Summary Background Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function ...mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs. Methods In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT00785785. Findings Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% 95% CI 50·9–66·5) than in the nilotinib group (51·6% 43·0–59·5; hazard ratio 1·47 95% CI 1·10–1·95). In the imatinib group, the most common grade 3–4 adverse events were hypophosphataemia (19 6%), anaemia (17 5%), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 4% in the imatinib group, 14 4% in the nilotinib group). Interpretation Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit. Funding Novartis Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Use of tenofovir disoproxil fumarate (TDF) improves patient outcomes in preventing mother-to-child transmission (pMTCT) of the hepatitis B virus (HBV) in mothers with chronic HBV and high viral ...loads. Given the lack of data for tenofovir alafenamide (TAF) in pMTCT, rates of early viral suppression with TAF and TDF were evaluated in women of childbearing potential (WOCBP) participating in 2 randomized, double-blind, Phase 3 studies in chronic HBV.
In a patient subset meeting WOCBP criteria and with baseline HBV DNA >200,000 IU/mL, rates of viral suppression with TAF or TDF in achieving the target of HBV DNA <200,000 IU/mL at weeks 12 and 24 were assessed. Multivariate logistic regression was used to identify factors predictive of failure to suppress HBV DNA to the target level.
In 275 of 1298 (21%) patients meeting WOCBP criteria with high viral load, 93% and 96% had HBV DNA <200,000 IU/mL at weeks 12 and 24, respectively. Results for TAF (n = 194) vs TDF (n = 81) treatment were similar at weeks 12 and 24 (94% vs. 90% and 97% vs. 93%), respectively. High baseline HBV DNA level, genotype D infection, and prior interferon (week 24 only) were predictive of failure to achieve the target level. Both treatments were well tolerated with TAF showing less impact on renal and bone parameters.
In WOCBP with high VL, no differences were found between TAF and TDF in reducing HBV DNA to levels associated with lower transmission risk. These data support ongoing studies of TAF for pMTCT.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Three new amide derivatives (alteralkaloids A–C,
1
–
3
) and three known alkaloids (
4
–
6
) were afforded after phytochemical investigation of fungus
Alternaria brassicicola
. The structures of ...these compounds were confirmed by NMR spectroscopic and HRESIMS data. Furthermore, the absolute configuration of
1
was determined using the single-crystal X-ray diffraction analysis. Compounds
1
–
3
belong to a class of amide derivatives that have not been found in nature before, sharing the same characteristic signals of the butyl moiety and amide group. These isolated compounds mentioned above were tested for the cytotoxic activity.
Graphical Abstract
Abstract
Soil-derived fungi represent an insufficiently tapped reservoir for discovering new and bioactive natural products (NPs), and despite an ever-increasing number of unknown NPs have been ...discovered over the past few decades, much of the hidden biosynthetic potential is still in an urgent need to be disclosed. In this research, a chemical investigation was performed on a wetland soil-derived fungus
Aspergillus
calidoustus
TJ403-EL05, leading to the isolation of a total of fourteen drimane sesquiterpenoids (
1
–
14
), incorporating three new ones, namely ustusols F–H (
1
–
3
). Their structures, comprising absolute configurations, were completely authenticated by widespread spectroscopic data, quantum chemical
13
C NMR and ECD calculations, and X-ray crystallography experiments. Compound
14
exhibited moderate anti-inflammatory activity by inhibiting the LPS-induced NO release (IC
50
= 25.6 μM).
Graphical Abstract
Two novel compounds including a cyclohelminthol type polyketide (namely oxaleimide K,
1
) and a maleimide derivative (namely peniroquefortine A,
2
), and a new natural product (namely ...2-(acetylamino)-
N
-(1
E
)-2-phenylethenyl-acetamide,
3
), together with four known compounds (
4
–
7
), were isolated and identified from fungus
Penicillium roqueforti
, which was separated from the root soil of
Hypericum beanii
N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures including absolute configurations were mainly established by the NMR spectroscopy analyses and single-crystal X-ray diffraction experiment. Compound
1
represents the second example of a cyclohelminthol type polyketide, which features a rare 6/6/5/5 tetracyclic system and a branched aliphatic chain containing a terminal olefin (oct-1-en-3-yl) moiety, and compound
2
possesses an unprecedented carbon skeleton that is uniquely defined by a maleimide moiety linked to the respective 4-methylene-2-(3-methylbut-2-en-1-yl)-phenol and
para
-substituted aromatic moieties via the carbon-carbon bonds. Remarkably, the absolute configuration of a cyclohelminthol type polyketide as exemplified by compound
1
is determined by the single-crystal diffraction analysis for the first time, highlighting an
E
-configuration for the linkage of a succinimide moiety and a tetrahydrofuran moiety for
1
rather than a
Z
-configuration as previously reported in the biosynthesis study, which gives a new insight into the structural elucidation of this category of polyketides. Additionally, compound
1
exhibited significant cytotoxic activity against multiple tumor cells, especially against the Farage and SU-DHL-2 cells (IC
50
< 20 µM, 48 h). Further mechanism study revealed that compound
1
significantly induced cell cycle arrest in Farage and SU-DHL-2 cells by causing abnormal ROS level and triggering oxidative stress.
Graphical Abstract
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict ...the HCC development for patients with chronic hepatitis.
A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).
We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%.
This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.
In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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•In total, 17,374 patients with viral and non-viral hepatitis from 11 global prospective cohorts/trials were studied.•An HCC risk score (called the aMAP score, ranging from 0 to 100), which involves only age, male, albumin–bilirubin and platelet data, was developed and validated.•The aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk irrespective of aetiology and ethnicity.•Patients with aMAP score <50, accounting for 44% of overall population, had an HCC incidence of <0.2% per year.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Guided by the Global Natural Products Social (GNPS) molecular networking strategy, five undescribed eremophilane-type sesquiterpenoid derivatives (1–5) were isolated and identified from fungus ...Penicillium roqueforti, which was separated from the root soil of plant Hypericum beanii collected in Shennongjia Forestry District, Hubei Province. Dipeniroqueforins A–B (1–2), representing a lactam-type sesquiterpenoid skeleton with a highly symmetrical and homodimeric 5/6/6–6/6/5 hexacyclic system, are reported within the eremophilane-type family for the first time. Peniroqueforin D (5) represents the first example of a 1,2-seco eremophilane-type sesquiterpenoid derivative featuring an undescribed 7/6-fused ring system. The structures of these compounds were elucidated by various spectroscopic analyses, DP4+ probability analyses, ECD calculations, and single-crystal X-ray diffraction experiments. Furthermore, these isolates were evaluated for cytotoxicity, and the result uncovered that compound 1 displayed broad-spectrum activity. Further mechanistic study revealed that compound 1 could significantly upregulate the mRNA expression of genes related to the oxidative induction, leading to the abnormal ROS levels in tumor cells and ultimately causing tumor cell apoptosis.
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IJS, KILJ, NUK, PNG, UL, UM
Nine undescribed eremophilane sesquiterpenes, one undescribed guaiane sesquiterpene, along with ten known analogues were isolated and identified from fungus Penicillium roqueforti, which was ...separated from the root soil of Hypericum beanii N. Robson collected from the Shennongjia Forestry District, Hubei Province. Their structures were elucidated on the basis of various spectroscopic analyses, mainly including NMR and HRESIMS data, 13C NMR calculations with DP4+ probability analyses, ECD calculations, and single-crystal X-ray diffraction experiments. Furthermore, all twenty compounds were evaluated for the in vitro cytotoxic activities against seven human tumor cell lines, and the result suggested that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A exhibited considerable cytotoxic activity against the Farage (IC50 < 10 μM, 48 h), SU-DHL-2, and HL-60 cells. Further mechanism study demonstrated that 14-hydroxymethylene-1(10)-ene-epi-guaidiol A could significantly promote apoptosis by inhibiting tumor cell respiration and decreasing intracellular ROS levels, thereby inducing S-phase blockade in tumor cells.
Nine undescribed eremophilane sesquiterpenes, one undescribed guaiane sesquiterpene, and ten known analogues were isolated from Penicillium roqueforti. 14-Hydroxymethylene-1(10)-ene-epi-guaidiol A could significantly promote apoptosis by inhibiting tumor cell respiration and decreasing intracellular ROS levels, thereby inducing S-phase blockade in tumor cells. Display omitted
•Ten undescribed sesquiterpenes were isolated from Penicillium roqueforti.•Their structures were elucidated by DP4+ analyses, ECD calculations, and crystallography.•14-Hydroxymethylene-1(10)-ene-epi-guaidiol A showed cytotoxic effect against Farage cells.•14-Hydroxymethylene-1(10)-ene-epi-guaidiol A induced S-phase blockade in tumor cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Two undescribed pairs of ester dimer enantiomers, namely glyceryl 4-hydroxy-3-prenyl-benzoate and anofinic glyceride, which represent the first examples of isoprenyl hydroxybenzoic acid derivatives ...bearing a glycerol moiety, were isolated from coculture of Pestalotiopsis sp. and Penicillium bialowiezense . The separation of enantiomers was achieved via chiral-phase HPLC. Their structures incorporating absolute configurations were characterized based on the extensive spectroscopic data, single-crystal X-ray crystallography analysis, Mo 2 (AcO) 4 -induced circular dichroism, and comparison of the experimental ECD curves. Additionally, glyceryl 4-hydroxy-3-prenyl-benzoate and anofinic glyceride were evaluated for the β-glucuronidase (GUS) and butyrylcholinesterase (BChE) inhibitory activities, and glyceryl 4-hydroxy-3-prenyl-benzoate showed remarkable GUS inhibitory potency with an IC 50 value of 22.31 ± 0.60 μM, which was comparable to the positive control DSA ( d -saccharic acid 1,4-lactone monohydrate) (IC 50 = 24.30 ± 0.80 μM).
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