: Delayed surgery was associated with significantly lower 30-day mortality (4.05%) compared to early surgery (27.85%) and conservative therapy (27.78%) (p<.001). Delayed surgery also resulted in shorter hospital stays (42.76 days) compared to conservative therapy (55.53 days) and early surgery (26.33 days) (p<.001), and shorter ICU stays (4.52 days) compared to conservative therapy (16.48 days) and early surgery (7.92 days) (p<.001). The optimal window for surgery, minimizing mortality, was identified as ten to fourteen days postadmission (p=.02). Risk factors for increased mortality included age (p<.05), multiple organ failure (p<.05), and vertebral body destruction (p<.05), whereas delayed surgery (p<.05) and the presence of an epidural abscess were associated with reduced mortality (p<.05). CONCLUSIONS: Delayed surgery, optimally between 10 to 14 days postadmission, was associated with lower mortality in critically ill spondylodiscitis patients. These findings highlight the potential benefits of considering surgical timing to improve patient outcomes.
- MeSH
- Anti-Bacterial Agents therapeutic use MeSH
- Length of Stay MeSH
- Discitis * therapy mortality surgery microbiology MeSH
- Conservative Treatment MeSH
- Critical Illness MeSH
- Middle Aged MeSH
- Humans MeSH
- Retrospective Studies MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
The aim of this study is to evaluate opportunistic pathogenic bacteria of the genus Pseudomonas in anthropogenically impacted bathing waters, primarily focusing on bathing ponds. The findings include the detection of these bacteria, their susceptibility to selected antibiotics, and the determination of the Exotoxin A (exoA) gene using PCR method. P. aeruginosa was present in most samples, albeit in low concentrations (1-14 CFU/100 mL). The presence of P. otitidis, which is associated with ear infection, in this type of bathing water, was not rare (up to 90 CFU/100 mL). This species would not be detected by the standard methods, including tests on acetamid medium, used for P. aeruginosa in water. The isolated strains of P. otitidis lack the exoA gene and exhibited higher resistance to meropenem compared to P. aeruginosa.
- MeSH
- ADP Ribose Transferases genetics MeSH
- Anti-Bacterial Agents * pharmacology MeSH
- Drug Resistance, Bacterial MeSH
- Bacterial Proteins genetics MeSH
- Bacterial Toxins genetics MeSH
- Pseudomonas aeruginosa Exotoxin A MeSH
- Exotoxins genetics MeSH
- Virulence Factors genetics MeSH
- Microbial Sensitivity Tests * MeSH
- Water Microbiology * MeSH
- Polymerase Chain Reaction MeSH
- Pseudomonas * genetics isolation & purification classification drug effects MeSH
- Ponds * microbiology MeSH
- Publication type
- Journal Article MeSH
Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.
- MeSH
- Anti-Inflammatory Agents pharmacology chemistry MeSH
- Dexamethasone * pharmacology chemistry analogs & derivatives MeSH
- Liver * drug effects metabolism MeSH
- Polylactic Acid-Polyglycolic Acid Copolymer * chemistry MeSH
- Macrophages * drug effects metabolism MeSH
- Mice MeSH
- Nanospheres * chemistry MeSH
- Drug Carriers chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies. RESULTS: Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect. CONCLUSION: 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
- MeSH
- Enzyme Inhibitors * chemistry pharmacology MeSH
- Catalysis MeSH
- Catechin * chemistry analogs & derivatives pharmacology MeSH
- Humans MeSH
- Mercaptopurine * chemistry pharmacology metabolism MeSH
- Oxidation-Reduction * MeSH
- Resveratrol * chemistry pharmacology MeSH
- Silymarin * pharmacology chemistry MeSH
- Xanthine chemistry metabolism pharmacology MeSH
- Xanthine Oxidase * antagonists & inhibitors metabolism chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Tailocins are nano-scale phage tail-like protein complexes that can mediate antagonistic interactions between closely related bacterial species. While the capacity to produce R-type tailocin was found widely across Gammaproteobacteria, the production of F-type tailocins seems comparatively rare. In this study, we examined the freshwater isolate, Pragia fontium 24613, which can produce both R- and F-type tailocins. We investigated their inhibition spectrum, focusing on clinically relevant enterobacteria, and identified the associated tailocin gene cluster. Transmission electron microscopy confirmed that inactivation of the tape measure protein within the tailocin cluster disrupted R-tailocin production. Comparative analysis of Budviciaceae gene clusters showed high conservation of R-type tailocin genes, whereas F-type tailocin genes were found in only a few species, with little conservation. Our findings indicate a high prevalence of bacteriocin production among underexplored Enterobacteriales species. Detected tailocins showed potential as antimicrobials targeting clinically significant pathogens.
Fructobacillus, a Gram-positive, non-spore-forming, facultative anaerobic bacterium, belongs to the fructophilic lactic acid bacteria (FLAB) group. The group's name originates from fructose, the favored carbon source for its members. Fructobacillus spp. are noteworthy for their distinctive traits, captivating the interest of scientists. However, there have been relatively few publications regarding the isolation and potential utilization of these microorganisms in the industry. In recent years, F. tropaeoli has garnered interest for its promising role in the food and pharmaceutical sectors, although the availability of isolates is rather limited. A more comprehensive understanding of Fructobacillus is imperative to evaluate their functionality in the industry, given their unique and exceptional properties. Our in vitro study on Fructobacillus tropaeoli KKP 3032 confirmed its fructophilic nature and high osmotolerance. This strain thrives in a 30% sugar concentration, shows resistance to low pH and bile salts, and exhibits robust autoaggregation. Additionally, it displays significant antimicrobial activity against foodborne pathogens. Evaluating its probiotic potential, it aligns with EFSA recommendations in antibiotic resistance, except for kanamycin, to which it is resistant. Further research is necessary, but preliminary analyses confirm the high probiotic potential of F. tropaeoli KKP 3032 and its ability to thrive in the presence of high concentrations of fructose. The results indicate that the isolate F. tropaeoli KKP 3032 could potentially be used in the future as a fructophilic probiotic, protective culture, and/or active ingredient in fructose-rich food.
- MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Fructose metabolism MeSH
- Hydrogen-Ion Concentration MeSH
- Fruit and Vegetable Juices * microbiology MeSH
- Citrus sinensis microbiology chemistry MeSH
- Food Microbiology MeSH
- Probiotics * isolation & purification MeSH
- RNA, Ribosomal, 16S genetics MeSH
- Bile Acids and Salts metabolism MeSH
- Publication type
- Journal Article MeSH
