Efficacy of Rac and Cdc42 Inhibitor MBQ-167 in Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, with a high predisposition for locally invasive and metastatic cancer. With the objective to reduce cancer metastasis, we developed small molecule inhibitors to target the drivers of metastasis, the Rho GTPases Rac and Cdc42. Of these, MBQ-167 inhibits both Rac and Cdc42 with IC50s of 103 and 78 nmol/L, respectively; and consequently, inhibits p21-activated kinase (PAK) signaling, metastatic cancer cell proliferation, migration, and mammosphere growth; induces cell-cycle arrest and apoptosis; and decreases HER2-type mammary fatpad tumor growth and metastasis (Humphries-Bickley and colleagues, 2017). Herein, we used nuclear magnetic resonance to show that MBQ-167 directly interacts with Rac1 to displace specific amino acids, and consequently inhibits Rac.GTP loading and viability in TNBC cell lines. Phosphokinome arrays in the MDA-MB-231 human TNBC cells show that phosphorylation status of kinases independent of the Rac/Cdc42/PAK pathway are not significantly changed following 200 nmol/L MBQ-167 treatment. Western blotting shows that initial increases in phospho-c-Jun and phospho-CREB in response to MBQ-167 are not sustained with prolonged exposure, as also confirmed by a decrease in their transcriptional targets. MBQ-167 inhibits tumor growth, and spontaneous and experimental metastasis in immunocompromised (human TNBC) and immunocompetent (mouse TNBC) models. Moreover, per oral administration of MBQ-167 at 100 mg/kg body weight is not toxic to immunocompetent BALB/c mice and has a half-life of 4.6 hours in plasma. These results highlight the specificity, potency, and bioavailability of MBQ-167, and support its clinical potential as a TNBC therapeutic.

Polymer-Derived Ceramic Nanoparticle/Edge-Functionalized Graphene Oxide Composites for Lithium-Ion Storage.

Polymer-derived ceramics demonstrate great potential as lithium-ion battery anode materials with good cycling stability and large capacity. SiCNO ceramic nanoparticles are produced by the pyrolysis of polysilazane nanoparticles that are synthesized via an oil-in-oil emulsion crosslinking and used as anode materials. The SiCNO nanoparticles have an average particle size of around 9 nm and contain graphitic carbon and Si3N4 and SiO2 domains. Composite anodes are produced by mixing different concentrations of SiCNO nanoparticles, edge-functionalized graphene oxide, polyvinylidenefluoride, and carbon black Super P. The electrochemical behavior of the anode is investigated to evaluate the Li-ion storage performance of the composite anode and understand the mechanism of Li-ion storage. The lithiation of SiCNO is observed at ∼0.385 V versus Li/Li+. The anode has a large capacity of 705 mA h g-1 after 350 cycles at a current density of 0.1 A g-1 and shows an excellent cyclic stability with a capacity decay of 0.049 mA h g-1 (0.0097%) per cycle. SiCNO nanoparticles provide a large specific area that is beneficial to Li+ storage and cyclic stability. In situ transmission electron microscopy analysis demonstrates that the SiCNO nanoparticles exhibit extraordinary structural stability with 9.36% linear expansion in the lithiation process. The X-ray diffraction and X-ray photoelectron spectroscopy investigation of the working electrode before and after cycling suggests that Li+ was stored through two pathways in SiCNO lithiation: (a) Li-ion intercalation of graphitic carbon in free carbon domains and (b) lithiation of the SiO2 and Si3N4 domains through a two-stage process.

Naturalization of the microbiota developmental trajectory of Cesarean-born neonates after vaginal seeding.

BACKGROUND: Early microbiota perturbations are associated with disorders that involve immunological underpinnings. Cesarean section (CS)-born babies show altered microbiota development in relation to babies born vaginally. Here we present the first statistically powered longitudinal study to determine the effect of restoring exposure to maternal vaginal fluids after CS birth. METHODS: Using 16S rRNA gene sequencing, we followed the microbial trajectories of multiple body sites in 177 babies over the first year of life; 98 were born vaginally, and 79 were born by CS, of whom 30 were swabbed with a maternal vaginal gauze right after birth. FINDINGS: Compositional tensor factorization analysis confirmed that microbiota trajectories of exposed CS-born babies aligned more closely with that of vaginally born babies. Interestingly, the majority of amplicon sequence variants from maternal vaginal microbiomes on the day of birth were shared with other maternal sites, in contrast to non-pregnant women from the Human Microbiome Project (HMP) study. CONCLUSIONS: The results of this observational study prompt urgent randomized clinical trials to test whether microbial restoration reduces the increased disease risk associated with CS birth and the underlying mechanisms. It also provides evidence of the pluripotential nature of maternal vaginal fluids to provide pioneer bacterial colonizers for the newborn body sites. This is the first study showing long-term naturalization of the microbiota of CS-born infants by restoring microbial exposure at birth. FUNDING: C&D, Emch Fund, CIFAR, Chilean CONICYT and SOCHIPE, Norwegian Institute of Public Health, Emerald Foundation, NIH, National Institute of Justice, Janssen.

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice.

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

Home chemical and microbial transitions across urbanization.

Urbanization represents a profound shift in human behaviour, and has considerable cultural and health-associated consequences1,2. Here, we investigate chemical and microbial characteristics of houses and their human occupants across an urbanization gradient in the Amazon rainforest, from a remote Peruvian Amerindian village to the Brazilian city of Manaus. Urbanization was found to be associated with reduced microbial outdoor exposure, increased contact with housing materials, antimicrobials and cleaning products, and increased exposure to chemical diversity. The degree of urbanization correlated with changes in the composition of house bacterial and microeukaryotic communities, increased house and skin fungal diversity, and an increase in the relative abundance of human skin-associated fungi and bacteria in houses. Overall, our results indicate that urbanization has large-scale effects on chemical and microbial exposures and on the human microbiota.

Pharmacokinetics of the Rac/Cdc42 Inhibitor MBQ-167 in Mice by Supercritical Fluid Chromatography-Tandem Mass Spectrometry.

The Rho GTPases Rac and Cdc42 are potential targets against metastatic diseases. We characterized the small molecule MBQ-167 as an effective dual Rac/Cdc42 inhibitor that reduces HER2-type tumor growth and metastasis in mice by ∼90%. This study reports the pharmacokinetics and tissue distribution of MBQ-167 following intraperitoneal and oral single-dose administrations. We first developed and validated a bioanalytical method for the quantitation of MBQ-167 in mouse plasma and tissues by supercritical fluid chromatography coupled with electrospray ionization tandem mass spectrometry. MBQ-167 was rapidly distributed into the kidneys after intraperitoneal dosing, whereas oral administration resulted in higher distribution to lungs. The elimination half-lives were 2.17 and 2.6 h for the intraperitoneal and oral dosing, respectively. The relative bioavailability of MBQ-167 after oral administration was 35%. This investigation presents the first analysis of the pharmacokinetics of MBQ-167 and supports further preclinical evaluation of this drug as a potential anticancer therapeutic.

Nanomaterials in Advanced, High-Performance Aerogel Composites: A Review.

Aerogels are one of the most interesting materials of the 21st century owing to their high porosity, low density, and large available surface area. Historically, aerogels have been used for highly efficient insulation and niche applications, such as interstellar particle capture. Recently, aerogels have made their way into the composite universe. By coupling nanomaterial with a variety of matrix materials, lightweight, high-performance composite aerogels have been developed for applications ranging from lithium-ion batteries to tissue engineering materials. In this paper, the current status of aerogel composites based on nanomaterials is reviewed and their application in environmental remediation, energy storage, controlled drug delivery, tissue engineering, and biosensing are discussed.

Characterization of the intestinal microbiota of the sea cucumber Holothuria glaberrima.

High-throughput 16S rRNA gene sequencing has been used to identify the intestinal microbiota of many animal species, but that of marine invertebrate organisms remains largely unknown. There are only a few high-throughput sequencing studies on the intestinal microbiota of echinoderms (non-vertebrate Deuterostomes). Here we describe the intestinal microbiota of the sea cucumber Holothuria glaberrima, an echinoderm, well-known for its remarkable power of regeneration. We characterized the microbiota from the anterior descending intestine, the medial intestine (these two comprise the small intestine) and the posterior descending intestine (or large intestine), using pyrosequencing to sequence the V4 region of the 16S rRNA gene. We compared animals in their natural marine environment and in sea-water aquaria. A total of 8,172 OTU's were grouped in 10 bacterial phyla, 23 classes, 44 orders, 83 families, 127 genera and 1 group of unknown bacteria, present across the digestive tract of 10 specimens. The results showed that the anterior intestine is dominated by Proteobacteria (61%) and Bacteroidetes (22%), the medium intestine is similar but with lower Bacteroidetes (4%), and the posterior intestine was remarkably different, dominated by Firmicutes (48%) and Bacteroidetes (35%). The structure of the community changed in animals kept in aquaria, which had a general dominance of Firmicutes and Bacteroidetes, regardless the intestinal segment. Our results evidence that in the natural sea environment, there is intestinal segment differentiation in the microbiota of H. glaberrima, which is lost in artificial conditions. This is relevant for physiological studies, such as mechanisms of digestive regeneration, which might be affected by the microbiota.

Características de los factores de riesgo cardiovascular en una población urbana y rural de la selva peruana, julio - 2014 / Characteristics of cardiovascular risk factors in an urban and rural population of the Peruvian jungle - July, 2014

Objetivo: Determinar las características del lugar de residencia y los factores de riesgo cardiovascular en una población de la selva peruana en julio 2014. Materiales y métodos: Estudio descriptivo transversal realizado en individuos entre 30 y 74 años sin diagnóstico ni tratamiento de enfermedad cardiovascular en una población urbana y una rural del distrito de Yantaló. La muestra se obtuvo a partir del programa Power Analysis and Sample Size Software (PASS) y estuvo conformada por 268 personas (152 habitantes urbanos y 116 rurales). Los factores estudiados fueron hipertensión arterial (HTA), diabetes mellitus (DM), índice de masa corporal (IMC), índice cintura-cadera (ICC) y tabaquismo. Resultados: La población urbana presentó un mayor porcentaje de HTA (18,4%), mientras que los otros factores de riesgo no presentaron diferencias significativas. Conclusiones: El único factor de riesgo que mostró asociación significativa con el lugar de residencia fue la HTA. En contraste, los otros factores de riesgo del estudio no presentaron diferencias entre ambas poblaciones, lo que demostraría que el distrito de Yantaló se encuentra inmerso en un proceso de transición epidemiológica debido a la urbanización.

Objective: To determine the characteristics of the place of residence and the cardiovascular risk factors in a Peruvian jungle population in July 2014. Materials and methods: A descriptive cross-sectional study conducted in individuals between 30 and 74 years old without a diagnosis of or treatment for a cardiovascular disease in an urban and rural population of the district of Yantaló. The sample was obtained using the Power Analysis and Sample Size Software (PASS) program, and consisted of 268 people (152 urban and 116 rural residents). The studied factors were hypertension (HBP), diabetes mellitus (DM), body mass index (BMI), waist-hip ratio (WHR) and smoking. Results: The urban population had higher rates of hypertension (18.4%), while the other risk factors showed no significant differences between the two populations. Conclusions: The only risk factor that showed a significant association with the place of residence was hypertension. In contrast, the other risk factors of the study showed no differences between the two populations, which demonstrates that the district of Yantaló is involved in a process of epidemiological transition due to urbanization.

A Graphene-Based Nanosensor for In Situ Monitoring of Polycyclic Aromatic Hydrocarbons (PAHs).

A graphene-based nanosensor was developed for in situ monitoring of polycyclic aromatic hydrocarbons (PAHs) in aqueous solutions. The sensor was fabricated using photolithography and etching of Au/Ti film on a silicon wafer followed by the transfer of a single graphene layer which was prepared separately by chemical vapor deposition (CVD). The performance of the graphene nanosensor was characterized using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The graphene-based sensor demonstrated a fast (<10 sec) and linear response to toluene (0 to 17 ppm) at +400 mV versus Ag/AgCl when measured amperometrically. The novelty can be found in utilizing high affinity of graphene to PAHs and intermolecular electron delocalization at the interface of graphene and a benzene ring for toluene detection in water. The developed sensor is applicable to many contaminated water bodies or engineered systems due to its reduced sensing cost, portability, and ease of use.

Walls talk: Microbial biogeography of homes spanning urbanization.

Westernization has propelled changes in urbanization and architecture, altering our exposure to the outdoor environment from that experienced during most of human evolution. These changes might affect the developmental exposure of infants to bacteria, immune development, and human microbiome diversity. Contemporary urban humans spend most of their time indoors, and little is known about the microbes associated with different designs of the built environment and their interaction with the human immune system. This study addresses the associations between architectural design and the microbial biogeography of households across a gradient of urbanization in South America. Urbanization was associated with households' increased isolation from outdoor environments, with additional indoor space isolation by walls. Microbes from house walls and floors segregate by location, and urban indoor walls contain human bacterial markers of space use. Urbanized spaces uniquely increase the content of human-associated microbes-which could increase transmission of potential pathogens-and decrease exposure to the environmental microbes with which humans have coevolved.

Coil-Type Asymmetric Supercapacitor Electrical Cables.

Cable-shaped supercapacitors (SCs) have recently aroused significant attention due to their attractive properties such as small size, lightweight, and bendability. Current cable-shaped SCs have symmetric device configuration. However, if an asymmetric design is used in cable-shaped supercapacitors, they would become more attractive due to broader cell operation voltages, which results in higher energy densities. Here, a novel coil-type asymmetric supercapacitor electrical cable (CASEC) is reported with enhanced cell operation voltage and extraordinary mechanical-electrochemical stability. The CASECs show excellent charge-discharge profiles, extraordinary rate capability (95.4%), high energy density (0.85 mWh cm(-3)), remarkable flexibility and bendability, and superior bending cycle stability (≈93.0% after 4000 cycles at different bending states). In addition, the CASECs not only exhibit the capability to store energy but also to transmit electricity simultaneously and independently. The integrated electrical conduction and storage capability of CASECS offer many potential applications in solar energy storage and electronic gadgets.

Determinación de riesgo cardiovascular y edad vascular según el score de Framingham en pacientes del Hospital Nacional Arzobispo Loayza / Determination of cardiovascular risk and vascular age by the Framingham score in patients at the Arzobispo Loayza Hospital

Las enfermedades cardiovasculares ocupan el cuarto lugar de carga de enfermedad en Perú, y en los últimos 7 años, la población de alto riesgo cardiovascular se ha incrementado. OBJETIVO: Determinar el riesgo cardiovascular y edad vascular según el score de Framingham de los pacientes del Hospital Nacional Arzobispo Loayza así como determinar su factor de riesgo más prevalente. Y las características clínicas de los pacientes con mediano y alto riesgo. MATERIAL Y MÉTODOS: Estudio descriptivo, observacional, transversal. Se encuestaron a 238 pacientes hospitalizados en el Servicio de Medicina Interna del hospital. Se consideró: edad, género, diabetes, tabaquismo, IMC y presión arterial. Los datos fueron analizados con el programa SPSS v.21. RESULTADOS: Se encontró que el mayor porcentaje de la población de estudio presentó mediano y alto riesgo, siendo el factor más prevalente la diabetes y la mayoría hombres. La diferencia entre la edad cronológica y la edad vascular fue en promedio 6,9 años. CONCLUSIÓN: La población estudiada tuvo mediano y alto riesgo por lo que se deberían tomar medidas de prevención primaria y secundaria.

Cardiovascular diseases rank fourth place of disease burden in Peru, and in the last 7 years, the population of high cardiovascular risk has increased. OBJECTIVE: Determine the cardiovascular risk and vascular age according to the Framingham score in patients attending the "Hospital Nacional Arzobispo Loayza", as well as to determine the most prevalent factor. Furthermore, to determine the clinical characteristics of patients with mild and high risk. MATERIAL AND METHODS: This is a descriptive, observational, cross-sectional study. 238 hospitalized patients in internal medicine wards were surveyed. Variables such as age, gender, diabetes, smoking, BMI and blood pressure were considered. The data were analyzed using SPSS v.21. RESULTS: The highest percentage of the population was found within the mild and high risk categories, with diabetes being the most prevalent factor. The average difference between chronological age and vascular age was 6.9 years. CONCLUSION: The majority of the population has mild and high risk, thus primary and secondary prevention measures should be taken. (Horiz Med 2015; 15(2): 27-34)