tbuckley/cabot-search huggingface dataset:
Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer
Authors: Fernando Salvador, Alberto Martin, Celia López-Menéndez, Gema Moreno-Bueno, Vanesa Santos, Alberto Vázquez-Naharro, Patricia G. Santamaría, Saleta Morales, Pierre R. Dubus, Laura Muinelo-Romay, Rafael López-López, Jason C. Tung, Valerie M. Weaver, Francisco Portillo, Amparo Cano
Journal: Cancer Research (2017)

The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote premetastatic niche formation. Taken together, our findings established a pathophysiologic role and new function for LOXL2 in breast cancer metastasis. Cancer Res; 77(21); 5846-59. ©2017 AACR.
Acute Achilles tendon rupture
Authors: Dishan Singh
Journal: British Journal of Sports Medicine (2017)

This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, professor of primary care, Department of Primary Care Health Sciences, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at practice@bmj.com.
Abstract 2174: Inhibition of CDK8 kinase with SEL120-34A allows for a personalized approach in AML
Authors: Tomasz Rzymski, Michal Mikula, Eliza Zylkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Iga Dudzicz, Katarzyna Kucwaj, Malgorzata Statkiewicz, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Jerzy Ostrowski, Urszula Kukliniska, Krzysztof Brzozka
Journal: Cancer Research (2017)

Abstract Inhibition of oncogenic transcriptional programs is recognized to be a promising therapeutic strategy. SEL120-34A is a novel inhibitor of Cyclin- dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. SEL120-34A interacts with the ATP binding site of CDK8 in type I inhibitor fashion and forms several types of interactions, including halogen bonds with the protein’s hinge region and hydrophobic complementarities within its front pocket. Although the compound was only modestly active in solid tumor cell lines, it repressed phosphorylation of STAT5 Ser726 and could differentially inhibit viability of AML and ALL cell lines in vitro and in vivo, along with other type I CDK8 inhibitors. Transcriptomic analysis identified major transcriptional programs altered in responder cell lines, which strongly indicated that apart from repression of survival pathways, CDK8 inhibitors could induce differentiation in cell lines with leukemia stem cells characteristics. Further studies on a large panels of responder and non-responder cell lines identified robust biomarkers which could be used with high confidence for stratification and personalized approach in CDK8-dependent AML cases. Favorable pharmacokinetics, confirmed safety and in vivo efficacy in leukemia models provide the rationale for further clinical development of SEL120-34A. Citation Format: Tomasz Rzymski, Michal Mikula, Eliza Zylkiewicz, Agnieszka Dreas, Katarzyna Wiklik, Aniela Golas, Katarzyna Wojcik, Magdalena Masiejczyk, Iga Dudzicz, Katarzyna Kucwaj, Malgorzata Statkiewicz, Krzysztof Goryca, Aleksandra Grochowska, Aleksandra Cabaj, Jerzy Ostrowski, Urszula Kukliniska, Krzysztof Brzozka. Inhibition of CDK8 kinase with SEL120-34A allows for a personalized approach in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2174. doi:10.1158/1538-7445.AM2017-2174
Abstract P047: A Novel Antiapoptotic Function of Thioredoxin-1 Is Mediated by Interaction with Caspase 3
Authors: Anna Eckers, Joachim Altschmied, Judith Haendeler
Journal: Circulation Research (2011)

Thioredoxin-1 (Trx-1) is one of the most important redox regulators in endothelial cells (EC). It is an oxidoreductase with anti-oxidative and anti-apoptotic properties. In EC not only the active site cysteines 32 and 35 but also the cysteine 69 are required for its anti-apoptotic function. Trx-1 has several interaction partners, but this list is far from complete. The underlying molecular mechanisms in apoptosis protection by Trx-1 are not completely understood. The most important apoptosis executor protein in EC is Caspase 3. Therefore, the aim of this study was to investigate whether Trx-1 interferes with Caspase 3 function. We first analyzed if Trx-1 is associated with Caspase 3. Coimmunoprecipitation revealed an interaction between both proteins, which was only found under non-reducing conditions, suggesting involvement of a disulfide bridge. To get insights into the functional relevance of the association between Trx-1 and Caspase 3, we investigated whether Trx-1 can directly interact with the catalytic subunit p17 of Caspase 3. After coexpression of p17 and Trx-1, coimmunoprecipitation experiments under non-reducing conditions revealed that p17 associates with Trx-1. Analysis of Trx-1 mutants demonstrated that the interaction depends on cysteine 32 and/or 69 in Trx-1. To assess the functional relevance of the Trx-1/Caspase 3 interaction in EC, we induced apoptosis by overexpression of p17 and investigated the influence Trx-1 wildtype (wt) and mutants in which single or multiple cysteine residues were replaced by serines thereby preventing disulfide bridge formation. Apoptosis induction by p17 was significantly reduced by Trx-1 wt (p17+lacZ 16.99±1.35% vs. p17+Trxwt 8.60±1.31% apoptotic cells). Interestingly, overexpression of Trx-1 with mutations of cysteines 32 and 69 enhanced apoptosis induction by Caspase 3 p17 (23.42±2.84% apoptotic cells). On the contrary, no increase in apoptosis was observed when only cysteine 32 or 69 were mutated, suggesting that both residues can scavenge p17 via disulfide bridge formation thereby preventing its association with the second Caspase 3 subunit p12 and thus activation of the enzyme. These data suggest that Trx-1 has a novel anti-apoptotic function by binding the apoptosis executing Caspase 3.
Prostate-Specific Membrane Antigen–Targeted Imaging With [18F]DCFPyL in High-Grade Gliomas
Authors: Roberto Andres Salas Fragomeni, Joshua R. Menke, Matthias Holdhoff, Clare Ferrigno, John Joseph Laterra, Lilja B. Solnes, Mehrbod S. Javadi, Zsolt Szabo, Martin G. Pomper, Steven P. Rowe
Journal: Clinical Nuclear Medicine (2017)

High-grade gliomas (World Health Organization grade III-IV) are highly lethal primary brain tumors. Imaging modalities, including MRI and FDG PET, provide a limited ability to differentiate treatment effects (such as radiation necrosis) from recurrent or residual tumor. As the first step in validating the applicability of prostate-specific membrane antigen (PSMA)-targeted imaging in high-grade gliomas, we evaluated the ability of the PSMA-targeted small molecule [F]DCFPyL (2-(3-(1carboxy-5-(6-[F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid) to image high-grade gliomas in a series of 3 prospectively recruited patients. We found [F]DCFPyL binds PSMA in the neovasculature of glioblastoma multiforme and tumor cells of anaplastic astrocytoma.
Abstract 408: Myocardial Knockdown of Mir-375 Attenuates Post-mi Inflammatory Response and Left Ventricular Dysfunction via Pdk-1-akt Signaling Axis
Authors: Venkata N Garikipati, Suresh K Verma, Mohsin Khan, Anna M Gumpert, Jibin Zhou, Zhongjian Cheng, Cindy Benedict, Emily Nickoloff, Jennifer Johnson, Ancai Yuan, Erhe Gao, Raj Kishore
Journal: Circulation Research (2015)

MicroRNAs are known to be dysregulated in the ischemic heart disease and have emerged as potential therapeutic targets for treatment of myocardial infarction (MI). Recently MicroRNA-375 has been shown to be up-regulated in humans with MI. In this study, we assessed whether inhibition of the miR-375 using an i.v.-delivered locked nucleic acid (LNA)-modified anti-miR (LNA-antimiR-375) can provide therapeutic benefit in mice with pre-existing pathological cardiac remodeling and dysfunction due to myocardial infarction (MI).After the induction of acute myocardial infarction, mice were treated with either control or LNA based miR-375 inhibitor, and inflammatory response, cardiomyocyte apoptosis and LV functional and structural remodeling changes were evaluated. Anti-miR-375 therapy significantly suppressed infiltration of inflammatory cells, expression of proinflammatory cytokines in the myocardium and cardiomyocyte apoptosis. These changes were associated with miR-375 mediated activation of 3-phosphoinositide-dependent protein kinase 1 (PDK-1) and downstream AKT phosphorylation on Thr-308. LNA anti-miR-375 therapy significantly improved LV functions, reduced infarct size, and attenuated infarct wall thinning. Moreover, LNA based miR-375 therapy significantly increased capillary density in the infarcted myocardium. Further, our in vitro studies demonstrated that miR-375 negatively regulates the expression of PDK-1 by directly targeting the 3’UTR of the PDK-1 transcript. Taken together, our studies demonstrate that anti miR-375 therapy suppresses inflammatory response, cardiomyocyte death and contributes to improved LV function and enhanced angiogenesis via activation of PDK-1/AKT signaling.
What is a symptomatic SLAP II tear? It is all about inclusion and exclusion criteria
Authors: Derek F P van Deurzen, Michel P J van den Bekerom
Journal: British Journal of Sports Medicine (2017)

We have read with great interest the article ‘Sham surgery versus labral repair or biceps tenodesis for type II superior labral tear from anterior to posterior (SLAP) lesions of the shoulder: a three-armed randomised clinical trial’.1 Although we highly appreciate the efforts of the authors to bring more understanding to the topic of treatment of SLAP II lesions, we have some comments and two questions concerning this high-quality and relevant study. We believe that the conclusions of the current trial have to be drawn in the light of these remarks.

The …
Denintuzumab Mafodotin Stimulates Immune Responses and Synergizes with CD20 Antibodies to Heighten Anti-Tumor Activity in Preclinical Models of Non-Hodgkin Lymphoma
Authors: Heather A. Van Epps, Ryan Heiser, Anthony Cao, Kerry Klussman, Changpu Yu, Ivan Stone, Jason Neale, Shyra J. Gardai, Che-Leung Law, Maureen C. Ryan
Journal: Blood (2016)
Inconsistent Guideline Recommendations for Cardiovascular Prevention and the Debate About Zeroing in on and Zeroing LDL-C Levels With PCSK9 Inhibitors
Authors: John P. A. Ioannidis
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cross-talk between EGFR and HIF-1 alpha signaling pathways increases resistance to apoptosis under normoxic conditions by upregulating survivin in human breast cancer cells
Authors: Xianghong Peng, Prasanthi Karna, Zehong Cao, Hua Zhong, Bing Hua Jiang, William C. Wood, Lily Yang
Journal: Cancer Research (2005)

4387  Epidermal growth factor receptor (EGFR) signaling plays important roles in the survival and proliferation of cancer cells. Overexpression of EGFR is found in many cancer types and has been associated with poor patient prognosis. Although it is well known that activation of EGFR signaling decreases apoptosis in tumor cells, the mechanism of resistance to apoptosis has yet to be elucidated. Recent studies have shown that survivin, a member of the inhibitor of apoptosis (IAP) family, is highly expressed in over 70% of breast cancers, although not in normal breast tissue. The role of survivin in blocking apoptosis and decreasing chemo- or radiotherapeutic response has been demonstrated in cancer cell lines and animal tumor models. In our study, we have found that EGF stimulation increases the level of survivin gene expression in breast cancer cell lines such as MDA-MB-231, MCF-7, and SKBr-3; but not in immortalized normal breast epithelial cell line MCF-10A. After EGF treatment, a 20% reduction of apoptotic rate is presented in breast cancer cells treated by chemotherapy drug docetaxel. As expected, we found that EGF stimulation increases AKT and MAPK activity while EGF-induced upregulation of survivin is blocked by the PI3K inhibitor LY294002, the MAPK inhibitor PD98059, and the EGFR inhibitor AG1478. We have previously shown that the level of survivin gene expression in breast cancer cells is increased under hypoxic conditions. In this study, we further found that under normoxic conditions, EGF treatment increases HIF-1 α, which then induces survivin gene expression by direct binding to a hypoxia-responsive element (HRE) located at -81 to -85 nt of the 5’-flanking region of the survivin gene as evidenced by a modified McKay assay. Furthermore, we showed that the effects of EGF on survivin gene expression and apoptosis resistance are blocked by HIF-1 α SiRNA administration. Therefore, HIF-1 α and survivin appear to be promising molecular targets for the development of novel therapeutic approaches to enhance chemosensitivity in human tumor cells receiving EGF/EGFR signaling.
Abstract 1555: Pan-cancer patterns of synthetic lethality: statistical modeling of gene dependency profiles
Authors: Huwate Yeerna, Ramya Rangan, Andrew Aguirre, William Kim, Francisca Vazquez, Barbara Weir, Mahmoud Ghandi, Aviad Tsherniak, Jesse Boehm, William Hahn, Jill Mesirov, Pablo Tamayo
Journal: Cancer Research (2017)

Abstract We present a methodology to fit statistical models of cell-viability profiles from RNAi-gene knockdowns. This method allows us to classify genes according to the degree of skewness in their viability distributions. The set of genes with the highest degree of skewness is highly enriched with many known oncogenes and tumor suppressors. We characterize many of these genes, compare them against the results of large sequencing efforts, and use them as inputs to a matrix-decomposition procedure that identifies the most salient cell viabilities shared by different cancer types. We catalog these pan-cancer patterns of synthetic lethality and characterize them by the genomic, transcriptional, and phenotypic features. This analysis provides a rich catalog of the most salient Achilles’ Heels of Pan-Cancer that can be helpful to identify new therapeutic strategies across cancers. Citation Format: Huwate Yeerna, Ramya Rangan, Andrew Aguirre, William Kim, Francisca Vazquez, Barbara Weir, Mahmoud Ghandi, Aviad Tsherniak, Jesse Boehm, William Hahn, Jill Mesirov, Pablo Tamayo. Pan-cancer patterns of synthetic lethality: statistical modeling of gene dependency profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2017-1555
Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model
Authors: Ming-Zhi Zhang, Xin Wang, Haichun Yang, Agnes B. Fogo, Brian J. Murphy, Robert Kaltenbach, Peter Cheng, Bradley Zinker, Raymond C. Harris
Journal: Journal of the American Society of Nephrology (2017)

Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA-LPAR signaling has been implicated in development of fibrosis. However, the role of LPA-LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (P<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, α-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-β; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n=4; at 20 weeks: 364±18 with vehicle, n=7, and 536±12 with LPAR inhibition, n=7; P<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.
Long‐Term Safety and Efficacy of Fulranumab in Patients With Moderate‐to‐Severe Osteoarthritis Pain: A Phase II Randomized, Double‐Blind, Placebo‐Controlled Extension Study
Authors: Panna Sanga, Nathaniel Katz, Elena Polverejan, Steven Wang, Kathleen M. Kelly, Juergen Haeussler, John Thipphawong
Journal: Arthritis & Rheumatology (2016)

Objective To evaluate the long‐term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate‐to‐severe chronic osteoarthritis (OA). Methods In this phase II double‐blind, placebo‐controlled extension study, patients who were randomized in equal proportions to receive subcutaneous doses of either placebo or fulranumab (1 mg every 4 weeks, 3 mg every 8 weeks, 3 mg every 4 weeks, 6 mg every 8 weeks, or 10 mg every 8 weeks) in the 12‐week double‐blind efficacy phase and who completed this double‐blind efficacy phase were eligible to continue the dosage throughout a 92‐week double‐blind extension phase, followed by a 24‐week posttreatment follow‐up period. Safety assessments included evaluation of treatment‐emergent adverse events (TEAEs), pre‐identified AEs of interest, and joint replacements. Efficacy assessments included changes from baseline to the end of the double‐blind extension phase in scores on the patient's global assessment and the pain and physical function subscales of the Western Ontario and McMaster Universities Osteoarthritis Index. Results Overall, 401 of the 423 patients who completed the 12‐week double‐blind efficacy phase entered the extension study. Long‐term sustained improvements were observed in all efficacy parameters following fulranumab treatment (1 mg every 4 weeks, 3 mg every 4 weeks, and 10 mg every 8 weeks) as compared with placebo. Similar percentages of patients in both groups experienced TEAEs (88% taking placebo and 91% taking fulranumab; all phases). Across all fulranumab groups, arthralgia (21%) and OA (18%) (e.g., exacerbation of OA pain) were the most common TEAEs. The most common serious TEAEs were the requirement for knee (10%) and hip (7%) arthroplasty, with 80% occurring during the posttreatment follow‐up period. Neurologic‐related TEAEs (28%; all phases) were generally mild‐to‐moderate. Overall, 81 joint replacements were performed in 71 patients (8 [11%] receiving placebo and 63 [89%] receiving fulranumab); 15 patients (21%) had rapid progression of OA (RPOA). All cases of RPOA occurred in fulranumab‐treated patients who were concurrently receiving nonsteroidal antiinflammatory drugs and occurred in joints with preexisting OA. Conclusion Long‐term treatment with fulranumab was generally well‐tolerated and efficacious. RPOA was observed as a safety signal. Future studies are warranted to demonstrate whether the risk of RPOA can be reduced in patients taking fulranumab.
Abstract 3553: Preserved Cardiac Function after Myocardial Infarction in Mice Lacking the Frizzled-2 Gene
Authors: Sanna K Janhunen, Sander S Rensen, Agnieska E Brouns-Strzelecka, Helena T Vervoort-Peters, J. W Voncken, Ben J Janssen, Jos F Smits, W M Blankesteijn
Journal: Circulation (2008)
Management of patients after primary percutaneous coronary intervention for myocardial infarction
Authors: Fatima Dalal, Hasnain M Dalal, Christos Voukalis, Manish M Gandhi
Journal: BMJ (2017)

#### What you need to know

For those who present with an acute ST elevation myocardial infarction (STEMI) in the UK, nearly 90% are treated with a primary angioplasty within 90 minutes of arrival at hospital.1 One out of every seven deaths is due to coronary heart disease, with one person having a “heart attack” every 40 seconds, based on US data.2 In the UK, 288 per 100 000 people visit hospital with a suspected heart attack each year.3

Patients are usually discharged three days after treatment for a STEMI with an uncomplicated primary percutaneous coronary intervention (PCI).1 4 They may present in the community for further advice shortly after discharge, so close collaboration between the cardiologist and the wider healthcare team is essential.5 This article provides an update on the immediate and longer term management of such patients (see fig 1⇓).



Fig 1  Management of patients after an acute ST elevation myocardial infarction



#### Sources and selection criteria

We searched PubMed, Cochrane Library, Medline, and Google using the terms “secondary prevention after a myocardial infarction,” “secondary prevention after a heart attack,” …