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Metastasis reduces survival in oral cancer patients and pain is their greatest complaint. We have shown previously that oral cancer metastasis and pain are controlled by the endothelin axis, which is a pathway comprised of the endothelin A and B receptors (ET A R and ET B R). In this study we focus on individual genes of the pathway, demonstrating that the endothelin axis genes are methylated and dysregulated in cancer tissue. Based on these findings in patients, we hypothesize that ET A R and ET B R play dichotomous roles in oral carcinogenesis and pain, such that ET A R activation and silenced ET B R expression result in increased carcinogenesis and pain. We test a treatment strategy that targets the dichotomous functions of the two receptors by inhibiting ET A R with macitentan, an ET A R antagonist approved for treatment of pulmonary hypertension, and re-expressing the ET B R gene with adenovirus transduction, and determine the treatment effect on cancer invasion (i.e., metastasis), proliferation and pain in vitro and in vivo. We demonstrate that combination treatment of macitentan and ET B R gene therapy inhibits invasion, but not proliferation, in cell culture and in a mouse model of tongue cancer. Furthermore, the treatment combination produces an antinociceptive effect through inhibition of endothelin-1 mediated neuronal activation, revealing the analgesic potential of macitentan. Our treatment approach targets a pathway shown to be dysregulated in oral cancer patients, using gene therapy and repurposing an available drug to effectively treat both oral cancer metastasis and pain in a preclinical model.

Background Oral squamous cell carcinoma (OSCC) has poor survival rates. There is a pressing need to develop more precise risk assessment methods to tailor clinical treatment. Epigenome-wide association studies in OSCC have not produced a viable biomarker. These studies have relied on methylation array platforms, which are limited in their ability to profile the methylome. In this study, we use MethylCap-Seq (MC-Seq), a comprehensive methylation quantification technique, and brush swab samples, to develop a noninvasive, readily translatable approach to profile the methylome in OSCC patients. Methods Three OSCC patients underwent collection of cancer and contralateral normal tissue and brush swab biopsies, totaling 4 samples for each patient. Epigenome-wide DNA methylation quantification was performed using the SureSelectXT Methyl-Seq platform. DNA quality and methylation site resolution were compared between brush swab and tissue samples. Correlation and methylation value difference were determined for brush swabs vs. tissues for each respective patient and site (i.e. , cancer or normal). Correlations were calculated between cancer and normal tissues and brush swab samples for each patient to determine the robustness of DNA methylation marks using brush swabs in clinical biomarker studies. Results There were no significant differences in DNA yield between tissue and brush swab samples. Mapping efficiency exceeded 90% across all samples, with no differences between tissue and brush swabs. The average number of CpG sites with at least 10x depth of coverage was 2,716,674 for brush swabs and 2,903,261 for tissues. Matched tissue and brush swabs had excellent correlation ( r  = 0.913 for cancer samples and r  = 0.951 for normal samples). The methylation profile of the top 1000 CpGs was significantly different between cancer and normal samples (mean p -value = 0.00021) but not different between tissues and brush swabs (mean p -value = 0.11). Conclusions Our results demonstrate that MC-Seq is an efficient platform for epigenome profiling in cancer biomarker studies, with broader methylome coverage than array-based platforms. Brush swab biopsy provides adequate DNA yield for MC-Seq, and taken together, our findings set the stage for development of a non-invasive methylome quantification technique for oral cancer with high translational potential.

Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort ( n  = 257) and an internal cohort ( n  = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.

Dye and heavy metal contaminants are mainly aquatic pollutants. Although many materials and methods have been developed to remove these pollutants from water, effective and cheap materials and methods are still challenging. In this study, highly porous hydroxyapatite/graphene oxide/chitosan beads (HGC) were prepared by a facile one-step method and investigated as efficient adsorbents. The prepared beads showed a high porosity and low bulk density. SEM images indicated that the hydroxyapatite (HA) nanoparticles and graphene oxide (GO) nanosheets were well dispersed on the CTS matrix. FT-IR spectra confirmed good incorporation of the three components. The adsorption behavior of the obtained beads to methylene blue (MB) and copper ions was investigated, including the effect of the contact time, pH medium, dye/metal ion initial concentration, and recycle ability. The HGC beads showed rapid adsorption, high capacity, and easy separation and reused due to the porous characteristics of GO sheets and HA nanoparticles as well as the rich negative charges of the chitosan (CTS) matrix. The maximum sorption capacities of the HGC beads were 99.00 and 256.41 mg g−1 for MB and copper ions removal, respectively.

The bitter melon, Momordica charantia L., was once an important food and medicinal herb. Various studies have focused on the potential treatment of stomach disease with M. charantia and on its anti-diabetic properties. However, very little is known about the specific compounds responsible for its anti-inflammatory activities. In addition, the in vitro inhibitory effect of M. charantia on pro-inflammatory cytokine production by lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) has not been reported. Phytochemical investigation of M. charantia fruit led to the isolation of 15 compounds (1−15). Their chemical structures were elucidated spectroscopically (one- and two-dimensional nuclear magnetic resonance) and with electrospray ionization mass spectrometry. The anti-inflammatory effects of the isolated compounds were evaluated by measuring the production of the pro-inflammatory cytokines interleukin IL-6, IL-12 p40, and tumor necrosis factor α (TNF-α) in LPS-stimulated BMDCs. The cucurbitanes were potent inhibitors of the cytokines TNF-α, IL-6, and IL-12 p40, indicating promising anti-inflammatory effects. Based on these studies and in silico simulations, we determined that the ligand likely docked in the receptors. These results suggest that cucurbitanes from M. charantia are potential candidates for treating inflammatory diseases.

A dated phylogeny and spatial distribution data for Chinese angiosperms show that eastern China has tended to act as a refugium for older taxa whereas western China has acted as a centre for their evolutionary diversification. A blossoming history of Chinese flora China is home to a vast range of flowering plants and has been seen as both a refuge for ancient lineages and a cradle for recent ones. Zhi-Duan Chen and colleagues examine the evolutionary history of Chinese flora and conclude that it is indeed both refuge and birthplace, but with a geographical twist. They find that 66% of Chinese flowering plant genera did not originate until the early Miocene (23 million years ago), but also uncover a distinct split between western and eastern China. Whereas lush, lowland eastern China tends to offer refuge for older genera, the rugged heights and harsh deserts of the west tend to be cradles for new evolutionary diversity. High species diversity may result from recent rapid speciation in a ‘cradle’ and/or the gradual accumulation and preservation of species over time in a ‘museum’ 1 , 2 . China harbours nearly 10% of angiosperm species worldwide and has long been considered as both a museum, owing to the presence of many species with hypothesized ancient origins 3 , 4 , and a cradle, as many lineages have originated as recent topographic changes and climatic shifts—such as the formation of the Qinghai–Tibetan Plateau and the development of the monsoon—provided new habitats that promoted remarkable radiation 5 . However, no detailed phylogenetic study has addressed when and how the major components of the Chinese angiosperm flora assembled to form the present-day vegetation. Here we investigate the spatio-temporal divergence patterns of the Chinese flora using a dated phylogeny of 92% of the angiosperm genera for the region, a nearly complete species-level tree comprising 26,978 species and detailed spatial distribution data. We found that 66% of the angiosperm genera in China did not originate until early in the Miocene epoch (23 million years ago (Mya)). The flora of eastern China bears a signature of older divergence (mean divergence times of 22.04–25.39 Mya), phylogenetic overdispersion (spatial co-occurrence of distant relatives) and higher phylogenetic diversity. In western China, the flora shows more recent divergence (mean divergence times of 15.29–18.86 Mya), pronounced phylogenetic clustering (co-occurrence of close relatives) and lower phylogenetic diversity. Analyses of species-level phylogenetic diversity using simulated branch lengths yielded results similar to genus-level patterns. Our analyses indicate that eastern China represents a floristic museum, and western China an evolutionary cradle, for herbaceous genera; eastern China has served as both a museum and a cradle for woody genera. These results identify areas of high species richness and phylogenetic diversity, and provide a foundation on which to build conservation efforts in China.

Background Patients experience an increasing treatment burden related to everything they do to take care of their health: visits to the doctor, medical tests, treatment management and lifestyle changes. This treatment burden could affect treatment adherence, quality of life and outcomes. We aimed to develop and validate an instrument for measuring treatment burden for patients with multiple chronic conditions. Methods Items were derived from a literature review and qualitative semistructured interviews with patients. The instrument was then validated in a sample of patients with chronic conditions recruited in hospitals and general practitioner clinics in France. Factor analysis was used to examine the questionnaire structure. Construct validity was studied by the relationships between the instrument's global score, the Treatment Satisfaction Questionnaire for Medication (TSQM) scores and the complexity of treatment as assessed by patients and physicians. Agreement between patients and physicians was appraised. Reliability was determined by a test-retest method. Results A sample of 502 patients completed the Treatment Burden Questionnaire (TBQ), which consisted of 7 items (2 of which had 4 subitems) defined after 22 interviews with patients. The questionnaire showed a unidimensional structure. The Cronbach's α was 0.89. The instrument's global score was negatively correlated with TSQM scores (r s = -0.41 to -0.53) and positively correlated with the complexity of treatment (r s = 0.16 to 0.40). Agreement between patients and physicians (n = 396) was weak (intraclass correlation coefficient 0.38 (95% confidence interval 0.29 to 0.47)). Reliability of the retest (n = 211 patients) was 0.76 (0.67 to 0.83). Conclusions This study provides the first valid and reliable instrument assessing the treatment burden for patients across any disease or treatment context. This instrument could help in the development of treatment strategies that are both efficient and acceptable for patients.

Sheet pile wall structures are commonly applied in coastal projects, particularly for the quay wall. This structural type normally is used in places where the ground has a low bearing capacity and is easily penetrable. Many sheet pile quay walls constructed in the past had low front water depth and did not satisfy the requirements of current standards. This issue could be addressed by improving the ground in front of the wall using cement deep mixing (CDM) and then excavating to increase the water depth in front of the wall. This paper numerically evaluated the dynamic behavior of the sheet pile wall after renovation. The numerical model was performed based on the finite element method (FEM) using the PLAXIS 2D program. The study focused on investigating typical parameters of the quay wall improved using the CDM, such as bending moment and displacement of sheet pile and the development of excess pore water pressure (EPWP) in the backfill. These results were compared to those of the quay wall without the CDM to elucidate the advantages of this method. In addition, the influence of some factors on the quay wall behavior, such as earthquake excitation characteristics, CDM area, and CDM strength, was also evaluated. The results demonstrated that the ground improvement using the CDM significantly decreased the bending moment and displacement of the sheet pile wall. The excitation characteristics did not affect the deformed shape of the sheet pile. With the constant CDM depth, the sheet pile displacement decreased with an increase in the improvement width until it reached a limitation. The increasing CDM strength also decreased the displacement of the wall until it raised a certain value. This demonstrated that this method was technically feasible, and it could be considered to study further by experiment before applying in practice.

A large number of white hard clam farms are in the estuary shoreline of Saigon-Dongnai Rivers, which flow through Ho Chi Minh City, a megacity, and numerous industrial zones in the basin catchment area. In this study, eleven trace elements (Mn, Fe, Co, Ni, Cu, Zn, As, Se, Cd, Hg, and Pb) in the hard clam Meretrix lyrata and its habitats including surface water, suspended particulate matter, and sediment were evaluated to understand the bioaccumulation of trace metals from the environment into the whole tissues of the hard clam as well as its different organs. The samples were collected monthly in dry, transition, and wet seasons of the southern part of Vietnam from March to September 2016. The results showed that seasonal and spatial variations of the studied metal concentrations in the hard clam M. lyrata might be influenced by the sea current as well as the surface runoff in the rainy season. The relationship between condition index and the element concentrations in M. lyrata might be affected by the living environment conditions and farming methods. In addition, the hazard index values of all trace elements in the hard clam M. lyrata harvested in the sampling time show that the hard clams farmed in the study area were safe for local consumers.

Gnetum formosum Markgr., a member of the Gnetaceae family, is distributed in Vietnam. This plant remains a botanical enigma with an unexplored diversity of chemical constituents and pharmacological effects. In this study, two new steroidal saponins, namely gnetumosides A (1) and B (2), were isolated from the aerial parts of G. formosum. Their chemical structures were elucidated using spectroscopic techniques, including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and NMR, along with chemical hydrolysis and comparison with the reported literature. The potential anti-inflammatory effects of the isolated compounds were evaluated by measuring lipopolysaccharide-stimulated nitric oxide (NO) production in murine macrophage cells. Notably, compound 1 exhibited the most potent inhibitory activity (IC50 = 14.10 ± 0.75 µM), comparable to dexamethasone. Additionally, the mechanisms underlying the observed anti-inflammatory effects were investigated through molecular docking and molecular dynamics simulations on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. This study is the first to investigate the chemical constituents and pharmacological effects of G. formosum.