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

International Stem Cell Collaboration: How Disparate Policies between the United States and the United Kingdom Impact Research

As the scientific community globalizes, it is increasingly important to understand the effects of international collaboration on the quality and quantity of research produced. While it is generally assumed that international collaboration enhances the quality of research, this phenomenon is not well examined. Stem cell research is unique in that it is both politically charged and a research area that often generates international collaborations, making it an ideal case through which to examine international collaborations. Furthermore, with promising medical applications, the research area is dynamic and responsive to a globalizing science environment. Thus, studying international collaborations in stem cell research elucidates the role of existing international networks in promoting quality research, as well as the effects that disparate national policies might have on research. This study examined the impact of collaboration on publication significance in the United States and the United Kingdom, world leaders in stem cell research with disparate policies. We reviewed publications by US and UK authors from 2008, along with their citation rates and the political factors that may have contributed to the number of international collaborations. The data demonstrated that international collaborations significantly increased an article's impact for UK and US investigators. While this applied to UK authors whether they were corresponding or secondary, this effect was most significant for US authors who were corresponding authors. While the UK exhibited a higher proportion of international publications than the US, this difference was consistent with overall trends in international scientific collaboration. The findings suggested that national stem cell policy differences and regulatory mechanisms driving international stem cell research in the US and UK did not affect the frequency of international collaborations, or even the countries with which the US and UK most often collaborated. Geographical and traditional collaborative relationships were the predominate considerations in establishing international collaborations

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

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

Does the Committee Peer Review Select the Best Applicants for Funding? An Investigation of the Selection Process for Two European Molecular Biology Organization Programmes

Does peer review fulfill its declared objective of identifying the best science and the best scientists? In order to answer this question we analyzed the Long-Term Fellowship and the Young Investigator programmes of the European Molecular Biology Organization. Both programmes aim to identify and support the best post doctoral fellows and young group leaders in the life sciences. We checked the association between the selection decisions and the scientific performance of the applicants. Our study involved publication and citation data for 668 applicants to the Long-Term Fellowship programme from the year 1998 (130 approved, 538 rejected) and 297 applicants to the Young Investigator programme (39 approved and 258 rejected applicants) from the years 2001 and 2002. If quantity and impact of research publications are used as a criterion for scientific achievement, the results of (zero-truncated) negative binomial models show that the peer review process indeed selects scientists who perform on a higher level than the rejected ones subsequent to application. We determined the extent of errors due to over-estimation (type I errors) and under-estimation (type 2 errors) of future scientific performance. Our statistical analyses point out that between 26% and 48% of the decisions made to award or reject an application show one of both error types. Even though for a part of the applicants, the selection committee did not correctly estimate the applicant's future performance, the results show a statistically significant association between selection decisions and the applicants' scientific achievements, if quantity and impact of research publications are used as a criterion for scientific achievement

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

Long term productivity and collaboration in information science

This is an accepted manuscript of an article published by Springer in Scientometrics on 02/07/2016, available online: https://doi.org/10.1007/s11192-016-2061-8 The accepted version of the publication may differ from the final published version.Funding bodies have tended to encourage collaborative research because it is generally more highly cited than sole author research. But higher mean citation for collaborative articles does not imply collaborative researchers are in general more research productive. This article assesses the extent to which research productivity varies with the number of collaborative partners for long term researchers within three Web of Science subject areas: Information Science & Library Science, Communication and Medical Informatics. When using the whole number counting system, researchers who worked in groups of 2 or 3 were generally the most productive, in terms of producing the most papers and citations. However, when using fractional counting, researchers who worked in groups of 1 or 2 were generally the most productive. The findings need to be interpreted cautiously, however, because authors that produce few academic articles within a field may publish in other fields or leave academia and contribute to society in other ways

Idiopathic toe walking and sensory processing dysfunction

<p>Abstract</p> <p>Background</p> <p>It is generally understood that toe walking involves the absence or limitation of heel strike in the contact phase of the gait cycle. Toe walking has been identified as a symptom of disease processes, trauma and/or neurogenic influences. When there is no obvious cause of the gait pattern, a diagnosis of idiopathic toe walking (ITW) is made. Although there has been limited research into the pathophysiology of ITW, there has been an increasing number of contemporary texts and practitioner debates proposing that this gait pattern is linked to a sensory processing dysfunction (SPD). The purpose of this paper is to examine the literature and provide a summary of what is known about the relationship between toe walking and SPD.</p> <p>Method</p> <p>Forty-nine articles were reviewed, predominantly sourced from peer reviewed journals. Five contemporary texts were also reviewed. The literature styles consisted of author opinion pieces, letters to the editor, clinical trials, case studies, classification studies, poster/conference abstracts and narrative literature reviews. Literature was assessed and graded according to level of evidence.</p> <p>Results</p> <p>Only one small prospective, descriptive study without control has been conducted in relation to idiopathic toe walking and sensory processing. A cross-sectional study into the prevalence of idiopathic toe walking proposed sensory processing as being a reason for the difference. A proposed link between ITW and sensory processing was found within four contemporary texts and one conference abstract.</p> <p>Conclusion</p> <p>Based on the limited conclusive evidence available, the relationship between ITW and sensory processing has not been confirmed. Given the limited number and types of studies together with the growing body of anecdotal evidence it is proposed that further investigation of this relationship would be advantageous.</p