Gotowa bibliografia na temat „378.1/2/092 b”

BackgroundGout is a common inflammatory arthritis caused by monosodium urate deposits around the joints[1]. The risk of cardiovascular events, including death, is substantially higher in people with gout than in those without gout[2]. Although epidemiological studies have reported a positive correlation between circulating urate levels and cardiac metabolic diseases, the causal relationship between gout and cardiovascular diseases(CVD) is still uncertain[3].ObjectivesThis study aimed to explore the causal relationship between gout and CVD from the genetic level. We examined the potential effects of gout on coronary heart disease(CHD), coronary artery disease(CAD), atrial fibrillation(AF), myocardial infarction(MI), pulmonary embolism(PE), any stroke, ischemic stroke and its subtypes [cardioembolic(CES), small-vessel(SVS), extensive artery atherosclerosis(LAS)].MethodsWe obtained genetic information related to gout from the Global Urate Genetics Consortium (GUGC), including 2115 cases and 67259 healthy controls with 5057528 single nucleotide polymorphisms(SNPs). SNPs significantly associated with CVD were obtained from large genome-wide association(GWAS) meta-analyses and the UK Biobank as instrumental variables(IVs) for Mendelian randomization(MR). The inverse variance weighting (IVW), MR Egger, and weighted median were used to estimate the effect size. MR-PRESSO was used to detect and eliminate SNPs that may bring significant pleiotropy.ResultsMR results supported that gout had significant causal effects in CHD, CAD, and MI. There was a significant positive correlation between the genetic responsibility of gout and the risk of CVD(CHD: OR=1.031, 95%CI:1.007-1.057, P=0.012; CAD: OR=1.031, 95%CI:1.007-1.057, P=0.012; MI: OR=1.037, 95%CI: 1.037-1.009, P=0.009). In reverse MR, we only observed that any stroke would increase the risk of gout(OR=1.265, 95%CI: 1.010-1.585, p=0.041). No pleiotropy was detected in the sensitivity analysis(all p>0.05).ConclusionThe responsibility of gout had a significant causal relationship with CHD, CAD, and MI, suggesting adequate management of gout could reduce the risk of CVD.References[1] Lai, B. et al. Assessing the causal relationships between gout and hypertension: a bidirectional Mendelian randomisation study with coarsened exposures. Arthritis Res Ther 24, 243, doi:10.1186/s13075-022-02933-4 (2022).[2] White, W. B. et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med 378, 1200-1210, doi:10.1056/NEJMoa1710895 (2018).[3] Keenan, T. et al. Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. J Am Coll Cardiol 67, 407-416, doi:10.1016/j.jacc.2015.10.086 (2016).Acknowledgements:NIL.Disclosure of InterestsNone Declared.

The electrochemical reduction of the anti-inflammatory drug ketoprofen was studied in a Britton-Robinson (B-R.) buffer series of pH 2–11 using dc-polarography, cyclic voltammetry, and coulometry techniques. The electrode reaction pathway of the drug at the dropping mercury electrode was proposed and discussed. A new adsorptive cathodic stripping square-wave voltammetric procedure was optimized for the assay of bulk drug in a B-R. buffer of pH 2.0. The peak current was linear with the drug concentration over the ranges 2 × 10–9 to 2 × 10–7 M of the bulk drug, using a 60 s accumulation time period at –0.6 V (vs. Ag/AgCl/KCls). The percentage recovery of the bulk drug was 99.57 ± 0.54 and a detection limit of 0.10 ng mL–1 was achieved. The proposed procedure was successfully applied for the assay of ketoprofen in pharmaceutical formulation (Ketofan®) and human plasma. The percentage recoveries were 99.66 ± 0.47 and 101.76 ± 0.64 in pharmaceutical formulation and human plasma, respectively. A detection limit of 0.14 ng mL–1 plasma was achieved which was below that reported in literature using the different analytical techniques.Key words: ketoprofen (Ketofan®) determination, polarography, cyclic voltammetry, adsorptive cathodic stripping square-wave voltammetry, human plasma.

Fusarium dry rot of potato (Solanum tuberosum L.) is a postharvest disease caused by several Fusarium species and is of worldwide importance. Thirteen species of Fusarium have been implicated in fungal dry rots of potatoes worldwide. Among them, eight species have been reported in the northern United States (2). In Michigan potato production, F. sambucinum was the predominant species reported to be affecting seed potato in storage and causing seed piece decay after planting (3). Some previous identifications of F. sambucinum as dry rot may have been F. torulosum since F. torulosum was previously classified within F. sambucinum (4). To further investigate this, dry rot symptomatic tubers were collected from Michigan seed lots in the summers of 2009 and 2010. Small sections from the margins of necrotic regions were cut with a scalpel, surface sterilized in 0.5% sodium hypochlorite for 10 s, rinsed twice in sterile distilled water, and blotted with sterile filter paper. The tissue pieces were plated on half-strength potato dextrose agar (PDA) amended with 0.5 g/liter of streptomycin sulfate and incubated at 23°C for 5 to 7 days. Cultures resembling Fusarium species were transferred onto water agar, and single hyphal tips from actively growing isolates were removed and plated either on carnation leaf agar (CLA) or on half-strength PDA to generate pure cultures. Among the Fusarium isolates obtained, five isolates were identified as F. torulosum (GenBank Accessions Nos. JF803658–JF803660). Identification was based on colony and conidial morphology on PDA and CLA, respectively. These features included slow growth (2.8 ± 0.2 cm in 5 days), white mycelium that became pigmented with age, narrow concentric rings, red or white pigmentation on agar, macroconidia (32.4 ± 0.4 μm average length) with five septa, a pointed apical cell, and a foot-shaped basal cell (4). The identity was confirmed through DNA extraction followed by amplification and sequencing of the translation elongation factor (EF-1α) gene region (1). The Fusarium-ID.v (1) and the NCBI database were used to obtain the closest match (99%) to previously sequenced materials (GenBank Accession No. AJ543611). Pathogenicity testing was done on disease-free potato tubers cv. Red Norland. Tubers were surface sterilized for 10 min in 0.5% sodium hypochlorite and rinsed twice in distilled water. Three tubers per isolate were injected with 20 μl of a conidial suspension (106 conidia/ml) made from F. torulosum cultures grown on PDA for 7 to 10 days. Control tubers were injected with 20 μl of sterile distilled water. All tubers inoculated with F. torulosum developed typical potato dry rot symptoms consisting of a brown and dry decay. There was no disease incidence on the control tubers. F. torulosum was reisolated from the symptomatic tubers. To our knowledge, this is the first report of F. torulosum causing potato dry rot in the United States. References: (1) D. Geiser et al. Eur. J. Plant Pathol. 110:473, 2004. (2) L. E. Hanson et al. Phytopathology 86:378, 1996. (3) M. L. Lacy and R. Hammerschmidt. Fusarium dry rot. Extension Bulletin. Retrieved from http://web1.msue.msu.edu/msue/iac/onlinepubs/pubs/E/E2448POT , 23 May 2010. (4) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Wiley-Blackwell, Hoboken, NJ, 2006.

Six monoclonal antibodies were developed to pregnancy-specific β1-glycoprotein (PSβ1G). Studies of ascitic fluid antibodies by a double-antibody radioimmunoassay (RIA) included an evaluation of titers, dose–response parameters, and mass action properties. Four of the antibodies demonstrated moderate to high titers ranging from 1/40 000 to > 1/120 000, as determined by the specific binding of 125I-labeled PSβ1G. In inhibition studies utilizing a standard containing known quantities of placental PSβ1G, two of the antibodies (AR#11 and B#2) were highly sensitive and only slightly lower in this regard than a high affinity polyclonal antiserum. The binding affinities of AR#11 and B#2 monoclonals were greater than 109 mol−1 which underline their importance as potential clinical reagents for the RIA of PSβ1G. The Scatchard plots, for several of the antibodies, were linear and in full agreement with a single order of binding sites predicted for specific monoclonal reagents. Immunodiffusion results provide preliminary evidence that at least three distinct determinants on PSβ1G are recognized by a number of the monoclonal antibodies. Further studies on the fine specificities of the antibodies by solid-phase RIA, as well as a detailed evaluation of their clinical applications, are in progress.

e16155 Background: Combining lenvatinib (a multikinase inhibitor) with programmed cell death protein-1 (PD-1) inhibitor has been explored in Unresectable hepatocellular carcinoma (uHCC) in phase 1b trials. This study aimed to investigate the real-word efficacy and safety of lenvatinib plus PD-1 inhibitor for large Chinese patients uHCC cohorts. Methods: BCLC stage B or C uHCC patients were included. Data was collected from Oct 2017 to Nov 2021 retrospectively. Patients were treated with lenvatinib and PD-1 inhibitor (pembrolizumab or nivolumab or camrelizumab or sintilimab or toripalimab or tislelizumab). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) evaluated by RECIST v1.1 criteria. Adverse events (AEs) were assessed using CTCAE v5.0. Prognostic factors of survival were also analyzed. Results: 378 uHCC patients of BCLC stage B (12.7%) and C (87.3%) from two medical centers were included in China. The median age was 55 (range 18-89) years and 86.5% patients were male. ECOG scores were 0 (43.7%), 1 (43.4%) and 2 (13.0%), while Child-pugh grade were A (77.5%) and B (22.5%) respectively. The median OS was 17.8 (95% CI 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) was 74/378 (19.6%) and 278/378 (73.5%) respectively. Child-pugh grade (A vs. B), ECOG score (0 vs. 1-2), BCLC stage (B vs. C) and achieve response (yes vs. no) were the prognostic factors for both OS and PFS. All (100%) experienced all-grade adverse events (AE). The most frequent AEs were fatigue, diarrhea, hypertension, decreased appetite. The most common ≥Grade 3 AEs were hypertension (13.2%), fatigue (7.1%), decreased platelet count (6.3%), increased blood bilirubin (6.1%), diarrhea (6.1%) and gastrointestinal hemorrhage (4.8%). Conclusions: This real-world study of lenvatinib plus PD-1 inhibitors achieved long survival and considerable ORR for uHCC patients in China. The tolerability of combination therapy was acceptable but should be still monitored closely. Clinical trial information: NCT03892577. [Table: see text]

Abstract Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.

<b><i>Objective:</i></b> This study aimed to explore the association of 14 proangiogenic microRNAs (miRNAs) with major adverse cardiac and cerebrovascular events (MACCE) occurrence in unprotected left main coronary artery disease (ULMCAD) patients who underwent coronary artery bypass grafting (CABG). <b><i>Methods:</i></b> A total of 196 ULMCAD patients who underwent first ever CABG were recruited. The peripheral blood samples were collected prior to CABG, and then plasma samples were separated to detect expressions of 14 proangiogenic miRNAs by the reverse transcription quantitative PCR. Patients were regularly followed up to MACCE occurrence or 36 months after CABG. <b><i>Results:</i></b> MACCE occurrence at 1 year, 2 years, and 3 years was 7.1, 11.2, and 14.3%, respectively, and accumulating MACCE occurrence time was 32.7 (95% confidence interval: 31.5–33.9) months. Both Kaplan-Meier curves and univariate Cox’s regression analyses displayed that miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 high expressions were associated with lower accumulating MACCE occurrence. Furthermore, forward stepwise multivariate Cox’s regression disclosed that miR-let-7f high expression and miR-378 high expression independently predicted decreased accumulating MACCE occurrence, whereas BMI (&#x3e;25.0 kg/m²), diabetes, previous stroke, and higher disease extent were independent predictive factors for elevated accumulating MACCE occurrence. <b><i>Conclusion:</i></b> Measurement of circulating proangiogenic miRNAs especially miR-let-7f, miR-19a, miR-126, miR-130a, and miR-378 helps predict MACCE risk in ULMCAD patients who underwent CABG.

Objective: Synthesis of novel 2-(1-benzofuran-2-yl)-N'-[(3Z)-2-oxo-1, 2-dihydro-3H-indol-3-ylidene] quinoline-4-carbohydrazide and its derivatives for antimicrobial and antitubercular activity.Methods: Synthesis was carried out using the general method and the structures were confirmed by IR, 1H-NMR, [13]C-NMR and mass spectral analysis. The antibacterial activity was carried by agar well diffusion method, antifungal activity was performed by poison food technique and antitubercular activity was carried out by Microplate Alamar Blue Assay (MABA) method with the help of H37Rv. In silico absorption, distribution, metabolism, excretion, toxicity (ADMET) study of the drug, likeliness was carried out in ACD/lab-2.Results: The results revealed that at 25 mg/ml concentration, compounds 3a and 5a showed good antibacterial activity at 3.5±0.1, 3.8±0.3, 3.6±0.2 respectively against E. coli, K. pneumonia and S. typhimurium, when compared with drug streptomycin with similar concentration. The percentage of inhibition found at 50 µg/ml concentration, compounds 2b and 6a exhibited good antifungal activity at 53±1.15, 57±1.52 against A. flavus and C. neoformans, compared with standard drug fluconazole. The increase in activity was found to be dose dependent. The analogue 2a showed good antitubercular activity at 12.5±0.5 µg/ml, compounds 2b, 3a, 4a-b, 5a-b and 6a-b exhibited significant activity at 25±0.57 µg/ml and compound 3b showed moderate activity at 50±0.57 µg/ml. The mean value of P<0.05 were considered to be statistically significant. The absorption, distribution, metabolism, excretion and toxicity studies of the entitled molecules were analyzed and found to be in acceptable range.Conclusion: The study reveals that compounds containing benzofuran coupled nitrogen heterocycles are essential for activity as they possess excellent drug-like characteristics, suggesting to be potentially best inhibitor of H37Rv strain. The in silico ADME analysis also revealed that all the compounds were in acceptable range to obey the pharmacokinetic parameters.

Room-temperature single-crystal X-ray structural characterizations are recorded for hydrated lan- thanoid(III) bromide/2,2′:6′,2″-terpyridine (tpy) (1 : 1) complexes, showing all to be ionic and of the form [(tpy)Ln(OH2)x]Br3.yH2O, where x and y are 6 and 1 for the isomorphous series Ln = La(-)Er (and intermediate members, by presumption), and 5 and various values for Ln = Tm, Yb, Lu. Crystals of [(tpy)Ln(OH2)6]Br3.H2O are monoclinic, P 21/c, a ≈ 8·5, b ≈ 18, c ≈ 16·3 Å, β ≈ 108°, Z = 4; for Ln = La, Er, conventional R values on |F| were 0·048, 0·080 for No 4027, 1347 ‘observed’ (I > 3σ(I)) diffractometer reflections respectively. The complex [(tpy)Tm(OH2)5]Br3.H2O is monoclinic, P 21/c, a 8·506(4), b 17·376(1), c 15·951(6) Å, β 106·87(3)°, Z = 4, (quasi-)isomorphous with the Ln = La-Er array, R 0·065 for No 2067. [(tpy)Yb(OH2)5]Br3.4H2O is triclinic, P 1, a 11·902(2), b 11·639(3), c 9·831(2) Å, α 98·92(2), β 106·84(2), γ 92·42(2)°, Z = 2, R 0·062 for No 3422, while [(tpy)Lu(OH2)5]Br3.H2O is monoclinic, P 21/n, a 13·635(8), b 9·022(5), c 19·03(1) Å, β 99·02(5)°, Z = 4, R 0·043 for No 3139. Despite a common N3LnO5 coordination sphere in the last three compounds, subtle differences are found in stereochemistry; in the N3LnO6 array, one of the outer water molecules becomes progressively detached as the lanthanoid radius contracts. Some tendency is found toward the end of the lanthanoid series toward the formation of di(hydroxy-bridged) neutral dimers, Ln(OH)Br2/tpy/H2O(1 : 1 : 8)(×2), [(tpy)(H2O)3Ln(µ-OH)2Ln(OH2)3(tpy)]Br4.10H2O, monoclinic, C 2/c, a ≈ 19·5, b ≈ 14·5, c ≈ 17·1 Å, β ≈ 92°, Z = 4 dimers, thus far defined by full determinations for the extrema Lu = Er, Lu (and Y), R 0·055, 0·043, (0·047) for No 3141, 4591, (2991) respectively; the dimer is disposed about a crystallographic 2 -axis. An Ln = Dy example, seemingly isomorphous, has also been characterized by cell determination.