Resolving a "W-Shaped" P100 Waveform: Is It Normal or Abnormal?

SUMMARY: Pattern-reversal visual evoked potentials are used to assess the visual pathways. The main waveform of interest is the P100, which is best recorded with electrodes over the mid-occipital region. Most often, the P100 waveform has negative-positive-negative components. Occasionally, it is "W-shaped," with positive-negative-positive components. Although most often a W-shaped P100 waveform indicates an abnormality in the visual pathway, occasionally, it can be normal. A case is presented in which a W-shaped P100 waveform is seen after monocular full-field stimulation of both eyes with 30' checks. To resolve this finding, the pattern-reversal visual evoked potentials is repeated with 60' and 15' checks. With 15' checks a single typical single-peak P100 waveform is seen with normal latency. Evaluation of a W-shaped P100 waveform should involve analysis of various montages, stimulation with different check sizes, and hemifield stimulation to confirm whether the W-shaped waveform is normal or abnormal.

Understanding the conservation-genetics gap in Latin America: challenges and opportunities to integrate genetics into conservation practices.

Introduction: Integrating genetic data into conservation management decisions is a challenging task that requires strong partnerships between researchers and managers. Conservation in Latin America is of crucial relevance worldwide given the high biodiversity levels and the presence of hotspots in this region. Methods: We conducted a survey across Latin America to identify gaps and opportunities between genetic researchers and conservation managers. We aimed to better understand conservation managers' points of view and how genetic research could help conservation practitioners to achieve their goals, by implementing genetic assessments that could effectively inform conservation practices. We distributed an online survey via four regional collaborating organizations and 32 focal points based in 20 Latin American countries. The target respondents were conservation managers of species or areas in Latin America. Results: We collected a total of 468 answered questionnaires from 21 Latin American countries. Most respondents (44%) were from an academic or research institution while non-academics were mainly from non-governmental institutions (30%) and government agencies (25%). Most respondents (65%) have performed or used genetic assessments in their managed area or species, either alone, in partnership, contracting someone else or using published results. For the majority of this group, the genetic results were relevant to their conservation management goals, helping to inform management decisions. Respondents that had not performed genetic assessments (35%) were mainly from the non-academic group, and their main barriers were limited access to funds, genetic lab facilities, and trained personnel to design studies and conduct lab work. Discussion: From the findings, we describe the current situation and provide a general diagnosis of the conservation-genetics gap in Latin America. We describe the gender gap, academic-practitioner co-development of conservation questions and projects, and the nationality and residency of Latin American conservation managers in relation to the countries where they work. We discuss opportunities to co-create research questions and co-develop studies based on conservation practitioners' needs. We offer recommendations for overcoming barriers to integrate genetic information into conservation actions, and advance agendas that fit the needs and realities of the highly heterogeneous, biodiverse and challenging Latin American region.

Phytochemical Profiles and Cytotoxic Activity of Bursera fagaroides (Kunth) Engl. Leaves and Its Callus Culture.

Bursera fagaroides, popularly used in México, possesses bioactive lignans. These compounds are low in the bark, and its extraction endangers the life of the trees. The aim of the present investigation was to search for alternative sources of cytotoxic compounds in B. fagaroides prepared as leaves and in vitro callus cultures. The friable callus of B. fagaroides was established using a combination of plant growth regulators: 4 mgL-1 of 2,4-dichlorophenoxyacetic acid (2,4-D), 1 mgL-1 Naphthaleneacetic Acid (NAA) and 1 mgL-1 Zeatin. The maximum cell growth was at day 28 with a specific growth rate of µ = 0.059 days-1 and duplication time td = 11.8 days. HPLC quantification of the dichloromethane callus biomass extract showed that Scopoletin, with a concentration of 10.7 µg g-1 dry weight, was the main compound inducible as a phytoalexin by the addition of high concentrations of 2,4-D, as well as by the absence of nutrients in the culture medium. In this same extract, the compounds γ-sitosterol and stigmasterol were also identified by GC-MS analysis. Open column chromatography was used to separate and identify yatein, acetyl podophyllotoxin and 7',8'-dehydropodophyllotoxin in the leaves of the wild plant. Cytotoxic activity on four cancer cell lines was tested, with PC-3 prostate carcinoma (IC50 of 12.6 ± 4.6 µgmL-1) being the most sensitive to the wild-type plant extract and HeLa cervical carcinoma (IC50 of 72 ± 5 µgmL-1) being the most sensitive to the callus culture extract.

Correction: Beyond words: From jaguar population trends to conservation and public policy in Mexico.

[This corrects the article DOI: 10.1371/journal.pone.0255555.].

Preserving the spots: Jaguar (Panthera onca) distribution and priority conservation areas in Colombia.

The jaguar (Panthera onca) is a charismatic species considered Vulnerable in Colombia but yet largely unknown in the country. The species is mostly threatened by the continuous decline in its habitats, mostly derived from deforestation and habitat loss, additional to hunting and conflicts with humans. Thus, the future of jaguars in Colombia depends on protecting and recovering existing habitats. The aims of this study were to 1) evaluate jaguar distribution and identify the remnant patches of habitat in Colombia, 2) define an ecological connectivity network within the country, and 3) propose a priority areas portfolio for the conservation and recovery of jaguars. We used a presence background model for estimating species potential distribution and subsequently identified remaining habitat patches across the country based on land cover and species-specific ecological attributes. We then created an ecological connectivity network based on circuit theory and following a multi-criteria approach identified jaguar priority areas for conservation (JPCA) and recovery (JPRA). Jaguar potential distribution comprises 1103122.43 km2, from which 56.71% maintain suitable patches of potential habitat. We identified 960 corridors between remnant patches of natural or semi-natural vegetation. Based on the criteria, JPCAs with greater importance were identified in each of the five Colombian regions. JPRAs were located mainly towards the Andean and Caribbean regions. These JPCAs and JPRAs could serve as a guide for designing and implementing management strategies for the long-term conservation and recovery of the species in Colombia.

Tannic Acid and Ethyl Gallate Potentialize Paclitaxel Effect on Microtubule Dynamics in Hep3B Cells.

Among broad-spectrum anticancer agents, paclitaxel (PTX) has proven to be one of the most effective against solid tumors for which more specific treatments are lacking. However, drawbacks such as neurotoxicity and the development of resistance reduce its therapeutic efficacy. Therefore, there is a need for compounds able to improve its activity by synergizing with it or potentiating its effect, thus reducing the doses required. We investigated the interaction between PTX and tannins, other compounds with anticancer activity known to act as repressors of several proteins involved in oncological pathways. We found that both tannic acid (TA) and ethyl gallate (EG) strongly potentiate the toxicity of PTX in Hep3B cells, suggesting their utility in combination therapy. We also found that AT and EG promote tubulin polymerization and enhance the effect of PTX on tubulin, suggesting a direct interaction with tubulin. Biochemical experiments confirmed that TA, but not EG, binds tubulin and potentiates the apparent binding affinity of PTX for the tubulin binding site. Furthermore, the molecular docking of TA to tubulin suggests that TA can bind to two different sites on tubulin, one at the PTX site and the second at the interface of α and ß-tubulin (cluster 2). The binding of TA to cluster 2 could explain the overstabilization in the tubulin + PTX combinatorial assay. Finally, we found that EG can inhibit PTX-induced expression of pAkt and pERK defensive protein kinases, which are involved in resistance to PXT, by limiting cell death (apoptosis) and favoring cell proliferation and cell cycle progression. Our results support that tannic acid and ethyl gallate are potential chemotherapeutic agents due to their potentiating effect on paclitaxel.

Finding a Novel Chalcone-Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach.

In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, A) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and ß rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC50 as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2LMO = 82.578, Q2BOOT = 80.436, and Q2EXT = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2LMO = 80.534, Q2BOOT = 78.186, and Q2EXT = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC (A) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone (B), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds A and B were synthesized by two- and three-step reactions. The structures were confirmed by 1H and 13C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC50 values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone B. Finally, we employed B as a molecular scaffold for the generation of cinnamate candidates (C-K), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds A and B, as well as the proposed chalcones C and G, are the best candidates with adequate drug-likeness properties. From all these results, we propose B (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line.

Identification of a cytotoxic factor from a non-pigmented entomopathogenic Serratia marcescens isolate toxic towards human carcinoma cell lines.

It has been reported that cell-free culture broths and some proteins from pigmented and non-pigmented Serratia spp. are cytotoxic towards cancerous and non-cancerous human cell lines. Looking for new molecules toxic against human cancerous cells but harmless towards normal human cells, the aim of this work was (a) to determine whether cell-free broths from the entomopathogenic non-pigmented S. marcescens 81 (Sm81), S. marcescens 89 (Sm89) and S. entomophila (SeMor4.1) presented cytotoxic activity towards human carcinoma cell lines; (b) to identify and purify the associated cytotoxic factor(s) and (c) to evaluate whether the cytotoxic factor(s) was cytotoxic towards non-cancerous human cells. This research was focussed on the observed morphology changes and the proportion of remaining viable cells after incubation in the presence of cell-free culture broths from the Serratia spp isolates to evaluate cytotoxic activity. The results showed that broths from both S. marcescens isolates presented cytotoxic activity and induced cytopathic-like effects on the human neuroblastoma CHP-212 and the breast cancer MDA-MB-231 cells. Slight cytotoxicity was observed in the SeMor4.1 broth. A serralysin-like protein of 50 kDa was identified in Sm81 broth as responsible for cytotoxic activity after purification by ammonium sulphate precipitation and ion-exchange chromatography followed by tandem-mass spectrometry (LC-MS/MS). The serralysin-like protein was toxic against CHP-212 (neuroblastoma), SiHa (human cervical carcinoma) and D-54 (human glioblastoma) cell lines in a dose-dependent manner and showed no cytotoxic activity in primary cultures of normal non-cancerous human keratinocytes and fibroblasts. Therefore, this protein should be evaluated for a potential use as an anticancer agent.

Exploring the Gallic and Cinnamic Acids Chimeric Derivatives as Anticancer Agents over HeLa Cell Line: An in silico and in†vitro Study.

Cervical cancer is one of the most aggressive and important cancer types in the female population, due to its low survival rate. Actually, the search for new bioactive compounds, like gallic and cinnamic acid, is one of the most employed options to finding a treatment. In the present study, 134 phenolic compounds with cytotoxic activity over HeLa cell line were used to generate a descriptive ( R 2 ${{R}^{2}}$ =0.76) and predictive ( Q 2 ${{Q}^{2}}$ =0.69 and Q e x t 2 ${{Q}_{{\rm e}{\rm x}{\rm t}}^{2}}$ =0.62) QSAR model. Structural, electronic, steric, and hydrophobic features are represented as different molecular descriptors in our QSAR model. From this model, nine gallate-cinnamate ester derivatives (N1-N9) were designed and synthesized. Furthermore, in vitro cytotoxic activity was evaluated against HeLa and non-tumorigenic cells. Derivatives N6, N5, N1, and N9 were the most active molecules with IC50ExpHeLa values from 7.26 to 11.95 µM. Finally, the binding of the synthesized compounds to the colchicine binding site on tubulin was evaluated by molecular docking as a possible action mechanism. N1, N5 and N6 can be considered as templates for the design of new cervical anticancer compounds.

Spotting what's important: Priority areas, connectivity, and conservation of the Northern Tiger Cat (Leopardus tigrinus) in Colombia.

Leopardus tigrinus is among the least known carnivore species in the Neotropics, including considerable taxonomic uncertainty. Here we model the distribution, connectivity and overlap with existing conservation areas for the species in Colombia. Using a Species Distribution Modeling approach, we estimated current potential range of the species in Colombia and identified potential habitat blocks remaining in the country. In addition, we designed a connectivity network across the available cores, using a circuit theory approach, to evaluate habitat linkage. Finally, we defined a prioritization scheme for the remaining habitat cores and assessed the level of coverage of protected areas for the country. L. tigrinus is potentially present across the three Andean branches of Colombia, with still considerable continuous habitat cores, mostly located on the eastern and central Andean ranges. Most habitat cores are theoretically connected, but nearly 15% are isolated. Priority areas were located across the eastern and central ranges, but with very significant and promising cores in the northern eastern and western ranges. Current level of protection indicates nearly 30% of the range is "protected", but only about 25% is under national strict protected areas. Evolution of this coverage showed some periods of significant increase but interestingly the number of cores grew at a faster rate than overall proportion protected, likely indicating numerous discontinuous fragments, and not contiguous functional landscapes. This represents the most updated assessment of the distribution and conservation status for the species in Colombia, and indicates the numerous conservation opportunities, especially in most populated areas of the country. We found unique business environmental passive's opportunities, including compensation and development potential, which are becoming more available in the country.

Biogeography of terrestrial vertebrates and its conservation implications in a transitional region in western Mexico.

Conservation biogeography, which applies principles, theories, and analyses of biodiversity distribution patterns to address conservation challenges, can provide valuable insight and guidance to policy making for protection of biodiversity at multiple scales. The temperate and tropical ecosystems of the Nearctic-Neotropical transition in the small western state of Colima, Mexico, support a mosaic of remarkably diverse fauna and flora and provide a rare opportunity to determine spatial distribution patterns of terrestrial vertebrate species, assess human-induced threats, and identify potential conservation strategies. We analyzed the spatial distribution patterns and correlated them with the current land cover and extent of the protected areas. Despite its limited geographic extension, 29% (866) of all vertebrates, and almost a quarter of both endemic and threatened species in Mexico, live in Colima. Our analysis identified clear high-richness concentration sites (i.e., "hotspots") coincident for all groups and that elevation and both temperate and tropical ecosystems composition exert significant influence on richness patterns. Furthermore, current species´ distribution also showed significant correlation with natural and disturbed landcover. Significant hotspots for all species groups coincided poorly with the limited protected areas in the state (only 3.8%). The current state of natural land cover (less than 16%) in the state, coupled with its remarkable biological importance, highlights the need for further complementary conservation efforts including expansion and creation of new protected areas, significant restoration efforts and other conservation measures to maintain this uniquely biogeographic and biological diverse region of the country.

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects.

The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules' origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.

Methyl benzoate and cinnamate analogs as modulators of DNA methylation in hepatocellular carcinoma.

Phenolic acids represent a large collection of phytochemical molecules present in the plant kingdom; they have an important role as epigenetic regulators, particularly as inhibitors of DNA methylation. In the present study, 14 methyl benzoate and cinnamate analogs were synthesized (11-24). Their cytotoxic activity on hepatocellular carcinoma cells (Hep3B) and immortalized human hepatocyte cells was then evaluated. In addition, its effect on the inhibition of global DNA methylation in Hep3B was also determined. Our results showed that the cinnamic derivatives 11-14 and 20-22 were more potent than the free caffeic acid (IC50 109.7-364.2 µM), being methyl 3,4-dihydroxycinammate (12) the most active with an IC50  = 109.7 ± 0.8 µM. Furthermore, 11-14, 20-23 compounds decreased overall DNA methylation levels by 63% to 97%. The analogs methyl 4-hydroxycinnamate (11), methyl 3,4,5-trimethoxycinnamate (14), methyl 4-methoxycinnamate (21), and methyl 3,4-dimethoxycinnamate (22) showed relevant activities of both cytotoxicity and global DNA methylation inhibition. The molecular docking of 21 and 14 suggested that they partly bind to the SAH-binding pocket of DNA methyltransferase 1. These results emphasize the importance of natural products and their analogs as potential sources of DNA methylation modulating agents.

Connectivity conservation at the crossroads: protected areas versus payments for ecosystem services in conserving connectivity for Colombian carnivores.

Protected areas (PAs) constitute one of the main tools for global landscape conservation. Recently, payments for environmental services (PES) have attracted interest from national and regional governments and are becoming one of the leading conservation policy instruments in tropical countries. However, the degree to which areas designated for PES overlap with areas that are critical for maintaining species' landscape connectivity is rarely evaluated. We estimated habitat distributions and connectivity for 16 of the 22 mammalian carnivores occurring in the Caribbean region of Colombia, and identified the overlap between existing PAs and areas identified as being important for connectivity for these species. We also evaluated the potential impact of creation of new PAs versus new PES areas on conserving connectivity for carnivores. Our results show that PAs cover only a minor percentage of the total area that is important for maintaining connectivity ( x = 26.8 % ± 20.2 s . d . ). On the other hand, PES, if implemented extensively, could contribute substantially to mammalian carnivores' connectivity ( x = 45.4 % ± 12.8 s . d . ). However, in a more realistic scenario with limited conservation investment in which fewer areas are set aside, a strategy based on implementing new PAs seems superior to PES. We argue that prioritizing designation of new PAs will be the most efficient means through which to maintain connectivity.

UPLC-QTOF-MS analysis of cytotoxic and antibacterial extracts of Hechtia glomerata Zucc.

Hechtia glomerata, a Mexican medicinal plant employed against bacterial infections and as food, is taxonomically related to the genus Tillandsia which has anticancer activity. Organic and aqueous extracts of H. glomerata leaves were prepared and tested for cytotoxic and antibacterial activity. UPLC-QTOF-MS analysis determined the chemical composition of active extracts to find cytotoxic and antibacterial compounds. Hexane extract was cytotoxic against HepG2, Hep3B and MCF7 (IC50: 24-28 µg/mL), whereas CHCl3/MeOH extract against PC3 and MCF7 (IC50: 25 and 32 µg/mL). CHCl3/MeOH extract showed antibacterial activity against Staphylococcus aureus and Enterococcus faecium (MIC: 125 and 62.5 µg/mL). Hexane extract cytotoxic compounds were ß-sitosterol, stigmasterol, phytol and ursolic acid. CHCl3/MeOH extract antibacterial and/or cytotoxic compounds were daucosterol, oleanolic acid, resveratrol, quercetin, kaempferol, apigenin, cyanidin, p-coumaric acid and caffeic acid. This plant could be useful against bacterial infections and cancer. However, in vivo studies are needed to determine its toxicity and therapeutic efficacy.

Beyond words: From jaguar population trends to conservation and public policy in Mexico.

The jaguar (Panthera onca) is one of the most threatened carnivores in the Americas. Despite a long history of research on this charismatic species, to date there have been few systematic efforts to assess its population size and status in most countries across its distribution range. We present here the results of the two National Jaguar Surveys for Mexico, the first national censuses in any country within the species distribution. We estimated jaguar densities from field data collected at 13 localities in 2008-2010 (2010 hereafter) and 11 localities in 2016-2018 (2018 hereafter). We used the 2010 census results as the basis to develop a National Jaguar Conservation Strategy that identified critical issues for jaguar conservation in Mexico. We worked with the Mexican government to implement the conservation strategy and then evaluated its effectivity. To compare the 2010 and 2018 results, we estimated the amount of jaguar-suitable habitat in the entire country based on an ecological niche model for both periods. Suitable jaguar habitat covered ~267,063 km2 (13.9% of the country's territory) in 2010 and ~ 288,890 km2 (~14.8% of the country's territory) in 2018. Using the most conservative density values for each priority region, we estimated jaguar densities for both the high and low suitable habitats. The total jaguar population was estimated in ~4,000 individuals for 2010 census and ~4,800 for the 2018 census. The Yucatan Peninsula was the region with the largest population, around 2000 jaguars, in both censuses. Our promising results indicate that the actions we proposed in the National Jaguar Conservation Strategy, some of which have been implemented working together with the Federal Government, other NGO's, and land owners, are improving jaguar conservation in Mexico. The continuation of surveys and monitoring programs of the jaguar populations in Mexico will provide accurate information to design and implement effective, science-based conservation measures to try to ensure that robust jaguar populations remain a permanent fixture of Mexico's natural heritage.

Metabolomic Profile and Cytotoxic Activity of Cissus incisa Leaves Extracts.

Cissus incisa leaves have been traditionally used in Mexican traditional medicine to treat certain cancerous illness. This study explored the metabolomic profile of this species using untargeted technique. Likewise, it determined the cytotoxic activity and interpreted all data by computational tools. The metabolomic profile was developed through UHPLC-QTOF-MS/MS for dereplication purposes. MetaboAnalyst database was used in metabolic pathway analysis and the network topological analysis. Hexane, chloroform/methanol, and aqueous extracts were evaluated on HepG2, Hep3B, HeLa, PC3, A549, and MCF7 cancer cell lines and IHH immortalized hepatic cells, using Cell Titer proliferation assay kit. Hexane extract was the most active against Hep3B (IC50 = 27 ± 3 µg/mL), while CHCl3/MeOH extract was the most selective (SI = 2.77) on the same cell line. A Principal Component Analysis (PCA) showed similar profiles between the extracts, while a Venn diagram revealed 80 coincident metabolites between the bioactive extracts. The sesquiterpenoid and triterpenoid biosynthesis pathway was the most significant identified. The Network Pharmacology (NP) approach revealed several targets for presqualene diphosphate, phytol, stearic acid, δ-tocopherol, ursolic acid and γ-linolenic acid, involved in cellular processes such as apoptosis. This work highlights the integration of untargeted metabolomic profile and cytotoxic activity to explore plant extracts, and the NP approach to interpreting the experimental results.

Cytotoxic Fractions from Hechtia glomerata Extracts and p-Coumaric Acid as MAPK Inhibitors.

Preliminary bioassay-guided fractionation was performed to identify cytotoxic compounds from Hechtia glomerata, a plant that is used in Mexican ethnomedicine. Organic and aqueous extracts were prepared from H. glomerata's leaves and evaluated against two cancer cell lines. The CHCl3/MeOH (1:1) active extract was fractionated, and the resulting fractions were assayed against prostate adenocarcinoma PC3 and breast adenocarcinoma MCF7 cell lines. Active fraction 4 was further analyzed by high-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry analysis to identify its active constituents. Among the compounds that were responsible for the cytotoxic effects of this fraction were flavonoids, phenolic acids, and aromatic compounds, of which p-coumaric acid (p-CA) and its derivatives were abundant. To understand the mechanisms that underlie p-CA cytotoxicity, a microarray assay was performed on PC3 cells that were treated or not with this compound. The results showed that mitogen-activated protein kinases (MAPKs) that regulate many cancer-related pathways were targeted by p-CA, which could be related to the reported effects of reactive oxygen species (ROS). A molecular docking study of p-CA showed that this phenolic acid targeted these protein active sites (MAPK8 and Serine/Threonine protein kinase 3) at the same binding site as their inhibitors. Thus, we hypothesize that p-CA produces ROS, directly affects the MAPK signaling pathway, and consequently causes apoptosis, among other effects. Additionally, p-CA could be used as a platform for the design of new MAPK inhibitors and re-sensitizing agents for resistant cancers.

Antibacterial and cytotoxic activities of new sphingolipids and other constituents isolated from Cissus incisa leaves.

Cissus incisa is used in traditional Mexican medicine to treat certain ailments, infectious or cancerous diseases. Excepting for our previous research, this species had no scientific reports validating its traditional use. In this study, we evaluated the antibacterial and cytotoxic properties of the sphingolipids and others phytocompounds isolated from C. incisa leaves to increase the scientific knowledge of the Mexican flora. The antibacterial activity was evaluated against Gram-positive and Gram-negative bacteria by the Microdilution method. Meanwhile, the cytotoxic potential was determined on six human cancer cells: PC3, Hep3B, HepG2, MCF7, A549, and HeLa; using an aqueous solution cell proliferation assay kit. A cell line of immortalized human hepatocytes (IHH) was included as a control of non-cancerous cells. Selectivity index (SI) was determined only against the hepatocellular carcinoma cell lines. The phytochemical investigation of C. incisa leaves resulted in the isolation and characterization of five compounds: 2-(2'-hydroxydecanoyl amino)-1,3,4-hexadecanotriol-8-ene (1), 2,3-dihydroxypropyl tetracosanoate (2), ß-sitosterol-D-glucopyranoside (3), α-amyrin-3-O-ß-D-glucopyranoside (4), and a mixture of cerebrosides (5). Until now, this is the first report of the sphingolipids (1), (5-IV) and (5-V). Only the compound (4) and cerebrosides (5) exhibited antibacterial activity reaching a MIC value of 100 µg/mL against Pseudomonas aeruginosa resistant to carbapenems. While, the acetylated derivate of (3), compound (3Ac) showed the best cytotoxic result against PC3 (IC50 = 43 ± 4 µg/mL) and Hep3B (IC50 = 49.0 ± 4 µg/mL) cancer cell lines. Likewise, (3Ac) achieved better SI values on HepG2 and Hep3B cell lines. This research reveals the importance of study medicinal plants, to identify bioactive molecules as sources of potential drugs. The presence of these compounds allows us to justify the use of this plant in traditional Mexican medicine.

European genetic ancestry associated with risk of childhood ependymoma.

BACKGROUND: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations. METHODS: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS). RESULTS: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients. CONCLUSIONS: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.