IAA Technology Development Center Report 2012

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АНАЛИЗ ГИНЗЕНОЗИДОВ В КОРНЯХ ЖЕНЬШЕНЯ НАСТОЯЩЕГО (PANAX GINSENG), ИНТРОДУЦИРОВАННОГО В ЦЕНТРАЛЬНОМ БОТАНИЧЕСКОМ САДУ НАН БЕЛАРУСИ

For the first time, a detailed study of the qualitative and quantitative composition of ginsenosides in the Panax ginseng roots was carried out with the help of high-performance liquid chromatography combined with mass spectrometry (HPLC-MS). The plants were introduced into the conditions of the Republic of Belarus at the experimental plot of the Central Botanical Garden of the National Academy of Sciences of Belarus. It was found that in the examined roots, all basic neutral glycosides of ginseng (ginsenosides Rb1, Rc, Rb2/Rb3, Rd, Rf, Rg1 and Re), as well as their malonylated derivatives (malonylginsenosides Rb1, Rc, Rb2/Rb3, Rd, Rg1 and Re) and some “minor” ginsenosides (20-gluco-ginsenoside Rf, notoginsenosides R1 and R2, isomers of malonyl-ginsenosides Rb1 and Rd) are present. The research also showed that different parts of the P. ginseng roots differ significantly in a total content of ginsenosides: for the main root, this parameter was 3.3 % of dry mass, and for the lateral roots – 7.8 % of dry mass.Впервые с помощью высокоэффективной жидкостной хроматографии, совмещенной с массспектрометрией (ВЭЖХ-МС) проведено подробное изучение качественного и количественного состава гинзенозидов в корнях женьшеня настоящего (P. ginseng C. A. Mey.), интродуцированного в условиях Республики Беларусь (опытный участок ЦБС НАН Беларуси). Установлено, что в изученных корнях присутствуют все основные нейтральные гликозиды женьшеня (гинзенозиды Rb1, Rc, Rb2/Rb3, Rd, Rf, Rg1 и Re), а также их малонилированные производные (малонил-гинзенозиды Rb1, Rc, Rb2/Rb3, Rd, Rg1 и Re) и некоторые «минорные» гинзенозиды (20-глюко-гинзенозид Rf, нотогинзенозиды R1 и R2, изомеры малонил-гинзенозидов Rb1 и Rd). Показано также, что разные части корней P. ginseng существенно отличаются по суммарному содержанию гинзенозидов: для основного корня этот параметр составил 3,3 % от сухой массы, а для боковых корней – 7,8 % от сухой массы

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial

Background The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. Methods In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatmentnaive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intentionto-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. Findings Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2–34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3–not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7–18·9] vs 11·1 months [9·1–12·5]; 0·71 [0·60–0·84], p<0·0001). The most frequent (≥10% patients in either group) treatmentrelated grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. Interpretation With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma

Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.450

Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): Updated analysis of KEYNOTE-426

The randomized, open-label, phase 3 KEYNOTE-426 study (NCT02853331) demonstrated that pembrolizumab (pembro) + axitinib (axi) significantly improved OS, PFS, and ORR vs sunitinib as first-line therapy for advanced RCC (aRCC) at the first pre-planned interim analysis (minimum study follow-up of 7 mo). Updated analyses are presented here

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Biochemical Atypia in Russian Neisseria gonorrhoeae Clinical Isolates Belonging to the G807 NG-MAST Genogroup/ST1594 MLST

Many current gonococcal clinical isolates in Russia show atypical taxonomically significant biochemical activity, which leads to species misidentification. Molecular typing of such cultures according Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) and multilocus sequence typing (MLST) protocols assigned them to the G807 NG-MAST GENOGROUP/ST1594 MLST that has been predominant in Russia in recent years. The goal of the study was to analyze the molecular mechanisms of biochemical atypia in N. gonorrhoeae clinical isolates characterized as the members of G807 NG-MAST GENOGROUP/ST1594 MLST. Sixteen isolates of this genogroup were included in the study, eight showed defective amino acid metabolism or loss of D-glucose fermentation. Comparative bioinformatic analysis based on WGS data divided these isolates into two clusters strictly associated with typical or atypical biochemical activity. Cultures with defective amino acid metabolism had a 5-nucleotide insertion in the pip-gene that caused a stop codon and led to synthesis of the non-functional enzyme. Comparison of the sequenced genomes with publicly available N. gonorrhoeae genomes showed the rarity of this insertion. In the global N. gonorrhoeae phylogenetic tree the G807 NG-MAST GENOGROUP/ST1594 MLST forms a distinct branch characterized by 170 SNPs, most of which are non-synonymous. We hypothesized a unique strategy for G807 NG-MAST GENOGROUP/ST1594 MLST clone persistence in the global N. gonorrhoeae population via escape of antimicrobial therapy due to diagnostic misidentification

Compounds for use in catalyst compositions for the production of polyolefins

The present invention relates to compds. according to formula I wherein: .bul. each R1-​R10 may individually be H, a halogen, an alkoxy moiety, a siloxy moiety, a nitrogen-​contg. moiety, an alkyl moiety, an aryl moiety, or an aralkyl moiety, wherein each R1-​R10 comprises ≤ 10 carbon atoms, wherein each of R1-​R10 may form a cyclic moiety with an adjacent R1-​R10 moiety; .bul. Y is O or N-​R11, wherein R11 is an alkyl, cycloalkyl, aryl or aralkyl moiety comprising 1-​12 carbon atoms; .bul. M is a group 3 or 4 transition metal, preferably Ti, Zr or Hf, more preferably Ti; .bul. X is .bul. a sigma-​bonded ligand, for example: (i) a halogen, (ii) an amine, or (iii) a moiety wherein each X may contain 1 to 10 carbon atoms, selected from an alkyl moiety, an aralkyl moiety, an alkoxy moiety, and an aryloxy moiety; or .bul. a diene, for example a butadiene moiety or an isoprene moiety; .bul. z is the no. of ligands X that are bonded to M. Such compds. may be used in a catalyst system for olefin polymn., particularly ethylene copolymn., providing at least one of a high catalyst activity, a high comonomer incorporation, and​/or a high mol. wt. polymer