High exposure of global tree diversity to human pressure.

Safeguarding Earth's tree diversity is a conservation priority due to the importance of trees for biodiversity and ecosystem functions and services such as carbon sequestration. Here, we improve the foundation for effective conservation of global tree diversity by analyzing a recently developed database of tree species covering 46,752 species. We quantify range protection and anthropogenic pressures for each species and develop conservation priorities across taxonomic, phylogenetic, and functional diversity dimensions. We also assess the effectiveness of several influential proposed conservation prioritization frameworks to protect the top 17% and top 50% of tree priority areas. We find that an average of 50.2% of a tree species' range occurs in 110-km grid cells without any protected areas (PAs), with 6,377 small-range tree species fully unprotected, and that 83% of tree species experience nonnegligible human pressure across their range on average. Protecting high-priority areas for the top 17% and 50% priority thresholds would increase the average protected proportion of each tree species' range to 65.5% and 82.6%, respectively, leaving many fewer species (2,151 and 2,010) completely unprotected. The priority areas identified for trees match well to the Global 200 Ecoregions framework, revealing that priority areas for trees would in large part also optimize protection for terrestrial biodiversity overall. Based on range estimates for >46,000 tree species, our findings show that a large proportion of tree species receive limited protection by current PAs and are under substantial human pressure. Improved protection of biodiversity overall would also strongly benefit global tree diversity.

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study.

BACKGROUND: Despite immunotherapy advancements for patients with advanced or metastatic non-small-cell lung cancer (NSCLC), pivotal first-line trials were limited to patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and a median age of 65 years or younger. We aimed to compare the efficacy and safety of first-line atezolizumab monotherapy with single-agent chemotherapy in patients ineligible for platinum-based chemotherapy. METHODS: This trial was a phase 3, open-label, randomised controlled study conducted at 91 sites in 23 countries across Asia, Europe, North America, and South America. Eligible patients had stage IIIB or IV NSCLC in whom platinum-doublet chemotherapy was deemed unsuitable by the investigator due to an ECOG PS 2 or 3, or alternatively, being 70 years or older with an ECOG PS 0-1 with substantial comorbidities or contraindications for platinum-doublet chemotherapy. Patients were randomised 2:1 by permuted-block randomisation (block size of six) to receive 1200 mg of atezolizumab given intravenously every 3 weeks or single-agent chemotherapy (vinorelbine [oral or intravenous] or gemcitabine [intravenous]; dosing per local label) at 3-weekly or 4-weekly cycles. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety analyses were conducted in the safety-evaluable population, which included all randomised patients who received any amount of atezolizumab or chemotherapy. This trial is registered with ClinicalTrials.gov, NCT03191786. FINDINGS: Between Sept 11, 2017, and Sept 23, 2019, 453 patients were enrolled and randomised to receive atezolizumab (n=302) or chemotherapy (n=151). Atezolizumab improved overall survival compared with chemotherapy (median overall survival 10·3 months [95% CI 9·4-11·9] vs 9·2 months [5·9-11·2]; stratified hazard ratio 0·78 [0·63-0·97], p=0·028), with a 2-year survival rate of 24% (95% CI 19·3-29·4) with atezolizumab compared with 12% (6·7-18·0) with chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilisation or improvement of patient-reported health-related quality-of-life functioning scales and symptoms and fewer grade 3-4 treatment-related adverse events (49 [16%] of 300 vs 49 [33%] of 147) and treatment-related deaths (three [1%] vs four [3%]). INTERPRETATION: First-line treatment with atezolizumab monotherapy was associated with improved overall survival, a doubling of the 2-year survival rate, maintenance of quality of life, and a favourable safety profile compared with single-agent chemotherapy. These data support atezolizumab monotherapy as a potential first-line treatment option for patients with advanced NSCLC who are ineligible for platinum-based chemotherapy. FUNDING: F Hoffmann-La Roche and Genentech Inc, a member of the Roche group.

Assessment of nutraceutical value, physicochemical, and anti-inflammatory profile of Odonthalia floccose and Odonthalia dentata.

The nutraceutical value, and physicochemical profile as well as anti-inflammatory activity potential of Odonthalia floccose and Odonthalia dentata (red macroalgae) dry biomass were investigated in this study. Proximate composition study results revealed that the dry biomass of O. floccose and O. dentae were found to be as ash: 9.11 & 8.7 g 100 g-1, moisture: 8.24 & 8.1 g 100 g-1, total fat: 6.9 & 7.2 g 100 g-1, protein: 24.52 & 25.6 g 100 g-1, and total carbohydrate/polysaccharides: 53.84 & 48.85 g 100 g-1 of dry weight biomass respectively. Both algae biomass contain considerable quantity of minerals (Fe, Cu, Mg, and Zn). Furthermore, the major saturated fatty acids (6.24 & 5.82 g FAME 100 g-1 of total fat of O. floccose and O. dentate) (ΣFAs) present in the test algae were stearic acid, palmitic acid, and margaric acids. O. floccose and O. dentata also contain remarkable protein composition profile that compiled with considerable quantity of essential and non-essential amino acids. The vitamins such as vitamin A, B1, B2, B3, B6, B9, C, and E of O. floccose and O. dentate biomass were also identified at sufficient quantity level. The swelling capacity (SWC), water holding capacity (WHC), and oil holding capacity (OHC) properties of O. floccose and O. dentate at various temperature conditions (25 and 37 ᵒC) were found to be 8.11 & 7.02 mL g-1 and 8.95 & 7.55 mL g-1, 5.1 & 4.87 and 4.8 & 4.1 mL g-1, as well as 2.11 & 1.81 and 1.96 & 1.89 mL g-1 respectively. Among these two marine red macroalgae samples, the O. dentate showed better anti-inflammatory activity than O. floccose at 150 µg mL-1 dosage. Thus, this O. floccose and O. dentate biomass can be considerable as nutritional supplement and pharmaceutical product development related research.

Aristolochia bracteolata flower extract based phytosynthesis and characterization of AgNPs: Antimicrobial, antidiabetic, and antioxidant activities potential assessment.

The study was carried out to evaluate the effectiveness of the Aristolochia bracteolata water flower extract-mediated AgNPs synthesis and assess their antimicrobial potential. According to the experimental and analytical results, A. bracteolata flower extract can produce valuable AgNPs. The characteristic features of these AgNPs were assessed with UV-visible spectrophotometer, Fourier transform-infrared spectroscopy, Transmission Electron Microscope, Scanning Electron Microscopy, as well as. Under UV-vis. spectrum results, showed major peak at 430 nm and recorded essential functional groups responsible for reducing, capping, and stabilizing AgNPs by FT-IR analysis. In addition, the size and shape of the synthesized AgNPs were found as 21.11-25.17 nm and spherical/octahedral shape. The A. bracteolata fabricated NPs showed remarkable antimicrobial activity against fish bacterial pathogens (V. parahaemolytics, Serratia sp., B. subtilis, and E. coli) as well as common fungal pathogens (A. niger, C. albicans, A. flavus, and A. terreus) at the quantity of 100 µg mL-1 than positive controls. Nevertheless, it was not effective against human bacterial pathogens. It concludes that AgNPs synthesized from A. bracteolata aqueous flower extract have excellent antimicrobial activity and may have a variety of biomedical applications.

Unveiling the role of heterophase nanostructure in MnO2-based colorimetric sensors for ascorbic acid detection.

Nanozymes based on manganese oxide (MnO2) are demonstrated to be promising probes in colorimetric sensing applications. In this study, the r-MnO2/ß-MnO2 heterophase nanostructure was simply prepared by a calcination process with controllable temperature. The characterization of the nanostructured material was confirmed by SEM, UV-vis spectroscopy, Raman, TGA-DSC, and XRD analysis. The r-MnO2/ß-MnO2 exhibits a remarkably good catalytic activity in the oxidation process of 3,3',5,5'-tetramethylbenzidine (TMB) compared with the r-MnO2 or Mn2O3 nanostructure owing to its heterophase junctions. The enhanced performance of the colorimetric sensor for ascorbic acid (AA) detection was investigated using the r-MnO2/ß-MnO2 heterophase nanostructure as probe. The r-MnO2/ß-MnO2 material enhanced the monitoring of AA in the wide linear range from 1 µM to 50 µM with a limit of detection of 0.84 µM. This work presents a promising and straightforward approach for the construction of MnO2-based colorimetric sensor and their practical application in plant growth monitoring.

Iterative Adaptive Spectroscopy of Short Signals.

We develop an iterative, adaptive frequency sensing protocol based on Ramsey interferometry of a two-level system. Our scheme allows one to estimate unknown frequencies with a high precision from short, finite signals consisting of only a small number of Ramsey fringes. It avoids several issues related to processing of decaying signals and reduces the experimental overhead related to sampling. High precision is achieved by enhancing the Ramsey sequence to prepare with high fidelity both the sensing and readout state and by using an iterative procedure built to mitigate systematic errors when estimating frequencies from Fourier transforms. A comparison with state-of-the-art dynamical decoupling techniques reveals a significant speedup of the frequency estimation without loss of precision.

A manganese dioxide-silver nanostructure-based SERS nanoplatform for ultrasensitive tricyclazole detection in rice samples: effects of semiconductor morphology on charge transfer efficiency and SERS analytical performance.

Taking advantage of metal-semiconductor junctions, functional nanocomposites have been designed and developed as active substrates for surface-enhanced Raman scattering (SERS) sensing systems. In this work, we prepared three types of nanocomposites based on manganese oxide (MnO2) nanostructures and electrochemically synthesized silver nanoparticles (e-AgNPs), which differed according to the morphologies of MnO2. The SERS performance of MnO2 nanosheet/e-Ag (MnO2-s/e-Ag), MnO2 nanorod/e-Ag (MnO2-r/e-Ag), and MnO2 nanowire/e-Ag (MnO2-w/e-Ag) was then evaluated using tricyclazole (TCZ), a commonly used pesticide, as an analyte. Compared to the others, MnO2-s/e-Ag exhibited the most remarkable SERS enhancement. Thanks to its large surface area and ability to accept/donate the electrons of the semiconductor, MnO2-s acted as a bridge to improve the charge transfer efficiency from e-Ag to TCZ. In addition, the MnO2 content of the nanocomposites was also considered to optimize the SERS sensing performance. With the optimal MnO2 content of 25 wt%, MnO2-s/e-Ag could achieve the best SERS performance, allowing the detection of TCZ at concentrations down to 6 × 10-12 M in standard solutions and 10-11 M in real rice samples.

Insight into the Influence of Analyte Molecular Structure Targeted on MoS2-GO-Coated Electrochemical Nanosensors.

MoS2-GO composites were fabricated by an ultrasonication method at room temperature. Raman spectra, emission scanning electron microscopy (SEM), and transmission electron microscopy (TEM) images were used to study the structural characteristics, morphologies, and sizes of the synthesized materials. An MoS2-GO/SPE (screen-printed electrode) was prepared by a facile dropping method and acted as an effective electrochemical sensor toward clenbuterol (CLB) and 4-nitrophenol (4-NP) detection. Based on the obtained results, the influence of analyte molecular structure on the adsorption ability and electronic interoperability between the targeted analyte and electrode surface were investigated in detail and discussed as well, through some electrochemical kinetic parameters (electron/proton-transfer number, electron transfer rate constant (ks), charge transfer coefficient, and adsorption capacity (Γ)). In particular, it should be stressed that 4-NP molecules possess a simple molecular structure with many positive effects (electronic, conjugation, and small steric effects) and flexible functional groups, resulting in fast electron transport/charge diffusion and effective adsorption process as well as strong interactions with the electrode surface. Therefore, 4-NP molecules have been facilitated better in electrochemical reactions at the electrode surface and electrode-electrolyte interfaces, leading to improved current response and electrochemical sensing performance, compared with those of CLB.

Ethnic Variations in Healthcare Service Utilization and Access in Vietnamese Mountainous Setting.

Evidence of health service use and access across different target groups is essential for policy development, health promotion, and promotion of equity in healthcare. This study aims to look at ethnic variations in health service use and access among residents in mountainous areas of Vietnam. A cross-sectional descriptive study was conducted on 321 adults from two mountainous communes in Bac Kan province. Healthcare service use and access were evaluated by using a structured questionnaire. Zero-inflated Poisson regression was used to examine the ethnic variations in the healthcare service use and access. Of 321 mountainous residents, 63.6% used health services in the previous 12 months, of which 24.9% respondents used inpatient services and 47.9% used outpatient services. The number of outpatient medical services used by the Tay participant was higher than that of the Kinh and other ethnic groups (p < 0.05). Multivariate regression results showed that compared to Kinh people, Tay people had a higher number of outpatient service use (Coef. = 0.25, p=0.04), while people in other ethnicities had a lower number of service use (Coef. = -0.64, p=0.01). Meanwhile, no difference was found among groups regarding the number of inpatient service use (p > 0.05). This study showed the ethnic differences in outpatient use of health services among communities living in the northern mountainous setting of Vietnam.

Stigma Related to HIV and Drug Use: Layers, Types, and Relations to Mental Health.

Stigma poses considerable challenges to the mental health of people living with HIV who use drugs (PLHWUD). In this study, we explored factors related to different types of stigma (perceived and internalized) attached to layered stigmatizing characters (HIV and drug use) and their mental health influences on PLHWUD. The study used baseline data of an ongoing randomized controlled trial among 241 PLHWUD recruited between March and December 2018 in Vietnam. A structural equation model was used to assess the relationships among different types and layers of stigma and mental health status. Both perceived and internalized drug-related stigma measures were significantly higher than their corresponding HIV-related stigma. HIV-related stigma was negatively associated with mental health status; however, we did not find a significant relationship between drug-related stigma and mental health. Tailored intervention strategies in consideration of types and layers of stigma are needed to address stigma-related challenges faced by PLHWUD.

Variation of Mitochondrial DNA HV1 AND HV2 of the Vietnamese Population.

BACKGROUND: The sequence polymorphism of mitochondrial DNA (mtDNA) hypervariable segment 1 (HV1) and hypervariable segment 2 (HV2) is studied and applied to genetic diversity and human evolution assessment, forensic genetics, consanguinity determination, and mitochondrial disease diagnosis. METHODS: The study identified the variations of HV1 and HV2 of 517 unrelated Vietnamese individuals in Kinh, Muong, Cham, and Khmer ethnic. We performed sequencing of two hypervariable segments of mitochondrial DNA: HV1 and HV2. RESULTS: Fifty haplogroups were identified in which F1a haplogroup frequency was highest at 15.7%, followed by B5a (10.8%), M (8.9%), and M7b1 (7.7%). The most frequently encountered SNPs in this study were A263G (100%), A73G (99.6%), 315insC (96%), 309insC (56%), C16223T (41%), and T16189C (39%). The genetic diversity was calculated at 99.83%, and the probability of random match of two individuals sharing the same mtDNA haplotype was 0.37%. CONCLUSION: We have assessed the genetic polymorphism of mtDNA HV1 and HV2 of 517 Kinh, Muong, Cham, and Khmer ethnic samples. The result will help in better understanding of Vietnamese's mitochondrial genome diversity and aid in population as well as forensic science.

Microstructure and Chemo-Physical Characterizations of Functional Graphene Oxide-Iron Oxide-Silver Ternary Nanocomposite Synthesized by One-Pot Hydrothermal Method.

In this work, a functional graphene oxide-iron oxide-silver (GO-Fe3O4-Ag) ternary nanocomposite was synthesized by using one-pot hydrothermal treatments of mixture solutions of silver nitrate (AgNO3), ferrous chloride tetrahydrate (FeCl2 4H2O), polyvinylpyrrolidone (PVP), graphene oxide (GO), and ammonium hydroxide solution (NH4OH). The systematic effects of synthesis conditions on the microstructure and formation of binary and ternary composite systems were studied. Importantly, high-crystalline GO-Fe3O4-Ag ternary nanomaterials with average sizes of Fe3O4 particles ~16 nm and of Ag particles ~20 nm were obtained at optimized conditions (125 °C, 2.5 mM of AgNO3 and 5 mL of NH4OH). Magnetic analysis indicated that the saturated magnetization value of Fe3O4-Ag binary composite sample (~73.1 emu/g) was improved as compared with pure Fe3O4 nanoparticles (~60.6 emu/g), while this of GO-Fe3O4-Ag ternary composite sample was about 57.3 emu/g. With exhibited advantages of low-cost, high purity and short synthesis time, the hydrothermal-synthesized GO-Fe3O4-Ag ternary nanocomposite can be a promising candidate for advanced environmental catalyst and biomedical applications.

Antibacterial activities of chemical constituents from the aerial parts of Hedyotis pilulifera.

CONTEXT: Hedyotis pilulifera (Pit.) T.N. Ninh (Rubiaceae) has been used in Vietnamese ethnomedicine; the methanol extract exhibited antibacterial activity in our preliminary screening. OBJECTIVES: In this study, compounds from H. pilulifera were isolated and their antibacterial activity in vitro was evaluated. MATERIALS AND METHODS: The aerial parts of H. pilulifera (1.4 kg) were extracted with MeOH, suspended in water and ethyl acetate extract was chromatographed on a silica gel column. The structures of isolated compounds were elucidated by the combination analyses of spectroscopy including 1D-, 2D-NMR, HRMS and in comparison with the reported NMR data in the literature. All isolated compounds were evaluated for inhibitory effect using the microdilution method toward Staphylococcus aureus, Bacillus subtilis and Mycobacterium smegmatis, and MIC values were determined. RESULTS: Twenty compounds were isolated, including five triterpenoids, two steroids, two aromatic compounds, three fatty acids, one quinone derivative, one lignan glycoside, one ceramide and five glycolipids. Among these, oleanolic acid showed significant antibacterial activity against M. smegmatis with the MIC value of 2.5 µg/mL. Remarkably, rotungenic acid showed strong activity against S. aureus, B. subtilis, M. smegmatis with MIC values of 2.5, 2.5 and 1.25 µg/mL, respectively. Rotundic acid exhibited significant antibacterial activity against B. subtilis with the MIC value of 5 µg/mL. To the best of our knowledge, the antibacterial activity of rotungenic acid, stigmast-4-ene-3,6-dione and (2S,3S,4R,2'R)-2-(2'-hydroxytetracosanoylamino) octadecane-1,3,4-triol was reported for the first time. CONCLUSIONS: Oleanolic acid, rotungenic acid, and rotundic acid were considered to be useful for developing new antimicrobial therapeutic agents for human.

Enhanced magnetic anisotropy and heating efficiency in multi-functional manganese ferrite/graphene oxide nanostructures.

A promising nanocomposite material composed of MnFe2O4 (MFO) nanoparticles of ∼17 nm diameter deposited onto graphene oxide (GO) nanosheets was successfully synthesized using a modified co-precipitation method. X-ray diffraction, transmission electron microscopy, and selected area electron diffraction confirmed the quality of the synthesized samples. Fourier transform infrared measurements and analysis evidenced that the MFO nanoparticles were attached to the GO surface. Magnetic measurements and analysis using the modified Langevin model evidenced the superparamagnetic characteristic of both the bare MFO nanoparticles and the MFO-GO nanocomposite at room temperature, and an appreciable increase of the effective anisotropy for the MFO-GO sample. Magnetic hyperthermia experiments performed by both calorimetric and ac magnetometry methods indicated that relative to the bare MFO nanoparticles, the heating efficiency of the MFO-GO nanocomposite was similar at low ac fields (0-300 Oe) but became progressively larger with increasing ac fields (>300 Oe). This has been related to the higher effective anisotropy of the MFO-GO nanocomposite. In comparison with the bare MFO nanoparticles, a smaller reduction in the heating efficiency was observed in the MFO-GO composites when embedded in agar or when their concentration was increased, indicating that the GO helped minimize the physical rotation and aggregation of the MFO nanoparticles. These findings can be of practical importance in exploiting this type of nanocomposite for advanced hyperthermia. Magnetoimpedance-based biodetection studies also indicated that the MFO-GO nanocomposite could be used as a promising magnetic biomarker in biosensing applications.

Synthesis, Characterizations of Superparamagnetic Fe3O4-Ag Hybrid Nanoparticles and Their Application for Highly Effective Bacteria Inactivation.

In recent years, outbreaks of infectious diseases caused by pathogenic micro-organisms pose a serious threat to public health. In this work, Fe3O4-Ag hybrid nanoparticles were synthesized by simple chemistry method and these prepared nanoparticles were used to investigate their antibacterial properties and mechanism against methicilline-resistant Staphylococcus aureus (MRSA) pathogen. The formation of dimer-like nanostructure of Fe3O4-Ag hybrid NPs was confirmed by X-ray diffraction and High-resolution Transmission Electron Microscopy. Our biological analysis revealed that the Fe3O4-Ag hybrid NPs showed more noticeable bactericidal activity than that of plain Fe3O4 NPs and Ag-NPs. We suggest that the enhancement in bactericidal activity of Fe3O4-Ag hybrid NPs might be likely from main factors such as: (i) enhanced surface area property of hybrid nanoparticles; (ii) the high catalytic activity of Ag-NPs with good dispersion and aggregation stability due to the iron oxide magnetic carrier, and (iii) large direct physical contacts between the bacterial cell membrane and the hybrid nanoparticles. The superparamagnetic hybrid nanoparticles of iron oxide magnetic nanoparticles decorated with silver nanoparticles can be a potential candidate to effectively treat infectious MRSA pathogen with recyclable capability, targeted bactericidal delivery and minimum release into environment.

Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the international randomised phase 3 CORRECT trial (NCT01103323), regorafenib significantly improved overall survival versus placebo in patients with treatment-refractory metastatic colorectal cancer. Of the 760 patients in CORRECT, 111 were Asian (mostly Japanese). This phase 3 trial was done to assess regorafenib in a broader population of Asian patients with refractory metastatic colorectal cancer than was studied in CORRECT. METHODS: In this randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial done in 25 hospitals in mainland China, Hong Kong, South Korea, Taiwan, and Vietnam, we recruited Asian patients aged 18 years or older with progressive metastatic colorectal cancer who had received at least two previous treatment lines or were unable to tolerate standard treatments. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and adequate bone marrow, liver, and renal function, without other uncontrolled medical disorders. We randomly allocated patients (2:1; with a computer-generated unicentric randomisation list [prepared by the study funder] and interactive voice response system; block size of six; stratified by metastatic site [single vs multiple organs] and time from diagnosis of metastatic disease [<18 months vs ≥18 months]) to receive oral regorafenib 160 mg once daily or placebo on days 1-21 of each 28 day cycle; patients in both groups were also to receive best supportive care. Participants, investigators, and the study funder were masked to treatment assignment. The primary endpoint was overall survival, and we analysed data on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01584830. FINDINGS: Between April 29, 2012, and Feb 6, 2013, we screened 243 patients and randomly assigned 204 patients to receive either regorafenib (136 [67%]) or placebo (68 [33%]). After a median follow-up of 7·4 months (IQR 4·3-12·2), overall survival was significantly better with regorafenib than it was with placebo (hazard ratio 0·55, 95% CI 0·40-0·77, one-sided p=0·00016; median overall survival 8·8 months [95% CI 7·3-9·8] in the regorafenib group vs 6·3 months [4·8-7·6] in the placebo group). Drug-related adverse events occurred in 132 (97%) of 136 regorafenib recipients and 31 (46%) of 68 placebo recipients. The most frequent grade 3 or higher regorafenib-related adverse events were hand-foot skin reaction (22 [16%] of 136 patients in the regorafenib group vs none in the placebo group), hypertension (15 [11%] vs two [3%] of 68 patients in the placebo group), hyperbilirubinaemia (nine [7%] vs one [1%]), hypophosphataemia (nine [7%] vs none), alanine aminotransferase concentration increases (nine [7%] vs none), aspartate aminotransferase concentration increases (eight [6%] vs none), lipase concentration increases (six [4%] vs one [1%]), and maculopapular rash (six [4%] vs none). Drug-related serious adverse events occurred in 12 (9%) patients in the regorafenib group and three (4%) in the placebo group. INTERPRETATION: This phase 3 trial is the second to show an overall survival benefit with regorafenib compared with placebo in patients with treatment-refractory metastatic colorectal cancer, substantiating the role of regorafenib as an important treatment option for patients whose disease has progressed after standard treatments. In this trial, preceding standard treatments did not necessarily include targeted treatments. Adverse events were generally consistent with the known safety profile of regorafenib in this setting. FUNDING: Bayer HealthCare Pharmaceuticals.

A new polyoxygenated cyclohexene and a new megastigmane glycoside from Uvaria grandiflora.

A new polyoxygenated cyclohexene, (-)-3-O-debenzoylzeylenone (1), and a new megastigmane glycoside, grandionoside A (2), were isolated from the aerial parts of Uvaria grandiflora collected in Vietnam, together with ten known compounds including polyoxygenated cyclohexenes (3-6), a triterpenoid (7), an alkaloid (8), a long chain alcohol (9), hexenyl glycopyranoside (10), and saponins (11-12). Their chemical structures were elucidated by a combination of extensive NMR spectroscopy with X-ray crystallographic analysis for 1, and chemical conversion for 2. Compound 1 exhibited significant cytotoxicity against the LU-1 and SK-Mel-2 cell lines with IC50 values of 4.68 and 3.63 µM, respectively. Remarkably, the cytotoxicity of 12 against the LU-1, KB, Hep-G2, MKN-7, and SW-480 cell lines was comparable to that of ellipticine, the positive control, with IC50 values ranging from 1.24 to 1.60 µM.

The role of chitosan in enhancing the solubility and antibacterial activity of emodin against drug-resistant bacteria.

Similar to most anthraquinone compounds, the pharmacological properties of emodin are limited because of its low water solubility. In this study, the formulation of chitosan and emodin (EMD/CS) was prepared by a bottom-up method with precipitation and sonication steps in order to enhance the solubility of emodin. Thanks to the interactions of oxygen-and nitrogen-containing groups in chitosan with emodin molecules, the solubility of emodin in the formulation was remarkably increased to 0.5 mg/mL. The EMD/CS particles were well dispersed and distributed in a range of sub-micrometer with an average particle size of 342 nm. The EMD/CS formulation exhibited synergic antibacterial activity of emodin and chitosan, against drug-resistant bacterial strains, namely Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli O157:H7 (E. coli O157:H7). When the compositions of emodin and chitosan increased, the antibacterial effectiveness of the EMD/CS formulation increased. The EMD/CS formulation with compositions of 0.5 mg/mL of emodin and 9.0 mg/mL of chitosan could significantly inhibit the proliferation of E. coli O157:H7. Meanwhile, the EMD/CS formulation with a lower concentration of emodin (0.4 mg/mL) and chitosan (7.2 mg/mL) could cause an extermination effect on MRSA. The enhanced solubility of EMD/CS formulation suggests that this formulation can be a potential candidate for the treatment of infectious diseases caused by drug-resistant bacterial pathogens.

Essential oil of the leaves of psychotria asiatica L.: chemical composition, antioxidant, anti-inflammatory, and cytotoxic properties.

This study is focused on investigating the chemical composition and bioactive properties of the essential oil extracted from Psychotria asiatica L., a plant species known for its medicinal properties. Utilising gas chromatography-mass spectrometry (GC-MS) analysis, the essential oil from P. asiatica was found to contain 53 distinct constituents. Major compounds identified include (E)-citral (20.6%), 10-epi-γ-eudesmol (15.9%), (Z)-citral (10.5%), geraniol (7.4%), α-cadinol (6.7%), 7-epi-α-eudesmol (4.4%), linalool (3.7%), and α-muurolol (3.4%). The essential oil did not exhibit antioxidant activity, as indicated by an IC50 value of > 100 µg/mL, whereas the positive control L-Ascorbic acid had an IC50 of 7.37 ± 0.27 µg/mL in the DPPH model. Assessment of its anti-inflammatory potential revealed an inhibitory effect on NO production, with an IC50 value of 29.08 ± 1.54 µg/mL in Lipopolysaccharide-induced RAW264.7 macrophage cells. Furthermore, the essential oil demonstrated significant cytotoxicity against the SK-LU-1 cancer cell line, with an IC50 value of 39.75 ± 1.79 µg/mL according to the sulforhodamine B (SRB) assay.