Conamonin A and dihydrochalcones from the whole plants of Conamomum rubidum (Lamxay & N.S.Lý) Skornick. & A.D. Poulsen showing anti-inflammatory and cytotoxic activities.

A new compound, conamonin A (1), was isolated from the whole plants of Conamomum rubidum with eight known dihydrochalcones (2-9). Their structures were elucidated by a combination of spectroscopic methods as well as by comparison with previously reported data. The absolute configuration of 1 was assigned by TDDFT-ECD method. Compounds 1 and 8 showed inhibitory activity against LPS-induced NO production in the RAW 264.7 cells, with IC50 values of 58.29 ± 2.88 and 81.77 ± 5.99 µM, respectively. Compounds 3/4 and 5/6 exhibited inhibitory effects, with IC50 values of 28.76 ± 1.16 and 29.89 ± 1.79 µg/mL, respectively. Compounds 2, 7-9 exhibited significant cytotoxic activity against human lung carcinoma (the SK-LU-1 cell line) with IC50 values ranging from 9.87 to 17.99 µM. This study offers valuable insights into the chemical constituents and biological activities of Conamomum rubidum, highlighting its potential as a source for discovering new anti-inflammatory and cytotoxic agents.

Homalolides C-D, two new sesquiterpenoids from the rhizomes of Homalomena pendula.

Two new sesquiterpenoids, homalolides C - D (1‒2), were co-isolated from the rhizomes of Homalomena pendula (Blume) Bakh.f collected in Vietnam with five known ones, aromadendrane-4α,10α-diol (3), bullatantriol (4), 1ß,4ß,6α-trihydroxy-eudesmane (5), 1ß,4ß,6ß-trihydroxyeudesmane (6), and 1ß,4ß,7α-trihydroxy-eudesmane (7). The structures and relative configuration of new compounds were elucidated by 1 D-/2D-NMR, IR, UV and HRESIMS analyses, and by comparisons to the reported data in the literature. Homalolide C presented an unprecedented skeleton with the 4/8 bicyclic system. All isolates did not exhibit appreciable inhibitory effects on LPS-induced NO production in the RAW 264.7 macrophage cell line and on the growth of human lung cancer cell line (SK-LU-1).

Conarubins A-D: Four Monoterpene-Chalcone Conjugates from Conamomum rubidum and Their Anti-inflammatory and Cytotoxic Activities.

Four novel compounds, conarubins A-D (1-4), were isolated from the whole plants of Conamomum rubidum collected in Vietnam. Their structures were elucidated by extensive spectroscopic analyses and by quantum chemical calculations of NMR and ECD. Compounds 1 and 2 were the first examples of monoterpene-monoterpene-chalcone conjugates in nature, whereas compound 4 was an unprecedented monoterpene-substituted chalcone containing a 3,4,5-trioxygenated cyclohexa-2,5-diene-1-one ring. The anti-inflammatory and cytotoxic activities of all isolates were investigated.

Sesquiterpenoids from the rhizomes of Homalomena pendula and their anti-inflammatory activities.

Sixteen sesquiterpenoids including two new ones, homalolides A - B (1‒2), were firstly isolated from the methanolic extract of the rhizomes of Homalomena pendula collected in Vietnam. The structures and relative stereochemistry of new compounds were elucidated by 1D-/2D-NMR, IR, UV and HRESIMS analyses. The GCMS experiment demonstrated that homalolide A (1) is an artifact due to the methylation during methanolic extraction process. All isolates (1‒16) were tested for their inhibitory activities against lipopolysaccharide-induced nitric oxide production in the RAW 264.7 macrophage cell line. Compounds 1, 3, 6‒8, 10‒12 displayed moderate inhibitory effect on NO production with IC50 values ranging from 35.41 to 64.06 µM.

Rac-dependent feedforward autoactivation of NOX2 leads to oxidative burst.

NADPH oxidase 2 (NOX2) produces the superoxide anion radical (O2-), which has functions in both cell signaling and immune defense. NOX2 is a multimeric-protein complex consisting of several protein subunits including the GTPase Rac. NOX2 uniquely facilitates an oxidative burst, which is described by initially slow O2- production, which increases over time. The NOX2 oxidative burst is considered critical to immune defense because it enables expedited O2- production in response to infections. However, the mechanism of the initiation and progression of this oxidative burst and its implications for regulation of NOX2 have not been clarified. In this study, we show that the NOX2 oxidative burst is a result of autoactivation of NOX2 coupled with the redox function of Rac. NOX2 autoactivation begins when active Rac triggers NOX2 activation and the subsequent production of O2-, which in turn activates redox-sensitive Rac. This activated Rac further activates NOX2, amplifying the feedforward cycle and resulting in a NOX2-mediated oxidative burst. Using mutagenesis-based kinetic and cell analyses, we show that enzymatic activation of Rac is exclusively responsible for production of the active Rac trigger that initiates NOX2 autoactivation, whereas redox-mediated Rac activation is the main driving force of NOX2 autoactivation and contributes to generation of ∼98% of the active NOX2 in cells. The results of this study provide insight into the regulation of NOX2 function, which could be used to develop therapeutics to control immune responses associated with dysregulated NOX2 oxidative bursts.

Effectively Conducting Oncology Clinical Trials During the COVID-19 Pandemic.

PURPOSE: Clinical trial enrollment has declined globally as a result of the coronavirus disease 2019 (COVID-19) pandemic. This underscores the importance of structured methods to continue critical medical research safely and efficiently. METHODS AND MATERIALS: We report the effect of a phased trial reopening strategy, remote research staffing, and telemedicine on cancer trial enrollment at one of the largest radiation oncology academic cancer centers. In phase 1, trials investigating definitive therapeutic benefit were opened, followed by trials not increasing patient exposure or pulmonary toxicity risk in phase 2. During phase 2.5, multicenter trials reopened and limited research staff were allowed on site. RESULTS: Despite initial enrollment declines during the early pandemic, the percentage of new patients enrolling in clinical trials from March to August 2020 was 8.8%, and represented a 10.5% relative increase from 2019. Monthly accrual enrollment from March to August 2019 ranged from 42 to 71, compared with enrollment during COVID-19 from 23 to 73 patients (P < .001). CONCLUSIONS: Through a phased approach to trial reopening and adaptive techniques, the division of radiation oncology maintained cancer trial accrual during the COVID-19 pandemic. The experience may help centers maintain accrual, preserve clinical trial integrity, and minimize risk to patients and staff.

Development of Noonan syndrome by deregulation of allosteric SOS autoactivation.

Ras family proteins play an essential role in several cellular functions, including growth, differentiation, and survival. The mechanism of action of Ras mutants in Costello syndrome and cancers has been identified, but the contribution of Ras mutants to Noonan syndrome, a genetic disorder that prevents normal development in various parts of the body, is unknown. Son of Sevenless (SOS) is a Ras guanine nucleotide exchange factor. In response to Ras-activating cell signaling, SOS autoinhibition is released and is followed by accelerative allosteric feedback autoactivation. Here, using mutagenesis-based kinetic and pulldown analyses, we show that Noonan syndrome Ras mutants I24N, T50I, V152G, and D153V deregulate the autoactivation of SOS to populate their active form. This previously unknown process has been linked so far only to the development of Noonan syndrome. In contrast, other Noonan syndrome Ras mutants-V14I, T58I, and G60E-populate their active form by deregulation of the previously documented Ras GTPase activities. We propose a novel mechanism responsible for the deregulation of SOS autoactivation, where I24N, T50I, V152G, and D153V Ras mutants evade SOS autoinhibition. Consequently, they are capable of forming a complex with the SOS allosteric site, thus aberrantly promoting SOS autoactivation, resulting in the population of active Ras mutants in cells. The results of this study elucidate the molecular mechanism of the Ras mutant-mediated development of Noonan syndrome.

Three new steroidal saponins from Aspidistra letreae plants and their cytotoxic activities.

Three new steroidal saponins, aspiletreins A-C (1-3), together with 2H-chromen-2-one (4), and α-tocopherol (5), were isolated from whole Aspidistra letreae plants collected in Vietnam. Their structures were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR, IR, and HRESIMS, and by comparison with the reported data in the literature. Compounds 1-3 exhibited moderate cytotoxicities against the LU-1, HeLa, MDA-MB-231, HepG2, and MKN-7 human cancer cell lines, with IC50 values ranging from 7.69 ± 0.40 to 20.46 ± 3.11 µM.

The dynein light chain 8 (LC8) binds predominantly "in-register" to a multivalent intrinsically disordered partner.

Dynein light chain 8 (LC8) interacts with intrinsically disordered proteins (IDPs) and influences a wide range of biological processes. It is becoming apparent that among the numerous IDPs that interact with LC8, many contain multiple LC8-binding sites. Although it is established that LC8 forms parallel IDP duplexes with some partners, such as nucleoporin Nup159 and dynein intermediate chain, the molecular details of these interactions and LC8's interactions with other diverse partners remain largely uncharacterized. LC8 dimers could bind in either a paired "in-register" or a heterogeneous off-register manner to any of the available sites on a multivalent partner. Here, using NMR chemical shift perturbation, analytical ultracentrifugation, and native electrospray ionization MS, we show that LC8 forms a predominantly in-register complex when bound to an IDP domain of the multivalent regulatory protein ASCIZ. Using saturation transfer difference NMR, we demonstrate that at substoichiometric LC8 concentrations, the IDP domain preferentially binds to one of the three LC8 recognition motifs. Further, the differential dynamic behavior for the three sites and the size of the fully bound complex confirmed an in-register complex. Dynamics measurements also revealed that coupling between sites depends on the linker length separating these sites. These results identify linker length and motif specificity as drivers of in-register binding in the multivalent LC8-IDP complex assembly and the degree of compositional and conformational heterogeneity as a promising emerging mechanism for tuning of binding and regulation.

Factors Associated with Cigarette Smoking and Motivation to Quit among Street Food Sellers in Vietnam.

Since 2013, smoke-free signs in public places, including in restaurants and food stores, have been introduced in Vietnam, aiming to prevent passive smoking. Although extensive research has been carried out on second-hand smoking among clients in public places (e.g., hospitals, restaurants) in Vietnam, no single study exists which captures the current practice of smoking among street food outlets. This study aims to estimate the prevalence of smoking and identify factors associated with smoking status and cessation motivation amongst food sellers in Vietnam. A cross-sectional study involving 1733 food providers at outlets was conducted in 29 districts in Hanoi capital, Vietnam, in 2015. The prevalence of smoking amongst food sellers was determined to be 8.5% (25% for men and 0.8% for women). The enforcement of the smoke-free policy remains modest, since only 7.9% observed outlets complied with the law, providing a room designated for smokers. Although approximately 80% of the participants were aware of the indoor smoke-free regulations in public places, such as restaurants and food stores, 40.2% of smokers reported no intention of quitting smoking. A percentage of 37.6% of current smokers reported that despite having intentions to quit, they did not receive any form of support for smoking cessation. Being male and having hazardous drinking habits and a poor quality of life were all factors that were significantly associated with smoking status. Additionally, having awareness of smoking's adverse effects and being frequently supervised by the authority were associated with a greater motivation to quit. This study highlights the importance of an accompanying education and smoking cessation program in addition to the frequent inspection and reinforcement of smoke-free policy in food stores. This research extends on our knowledge of smoking prevalence and its factors related to smoking events and motivation to quit among street food outlets. Overall, this study strengthens the idea that more government efforts towards preventing passive smoking and smoking cessation education are necessary in restaurants and other street food outlets.

A new triterpene ester and other chemical constituents from the aerial parts of Anodendron paniculatum and their cytotoxic activity.

The aim of the research was to study the active constituents of Anodendron paniculatum Roxb. (Apocynaceae). A new triterpene ester, named anopaniester (1), and cycloartenol (2), ursolic acid (3), esculenic acid (4), bis-(2-ethylhexyl) phthalate (5), desmosterol (6), stigmasterol (7), vaniline (8), and (E)-phytol (9), were isolated from the aerial parts of A. paniculatum. Compounds 3 and 6 showed the significant inhibitory effect (IC50 values ranging from 30.89 ± 3.60 to 44.37 ± 5.40 µg/ml) against tested human cancer cell lines LU-1 and MKN-7. The compounds 1-4, and 6 were isolated from this genus Anodendron for the first time.

Enhancing cancer immunotherapy through nanotechnology-mediated tumor infiltration and activation of immune cells.

Cancer immunotherapy has become arguably the most promising advancement in cancer research and therapy in recent years. The efficacy of cancer immunotherapy is critically dependent on specific physiological and physical processes - collectively referred to as transport barriers - including the activation of T cells by antigen presenting cells, T cells migration to and penetration into the tumor microenvironment, and movement of nutrients and other immune cells through the tumor microenvironment. Nanotechnology-based approaches have great potential to help overcome these transport barriers. In this review, we discuss the ways that nanotechnology is being leveraged to improve the efficacy and potency of various cancer immunotherapies.

New iron tetrazolate frameworks: synthesis, temperature effect, thermal behaviour, Mössbauer and magnetic studies.

The exploration of the FeF3/FeF2-Hamtetraz-HF system in dimethylformamide by solvothermal synthesis evidences two isostructural 3D hybrid fluoroferrates. They are prepared from the same starting mixture at two different synthesis temperatures: 120 °C for [Hdma]·(Fe4(II)Fe(III)F8(H2O)2(amtetraz)4) () and 140 °C for [Hdma]1.5·(Fe4.5(II)Fe0.5(III)F7(H2O)(HCOO)(amtetraz)4) (). Both compounds are characterized by single crystal X-ray diffraction, X-ray thermodiffraction, TGA analysis, Mössbauer spectrometry and SQUID magnetometry. They crystallize in the monoclinic system and are built from two distinct chains connected by aminotetrazolate anions. The first chain ∞(Fe(II)FN4) is common to and and can be found in numerous fluorides. In the second chain ∞(Fe3X12) (X = F, N, O), iron cations adopt both valence states Fe(ii)/Fe(iii). The hydrolysis of DMF implies the formation of a [Hdma](+) cation and a (HCOO)(-) anion. The presence of Fe(3+) in both phases is evidenced by (57)Fe Mössbauer spectrometry. The magnetic properties are studied and two transitions from a paramagnetic regime to a long range ordered state below 30 K and 5 K are identified.

Synergistic co-delivery of doxorubicin and paclitaxel using multi-functional micelles for cancer treatment.

The main purposes of this study are to demonstrate the synergistic anticancer drug systems with the combined doxorubicin (D) and paclitaxel (P) via the aid of cell penetrating and cell targeting moieties for enhancing the cancer therapeutic effect. Firstly, the synergistic effect of combined free drugs (D/P) was investigated to obtain the suitable dose combination for subsequent studies. The combination of free drugs D/P at molar ratio of 1/0.2 shows synergistic therapeutic effect compared with the treatment of a free single drug D or P. Secondly, sustainable release systems of two single drug-loaded micelles, (i) co-delivered D-FOL micelle & P-FOL micelle system and (ii) co-delivered D-TAT/FOL micelle & P-TAT/FOL micelle system, at D/P molar ratio of 1/0.2 were investigated. The results show synergistic effect with the higher efficacy of the TAT/FOL system compared to FOL only system. Finally, a dual D/P-loaded system with sustainable release rate, synergistic drug interaction, selective targeting to cancer cells and high cell penetrating ability was designed. The D/P-TAT/FOL micelles exhibit an IC50 value of 0.172 µM D/0.043 µM P, which is much lower than the IC50 values of the single drug-loaded micelles without functionalization (3.873 µM for D-micelles and 0.790 µM for P-micelles). Overall, this newly developed dual encapsulation of D and P in the multifunctional carrier would be a promising technology for cancer treatment.

Wandering liver: ultrasound and magnetic resonance imaging diagnosis.

"Wandering liver" describes an excessive mobility of the liver caused by abnormalities of hepatic fixation that could lead to hepatic pedicle torsion or bowel obstruction. It is considered a rare entity, but because of the evolution in medical imaging techniques, this unusual condition is being identified more often. We report 2 cases presenting with chronic vague abdominal pain, diagnosed by abdominal ultrasonography and the use of cine-magnetic resonance imaging sequences with dynamic maneuvers. We tried to correlate our ultrasound and magnetic resonance imaging findings to peroperative findings and insist on the usefulness of dynamic maneuvers when confronted with atypical symptoms and a normal abdominal ultrasound scan finding.

Folate-Conjugated Polymer Micelles with pH-Triggered Drug Release Properties.

Folate has been applied as a targeting moiety for various anticancer drug-delivery agents to avoid non-specific attack of normal tissues as well as to increase cellular uptake at the target tumor cells. Polymer micelles made of poly[(D,L-lactide)-co-glycolide)]-poly(ethylene glycol)-folate (PLGA-PEG-FOL) was fabricated as a tumor targeting carrier for encapsulating the anticancer drug doxorubicin. To accelerate the drug release in the endosome after folate-mediated cellular uptake, pH-sensitive poly(ß-amino ester)-PEG-FOL (PAE-PEG-FOL) was added together with PLGA-PEG-FOL to form mixed micelles. The results showed that the drug release can be triggered at different pH due to the ionization of PAE. The IC(50) of PLGA-PEG-FOL micelles is 0.46 × 10(-6) M. With 20% PAE in the mixed micelles (20:80 mixed micelles), the IC(50) decreases to 0.34 × 10(-6) M, which is comparable to that of pure PAE-PEG-FOL micelles at pH 7.4. As a result of the pH sensitivity, the PAE-PEG-FOL micelles are not stable at pH 6.5 or lower, and the drug may be released from the micelles into the extracellular environment before uptake by the cells. The 20:80 mixed micelles are relatively stable at this condition. As a result, the micelles retain more drug in the micelles for a higher degree of cellular uptake by folate receptor-mediated endocytosis, and exhibit higher cytotoxicity.