Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor β Superfamily Type 1 Receptors.

The transforming growth factor β (TGFβ) superfamily includes TGFβ, activins, inhibins, and bone morphogenetic proteins (BMPs). These extracellular ligands have essential roles in normal tissue homeostasis by coordinately regulating cell proliferation, differentiation, and migration. Aberrant signaling of superfamily members, however, is associated with fibrosis as well as tumorigenesis, cancer progression, metastasis, and drug-resistance mechanisms in a variety of cancer subtypes. Given their involvement in human disease, the identification of novel selective inhibitors of TGFβ superfamily receptors is an attractive therapeutic approach. Seven mammalian type 1 receptors have been identified that have context-specific roles depending on the ligand and the complex formation with the type 2 receptor. Here, we characterize the biologic effects of two transforming growth factor β receptor 1 (TGFBR1) kinase inhibitors designed to target TGFβ signaling. AZ12601011 [2-(2-pyridinyl)-4-(1H-pyrrolo[3,2-c]pyridin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine]; structure previously undisclosed] and AZ12799734 [4-({4-[(2,6-dimethyl-3-pyridinyl)oxy]-2-pyridinyl}amino)benzenesulfonamide] (IC50 = 18 and 47 nM, respectively) were more effective inhibitors of TGFβ-induced reporter activity than SB-431542 [4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]benzamide] (IC50 = 84 nM) and LY2157299 [4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide monohydrate]] (galunisertib) (IC50 = 380 nM). AZ12601011 inhibited phosphorylation of SMAD2 via the type 1 receptors activin A receptor type 1B (ALK4), TGFBR1, and activin A receptor type 1C (ALK7). AZ12799734, however, is a pan TGF/BMP inhibitor, inhibiting receptor-mediated phosphorylation of SMAD1 by activin A receptor type 1L, bone morphogenetic protein receptor type 1A, and bone morphogenetic protein receptor type 1B and phosphorylation of SMAD2 by ALK4, TGFBR1, and ALK7. AZ12601011 was highly effective at inhibiting basal and TGFβ-induced migration of HaCaT keratinocytes and, furthermore, inhibited tumor growth and metastasis to the lungs in a 4T1 syngeneic orthotopic mammary tumor model. These inhibitors provide new reagents for investigating in vitro and in vivo pathogenic processes and the contribution of TGFβ- and BMP-regulated signaling pathways to disease states

Smart Antennas and Front-End Modules in Q-band for Backhaul Networks

[EN] As mobile operators face increasing density of base stations as well as growing bandwidth requirements, mobile backhaul has become the new challenge. This article defines the architecture for future mobile backhaul networks as proposed in the framework of the FP7 EU SARABAND project. This solution exploits a new and wider frequency spectrum band, the Q-band (40.5 43.5 GHz), to provide massive amounts of capacity. However, for the full deployment of such backhaul networks, new technology development in the Q-band must be addressed. In particular, this article gives an overview of the disruptive technology on antennas and front-end modules developed within this project.Vilar Mateo, R.; Martí Sendra, J.; Czarny, R.; Sypek, M.; Makowski, M.; Martel, C.; Crepin, T.... (2014). Smart Antennas and Front-End Modules in Q-band for Backhaul Networks. Microwave Journal. S:28-34. http://hdl.handle.net/10251/52765S2834

The TEXES Survey For H2 Emission From Protoplanetary Disks

We report the results of a search for pure rotational molecular hydrogen emission from the circumstellar environments of young stellar objects with disks using the Texas Echelon Cross Echelle Spectrograph (TEXES) on the NASA Infrared Telescope Facility and the Gemini North Observatory. We searched for mid-infrared H2 emission in the S(1), S(2), and S(4) transitions. Keck/NIRSPEC observations of the H2 S(9) transition were included for some sources as an additional constraint on the gas temperature. We detected H2 emission from 6 of 29 sources observed: AB Aur, DoAr 21, Elias 29, GSS 30 IRS 1, GV Tau N, and HL Tau. Four of the six targets with detected emission are class I sources that show evidence for surrounding material in an envelope in addition to a circumstellar disk. In these cases, we show that accretion shock heating is a plausible excitation mechanism. The detected emission lines are narrow (~10 km/s), centered at the stellar velocity, and spatially unresolved at scales of 0.4 arcsec, which is consistent with origin from a disk at radii 10-50 AU from the star. In cases where we detect multiple emission lines, we derive temperatures > 500 K from ~1 M_earth of gas. Our upper limits for the non-detections place upper limits on the amount of H2 gas with T > 500 K of less than a few Earth masses. Such warm gas temperatures are significantly higher than the equilibrium dust temperatures at these radii, suggesting that the gas is decoupled from the dust in the regions we are studying and that processes such as UV, X-ray, and accretion heating may be important.Comment: 24 pages, 16 figures, 5 tables, ApJ accepte

Establishment, molecular and biological characterization of HCB-514: a novel human cervical cancer cell line

Cervical cancer is the fourth most common cancer in women. Although cure rates are high for early stage disease, clinical outcomes for advanced, metastatic, or recurrent disease remain poor. To change this panorama, a deeper understanding of cervical cancer biology and novel study models are needed. Immortalized human cancer cell lines such as HeLa constitute crucial scientific tools, but there are few other cervical cancer cell lines available, limiting our understanding of a disease known for its molecular heterogeneity. This study aimed to establish novel cervical cancer cell lines derived from Brazilian patients. We successfully established one (HCB-514) out of 35 cervical tumors biopsied. We confirmed the phenotype of HCB-514 by verifying its' epithelial and tumor origin through cytokeratins, EpCAM and p16 staining. It was also HPV-16 positive. Whole-exome sequencing (WES) showed relevant somatic mutations in several genes including BRCA2, TGFBR1 and IRX2. A copy number variation (CNV) analysis by nanostring and WES revealed amplification of genes mainly related to kinases proteins involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and validated by western blot analysis. Furthermore, the HCB-514 cell line was sensitive to cisplatin. In summary, this novel Brazilian cervical cancer cell line exhibits relevant key molecular features and constitutes a new biological model for pre-clinical studies.Barretos Cancer Hospital Research Support Department (NAP) for sample collection, Barretos Cancer Hospital Biobank for sample processing, Dr. Flávia de Paula and Gabriela Fernandes for technical support of STRs and BRCA2 Sanger validation, respectively, and Dr. Laura Musselwhite (Duke University) for revising the manuscript. This study was supported by grants from the FINEP (MCTI/FINEP/MS/SCTIE/DECIT-01/2013 - FPXII- BIOPLAT - Process number 01.13.0469.00) and Barretos Cancer Hospital. PhD scholarship from FINEP (Grant numbers 384088/2014-7 and 380434/2015-6) and Barretos Cancer Hospital to MNR

Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies

Lateral hydrogen microsensors prepared on-chip by local oxidation of platinum-decorated titanium films

Titanium microstripes on silicon dioxide substrates are oxidized locally by applying voltages on-chip to lateral electrodes under ambient conditions. This technique enables profound modifications of the electronic circuit. As an example, we transform Ti films decorated by a sub-monolayer of platinum into hydrogen gas microsensors in an otherwise completed device by a silicon-MOS compatible process