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Dynamic changes in the endoplasmic reticulum (ER) morphology are central to maintaining cellular homeostasis. Microtubules (MT) facilitate the continuous remodeling of the ER network into sheets and tubules by coordinating with many ER-shaping protein complexes, although how this process is controlled by extracellular signals remains unknown. Here we report that TAK1, a kinase responsive to various growth factors and cytokines including TGF-β and TNF-α, triggers ER tubulation by activating αTAT1, an MT-acetylating enzyme that enhances ER-sliding. We show that this TAK1/αTAT1-dependent ER remodeling promotes cell survival by actively downregulating BOK, an ER membrane-associated proapoptotic effector. While BOK is normally protected from degradation when complexed with IP3R, it is rapidly degraded upon their dissociation during the ER sheets-to-tubules conversion. These findings demonstrate a distinct mechanism of ligand-induced ER remodeling and suggest that the TAK1/αTAT1 pathway may be a key target in ER stress and dysfunction.

Abstract In pathologies including cancer, aberrant Transforming Growth Factor-β (TGF-β) signaling exerts profound tumor intrinsic and extrinsic consequences. Intense clinical endeavors are underway to target this pathway. Central to the success of these interventions is pinpointing factors that decisively modulate the TGF-β responses. Betaglycan/type III TGF-β receptor (TβRIII), is an established co-receptor for the TGF-β superfamily known to bind directly to TGF-βs 1–3 and inhibin A/B. Betaglycan can be membrane-bound and also undergo ectodomain cleavage to produce soluble-betaglycan that can sequester its ligands. Its extracellular domain undergoes heparan sulfate and chondroitin sulfate glycosaminoglycan modifications, transforming betaglycan into a proteoglycan. We report the unexpected discovery that the heparan sulfate glycosaminoglycan chains on betaglycan are critical for the ectodomain shedding. In the absence of such glycosaminoglycan chains betaglycan is not shed, a feature indispensable for the ability of betaglycan to suppress TGF-β signaling and the cells' responses to exogenous TGF-β ligands. Using unbiased transcriptomics, we identified TIMP3 as a key inhibitor of betaglycan shedding thereby influencing TGF-β signaling. Our results bear significant clinical relevance as modified betaglycan is present in the ascites of patients with ovarian cancer and can serve as a marker for predicting patient outcomes and TGF-β signaling responses. These studies are the first to demonstrate a unique reliance on the glycosaminoglycan chains of betaglycan for shedding and influence on TGF-β signaling responses. Dysregulated shedding of TGF-β receptors plays a vital role in determining the response and availability of TGF-βs’, which is crucial for prognostic predictions and understanding of TGF-β signaling dynamics.

Abstract Background Tumor‐associated angiogenesis mediates the growth and metastasis of most solid cancers. Targeted therapies of the VEGF pathways can effectively block these processes but often fail to provide lasting benefits due to acquired resistance and complications. Results Recently, we discovered βIV‐spectrin as a powerful regulator of angiogenesis and potential new target. We previously reported that βIV‐spectrin is dynamically expressed in endothelial cells (EC) to induce VEGFR2 protein turnover during development. Here, we explored how βIV‐spectrin influences the tumor vasculature using the murine B16 melanoma model and determined that loss of EC‐specific βIV‐spectrin dramatically promotes tumor growth and metastasis. Intraperitoneally injected B16 cells formed larger tumors with increased tumor vessel density and greater propensity for metastatic spread particularly to the chest cavity and lung compared to control mice. These results support βIV‐spectrin as a key regulator of tumor angiogenesis and a viable vascular target in cancer.

Hypoxia increases levels of the heteromeric TGFβ ligand inhibin in ovarian cancer and inhibin promotes tumor growth, endothelial cell invasion and permeability.

Defective angiogenesis remains a high source of morbidity in multiple disorders. Here they show that βIV-spectrin, a membrane-associated cytoskeletal protein, is essential for regulation of endothelial tip cell populations and VEGF signaling during sprouting angiogenesis.

Leah B Sansbury,1 Robert P Wood,2 Glenn A Anley,3 Yein Nam,2 Afisi S Ismaila4,5 1Epidemiology, Value Evidence and Outcomes, GlaxoSmithKline, Research Triangle Park, NC, USA; 2Observational Research, Adelphi Real World, Bollington, UK; 3UK Health Outcomes, GlaxoSmithKline, Uxbridge, UK; 4Value Evidence and Outcomes, GlaxoSmithKline, Collegeville, PA, USA; 5Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, CanadaCorrespondence: Afisi S IsmailaValue Evidence and Outcomes, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426-0989, USATel +1 919 315 8229Email afisi.s.ismaila@gsk.comPurpose: To assess if early multiple-inhaler triple therapy (MITT) initiation in patients with chronic obstructive pulmonary disease (COPD) reduces subsequent healthcare resource utilization (HCRU), direct medical costs, and acute exacerbations of COPD (AECOPDs).Patients and Methods: This retrospective, longitudinal cohort study used electronic health records and linked hospital administrative data in England. COPD patients with an AECOPD between July 2012 and May 2016 (index), and who subsequently started MITT within 180 days were eligible. Patients with an AECOPD 6 months prior to index were excluded. HCRU, direct healthcare costs, and AECOPDs were assessed in the following 24-month period for early (≤ 30 days) and delayed (31– 180 days) MITT initiators.Results: A total of 934 patients were included in the analysis and categorized as early (n=367, 39%) or delayed (n=567, 61%) MITT initiators. Mean patient age was 68.5 years and 53.2% were male. A significantly higher proportion of delayed MITT initiators required ≥ 1 outpatient appointment (all-cause) compared with early MITT initiators (87% vs 79%; p=0.0016). A significantly higher proportion of delayed MITT initiators required ≥ 1 COPD‑related inpatient stay versus early MITT initiators (47% vs 40%; p=0.0262). Over the 24-month follow-up, mean all-cause and COPD-related total healthcare costs were significantly higher in delayed MITT initiators compared with early MITT initiators (all‑cause: £ 11,348 vs £ 8126; p=0.0011; COPD-related: £ 7307 vs £ 4535; p=0.0009).Conclusion: Delayed initiation of multiple-inhaler triple therapy was associated with higher all-cause and COPD-related costs, suggesting that earlier initiation of triple therapy in COPD patients may help reduce the economic burden on the healthcare system.Keywords: chronic obstructive pulmonary disease, England, exacerbation, healthcare utilization, multiple-inhaler triple therapy, triple therapy

Summary: Growth factors in tumor environments are regulators of cell survival and metastasis. Here, we reveal the dichotomy between TGF-β superfamily growth factors BMP and TGF-β/activin and their downstream SMAD effectors. Gene expression profiling uncovers SOX2 as a key contextual signaling node regulated in an opposing manner by BMP2, -4, and -9 and TGF-β and activin A to impact anchorage-independent cell survival. We find that SOX2 is repressed by BMPs, leading to a reduction in intraperitoneal tumor burden and improved survival of tumor-bearing mice. Repression of SOX2 is driven by SMAD1-dependent histone H3K27me3 recruitment and DNA methylation at SOX2’s promoter. Conversely, TGF-β, which is elevated in patient ascites, and activin A can promote SOX2 expression and anchorage-independent survival by SMAD3-dependent histone H3K4me3 recruitment. Our findings identify SOX2 as a contextual and contrastingly regulated node downstream of TGF-β members controlling anchorage-independent survival and metastasis in ovarian cancers.

Dominique Milea,1 See-Hwee Yeo,1 Yein Nam,2 Aldo Amador Navarro Rojas,1 Sumitra Shantakumar,1 Janine Beale,3 Brett Marett,3 Robert P Young,4 Raewyn J Scott,4 Barry Gribben5 1Value Evidence and Outcomes, GlaxoSmithKline plc., Greater China and Intercontinental, 139234, Singapore; 2Real World Evidence & Epidemiology, Adelphi Real World, Macclesfield, Cheshire, UK; 3Medical Affairs, GlaxoSmithKline plc., Auckland, New Zealand; 4Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 5Public Sector Surveying, CBG Health Research Limited, Auckland, New ZealandCorrespondence: Dominique MileaValue Evidence and Outcomes, GlaxoSmithKline plc., Greater China and Intercontinental, 23 Rochester Park, 139234, SingaporeTel +65 9830 7891Email dominique.x.milea@gsk.comPurpose: Long-acting bronchodilator (LABD) use is the mainstay of pharmacologic treatment for chronic obstructive pulmonary disease (COPD). Few studies describe evolving patterns of LABD use in the setting of changing inhaler availability and updated clinical guidelines.Methods: A retrospective cohort study in New Zealand using the HealthStat general practice database (01/2014 to 04/2018). Eligible patients (aged ≥ 40 years) had COPD and ≥ 1 LABD prescription (long-acting muscarinic antagonist [LAMA] and/or long-acting β2-agonist [LABA]) during the index period (05/2015 to 04/2016). Demographics and clinical characteristics of all LABD users (overall/by treatment) were described at baseline. Patients starting LABD treatment during the index period, termed “new” users, were also described, as was their treatment evolution over 24 months of follow-up. Yearly LABD initiation rates were assessed from 2015 to 2017, covering changes to Pharmaceutical Management Agency criteria and clinical guidelines.Results: Across 2140 eligible patients, the most common index treatments were inhaled corticosteroid (ICS)/LABA (59.0%) and open triple therapy (LAMA+LABA+ICS; 26.7%). ICS/LABA therapy was highest in younger patients, with open triple therapy highest in older patients. Prior yearly exacerbation rates were lowest in those receiving monotherapy (LABA: 0.9/year; LAMA: 1.1/year) versus dual therapy (all 1.4/year) and open triple therapy (2.2/year). Of 312 new LABD users, ICS/LABA was the most common index treatment (69.6%), followed by LAMA monotherapy (16.0%). Continuous use with index treatment was 31.1% at 12 months and 13.5% at 24 months; mean time to treatment change was 175.5 and 244.1 days, respectively. Among patients modifying treatment at 24 months, 23.0% augmented, 7.0% switched, 45.6% re-started, and 24.4% discontinued/stepped down. Among patients initiating LABD each year from 2015 to 2017, LAMA prescription increased (17% to 46%) while ICS prescription remained stable (approximately 20%).Conclusion: Predominant use of ICS/LABA (05/2015 to 04/2016) reflects available LABDs and previous restrictions on LAMA use in New Zealand.Keywords: bronchodilator therapy, chronic obstructive pulmonary disease, long-acting muscarinic antagonist, long-acting β2-agonist, inhaled corticosteroid, New Zealand

GIPC is a PDZ-domain containing adaptor protein that regulates the cell surface expression and endocytic trafficking of numerous transmembrane receptors and signaling complexes. Interactions with over 50 proteins have been reported to date including VEGFR, insulin-like growth factor-1 receptor (IGF-1R), GPCRs, and APPL, many of which have essential roles in neuronal and cardiovascular development. In cancer, a major subset of GIPC-binding receptors and cytoplasmic effectors have been shown to promote tumorigenesis or metastatic progression, while other subsets have demonstrated strong tumor-suppressive effects. Given that these diverse pathways are widespread in normal tissues and human malignancies, precisely how these opposing signals are integrated and regulated within the same tumor setting likely depend on the strength and duration of their interactions with GIPC. This review highlights the major pathways and divergent mechanisms of GIPC signaling in various cancers and provide a rationale for emerging GIPC-targeted cancer therapies.

Inhibins and activins are dimeric ligands belonging to the TGFβ superfamily with emergent roles in cancer. Inhibins contain an α-subunit (INHA) and a β-subunit (either INHBA or INHBB), while activins are mainly homodimers of either βA (INHBA) or βB (INHBB) subunits. Inhibins are biomarkers in a subset of cancers and utilize the coreceptors betaglycan (TGFBR3) and endoglin (ENG) for physiological or pathological outcomes. Given the array of prior reports on inhibin, activin and the coreceptors in cancer, this study aims to provide a comprehensive analysis, assessing their functional prognostic potential in cancer using a bioinformatics approach. We identify cancer cell lines and cancer types most dependent and impacted, which included p53 mutated breast and ovarian cancers and lung adenocarcinomas. Moreover, INHA itself was dependent on TGFBR3 and ENG/CD105 in multiple cancer types. INHA, INHBA, TGFBR3, and ENG also predicted patients' response to anthracycline and taxane therapy in luminal A breast cancers. We also obtained a gene signature model that could accurately classify 96.7% of the cases based on outcomes. Lastly, we cross-compared gene correlations revealing INHA dependency to TGFBR3 or ENG influencing different pathways themselves. These results suggest that inhibins are particularly important in a subset of cancers depending on the coreceptor TGFBR3 and ENG and are of substantial prognostic value, thereby warranting further investigation.

Acetylation of microtubules (MT) confers mechanical stability necessary for numerous cellular functions but its regulation is unclear. Here the authors show that the MT acetyltransferase αTAT1 is regulated by TGF-β-activated kinase 1 implicating TGF-β signaling in MT-related functions and disease.

Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis. Keywords: Extracellular glutathione peroxidase, GPx3, Ovarian cancer, Ascites, Ascorbate

Anoikis, a cell death mechanism triggered upon cell-matrix detachment, is regarded as a physiological suppressor of metastasis that can be regulated by a diverse array of signals. The protein encoded by GDF2 is BMP9 and is a member of the bone morphogenetic protein family and the transforming growth factor (TGF) β superfamily with emerging yet controversial roles in carcinogenesis. In an attempt to identify the function of growth and differentiation factor 2 (GDF2) in epithelial systems, we examined the signaling machinery that is involved and cell fate decisions in response to GDF2 in ovarian and breast epithelia. We find that GDF2 can robustly activate the SMAD1/5 signaling axis by increasing complex formation between the type I receptor serine threonine kinases activin receptor-like kinase (ALK) 3 and ALK6 and the type II receptor serine threonine kinase BMPRII. This activation is independent of cross talk with the SMAD2-transforming growth factor β pathway. By activating SMAD1/5, epithelial cells regulate anchorage-independent growth by increasing anoikis sensitivity that is dependent on GDF2’s ability to sustain the activation of SMAD1/5 via ALK3 and ALK6. Consistent with a role for GDF2 in promoting anoikis susceptibility, the analysis of cell lines and patient data suggests epigenetic silencing of GDF2 in cancer cell lines and increased promoter methylation in patients. These findings collectively indicate an antimetastatic role for GDF2 in ovarian and breast cancer. The work also implicates loss of GDF2 via promoter methylation-mediated downregulation in promotion of carcinogenesis with significant relevance for the use of epigenetic drugs currently in clinical trials.

The Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak is capable of operating at a wide range of toroidal magnetic fields up to 3.5 T at the major radius. The electron cyclotron emission (ECE) diagnostic on KSTAR is required to cover a broad frequency range for electron temperature profile measurements in both the low and high field sides. To meet these broadband requirements, the ECE system consists of W-band (78–110 GHz) and D-band (110–162 GHz) heterodyne radiometers. The two radiometers are connected to 28 and 48 detection channels, respectively. However, since the absolute ECE calibration based on the hot–cold calibration has been very challenging, an alternative method of calibration was performed using Thomson scattering measurements and varying toroidal magnetic fields. As the toroidal magnetic field is scanned from 1.6 to 3.2 T in steps of 0.2 T, most of the 76 ECE channels are calibrated relatively by the electron temperature values of Thomson scattering in a narrow region (0.2 < r/a <0.6). In this article, the methodological details of the ECE calibration are described. In addition, to demonstrate the robustness of the ECE calibration factors, the calibrated electron temperature profiles from ECE measurements are compared with the ion temperature profiles in terms of the plasma position as the plasma positon shifts outward. [ABSTRACT FROM AUTHOR]

For the past 10 years, a climate change course has been offered in a large Midwest university. This course has been focusing on improving college students' scientific knowledge of climate change and human interactions using historical evidence as well as improving their information literacy in science through a course project that requires students to prepare a group presentation and a paper about an example of historical evidence of climate change and human interactions. This study evaluates the course's impact on students' learning of climate change and human interaction and improvement of information literacy in science based on students' responses to several questionnaires and interview data collected through the academic year of 2009. Results show that even if individual students had a different level of background knowledge of climate change and human interactions before the course, their content knowledge improved through the course. The students agreed that the course positively affected their information literacy in science (climate change) and interest. However, they neither disagreed nor agreed that they learned science knowledge relevant to their everyday lives and current socioeconomic issues related to climate change. They also thought that their environmental behavior did not change much as a result of the course.

A comparative study of oxidation methods to create Cu surfaces with controlled wettability is reported. Micro/nanostructures of Cu oxides are formed on Cu substrates using different chemical and thermal oxidation methods. The morphology and wetting characteristics of the resulting surfaces are characterized using atomic force microscopy, scanning electron microscopy, X-ray diffraction, and contact angle measurements. Chemical oxidation in alkali solutions can form uniform copper oxide layers with high roughness factors without causing thermal stress problems that often hamper thermal oxidation. By combining chemical oxidation with a hydrophobic coating, a wide range of wettability control is demonstrated from superhydrophilic (< 10°) to superhydrophobic (> 170°). Superhydrophilic CuO layers uniformly formed on Cu powder and Cu micropost wick surfaces lead to significant improvement in the capillary and heat transfer performance compared with comparable unoxidized Cu wicks. The present work motivates further studies to exploit the benefits of nanostructured Cu surfaces in various phase change heat transfer applications. © 2013 Taylor and Francis Group, LLC.

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility