tbuckley/cabot-search huggingface dataset:
Newer-Generation Ultrathin Strut Drug-Eluting Stents Versus Older Second-Generation Thicker Strut Drug-Eluting Stents for Coronary Artery Disease
Authors: Sripal Bangalore, Bora Toklu, Neil Patel, Frederick Feit, Gregg W. Stone
Journal: Circulation (2018)

Contemporary second-generation drug-eluting stents (DES) have superior efficacy and safety in comparison with early-generation stents in patients undergoing percutaneous coronary intervention, in part, related to their thinner struts. Whether newer-generation ultrathin DES further improve clinical outcomes in comparison with older second-generation thicker strut DES is unknown.We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for randomized clinical trials that compared newer-generation ultrathin strut DES (defined as strut thickness <70 µm) versus thicker strut second-generation DES and reported clinical outcomes. The primary outcome was target lesion failure (composite of cardiovascular death, target vessel myocardial infarction or ischemia-driven target lesion revascularization) evaluated at 1-year follow-up. Tests for subgroup effects based on the ultrathin strut DES type and the comparator DES type were performed by using meta-regression analysis.We identified 10 trials that randomly assigned 11 658 patients and evaluated 3 newer-generation ultrathin strut DES: Orsiro stent (60 μm), MiStent (64 μm), and BioMime (65 µm). In comparison with thicker strut second-generation DES, newer-generation ultrathin strut DES were associated with a 16% reduction in target lesion failure (relative risk, 0.84; 95% CI, 0.72-0.99) driven by less myocardial infarction (relative risk, 0.80; 95% CI, 0.65-0.99). Ultrathin strut DES were also associated with qualitatively lower rates of any stent thrombosis (relative risk, 0.72; 95% CI, 0.51-1.01). Tests for subgroup effects based on the ultrathin strut DES type ( P=0.58) and the comparator DES type ( P=0.98) were not significant, suggesting consistent outcomes across the 3 ultrathin strut DES and with the different DES comparators.In patients undergoing percutaneous coronary intervention, newer-generation ultrathin strut DES further improve 1-year clinical outcomes in comparison with contemporary thicker strut second-generation DES.
Endoglin Expression on Cancer-Associated Fibroblasts Regulates Invasion and Stimulates Colorectal Cancer Metastasis
Authors: Madelon Paauwe, Mark J.A. Schoonderwoerd, Roxan F.C.P. Helderman, Tom J. Harryvan, Arwin Groenewoud, Gabi W. van Pelt, Rosalie Bor, Danielle M. Hemmer, Henri H. Versteeg, B. Ewa Snaar-Jagalska, Charles P. Theuer, James C.H. Hardwick, Cornelis F.M. Sier, Peter ten Dijke, Lukas J.A.C. Hawinkels
Journal: Clinical Cancer Research (2018)

Cancer-associated fibroblasts (CAF) are a major component of the colorectal cancer tumor microenvironment. CAFs play an important role in tumor progression and metastasis, partly through TGF-β signaling pathway. We investigated whether the TGF-β family coreceptor endoglin is involved in CAF-mediated invasion and metastasis.CAF-specific endoglin expression was studied in colorectal cancer resection specimens using IHC and related to metastases-free survival. Endoglin-mediated invasion was assessed in vitro by transwell invasion, using primary colorectal cancer-derived CAFs. Effects of CAF-specific endoglin expression on tumor cell invasion were investigated in a colorectal cancer zebrafish model, whereas liver metastases were assessed in a mouse model.CAFs specifically at invasive borders of colorectal cancer express endoglin and increased expression intensity correlated with increased disease stage. Endoglin-expressing CAFs were also detected in lymph node and liver metastases, suggesting a role in colorectal cancer metastasis formation. In stage II colorectal cancer, CAF-specific endoglin expression at invasive borders correlated with poor metastasis-free survival. In vitro experiments revealed that endoglin is indispensable for bone morphogenetic protein (BMP)-9-induced signaling and CAF survival. Targeting endoglin using the neutralizing antibody TRC105 inhibited CAF invasion in vitro. In zebrafish, endoglin-expressing fibroblasts enhanced colorectal tumor cell infiltration into the liver and decreased survival. Finally, CAF-specific endoglin targeting with TRC105 decreased metastatic spread of colorectal cancer cells to the mouse liver.Endoglin-expressing CAFs contribute to colorectal cancer progression and metastasis. TRC105 treatment inhibits CAF invasion and tumor metastasis, indicating an additional target beyond the angiogenic endothelium, possibly contributing to beneficial effects reported during clinical evaluations.See related commentary by Becker and LeBleu, p. 6110.
Genotype-phenotype data from a case series of patients with mosaic neurofibromatosis type 1
Authors: A. Marwaha, J. Malach, A. Shugar, S. Hedges, M. Weinstein, P.C. Parkin, E. Pope, I. Lara-Corrales, P. Kannu
Journal: British Journal of Dermatology (2018)
Does the intramuscular tendon act like a free tendon?
Authors: Peter Brukner, Jill L Cook, Craig Robert Purdam
Journal: British Journal of Sports Medicine (2018)

There​ ​has​ ​been​ ​a​n​ ​upsurge​ ​of​ ​interest,​ ​and​ ​some​ ​confusion, about​ ​the​ ​role​ ​of​ ​the ​connective​ ​tissue​ ​condensations within​ ​the​​ ​lower​ ​limb​ ​muscles, notably​​ ​biceps​ ​femoris,​ ​rectus femoris, ​gastrocnemius​ ​and​ ​soleus.​ ​These​ ​bands​ ​are​​ ​variably referred​ ​to​ ​in the​ ​literature​ ​as ​intramuscular​ ​tendon, connective tissue, central tendon​ ​or​ ​aponeurosis, and can have a variable appearance (aponeurotic, cord-like) and vary between individuals.1​ ​

These intramuscular tendons (​IMTs) act as​ central​ ​supporting​ ​struts​ ​to​ ​which​ ​the​ ​muscle fibres​ ​attach​, and they smooth and amalgamate asynchronous motor unit contribution. ​ ​ ​Muscle strain may tear the myofibrillar attachments​​ ​from​ ​the​ intramuscular​ ​tendon, ​​ with resultant​ bleeding and oedema. Occasionally​, ​the​ ​damage​ ​may also involve a partial or complete tear of ​the​ ​ intramuscular​ ​tendon itself.

When​ ​the​ ​ intramuscular​ ​tendon ​is​ ​damaged, ​ ​the​ ​injury​ ​is​ ​regarded​ ​as​ a ​more severe strain. ​ Damage to​ ​the​ intramuscular​ ​tendon ​of​ ​the hamstring group ​ has been associated with a prolonged ​​return​ ​to​ ​play​​,2 3 although van​ ​der​ ​Made​ ​ et​ ​al 4 reported​ ​only​ ​a​ modest increase in return to play duration. ​​​ Differences in the sporting demands of these cohorts may contribute to the …
Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization
Authors: Binghe Tan, Xiujuan Shi, Jie Zhang, Juliang Qin, Na Zhang, Hua Ren, Min Qian, Stefan Siwko, Kendra Carmon, Qingyun Liu, Honghui Han, Bing Du, Mingyao Liu
Journal: Cancer Research (2018)

Therapies targeting immune checkpoints have shown great clinical potential in a subset of patients with cancer but may be hampered by a failure to reverse the immunosuppressive tumor microenvironment (TME). As the most abundant immune cells in TME, tumor-associated macrophages (TAM) play nonredundant roles in restricting antitumor immunity. The leucine-rich repeat-containing G-protein-coupled receptor 4 (Lgr4, also known as Gpr48) has been associated with multiple physiologic and pathologic functions. Lgr4 and its ligands R-spondin 1-4 have been shown to promote the growth and metastasis of tumor cells. However, whether Lgr4 can promote tumor progression by regulating the function of immune cells in the tumor microenvironment remains largely unknown. Here, we demonstrate that Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling. Notably, urethane-induced lung carcinogenesis, Lewis lung carcinoma (LLC), and B16F10 melanoma tumors were all markedly reduced in Lgr4fl/flLyz2cre/+ mice, characterized by fewer protumoral M2 TAMs and increased CD8+ T lymphocyte infiltration in the TME. Furthermore, LLC tumor growth was greatly depressed when Rspo/Lgr4/Erk/Stat3 signaling was blocked with either the LGR4 extracellular domain or an anti-Rspo1 antibody. Importantly, blocking Rspo-Lgr4 signaling overcame LLC resistance to anti-PD-1 therapy and improved the efficacy of PD-1 immunotherapy against B16F10 melanoma, indicating vital roles of Rspo-Lgr4 in host antitumor immunity and a potential therapeutic target in cancer immunotherapy.Significance: This study identifies a novel receptor as a critical switch in TAM polarization whose inhibition sensitizes checkpoint therapy-resistant lung cancer to anti-PD-1 therapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4929/F1.large.jpg Cancer Res; 78(17); 4929-42. ©2018 AACR.
Abstract 2031: The noncanonical pathways of transforming growth factor β in ovarian carcinoma
Authors: Liora Jacobs Catane, Claes G. Trope, Ben Davidson, Reuven Reich
Journal: Cancer Research (2018)

Abstract Introduction: Of all the gynecological malignancies, ovarian cancer (OC) has the highest mortality rate. This can be attributed to the late detection and acquired drug resistance. It metastasizes mainly in the serosal cavities, and produces cancerous cells dispersed in the peritoneal and pleural fluids called effusions. Transforming Growth Factor β (TGFβ) is a family of growth factors that play a significant role in cellular processes. There are three homologous isoforms of TGFβ expressed in humans: TGFβ1-3. These 3 ligands activate 3 transmembrane receptors, TβRI-III. The 3 receptors and the ligand TGF-β2 have different splice variants. TGFβ signaling induces canonical and non-canonical signaling. The Non-canonical pathways consist of a variety of different pathways, including MAP kinase, Rho-like GTPase, and phosphatidylinositol-3-kinase (PI3K)/ AKT pathways. Aims and methods: Our first aim was to investigate the metastatic role of TGFβ receptor variants. This was accomplished through the creation of specific receptor variant knockouts (KO's) using the CRISPR/Cas9 genome editing system and subsequent metastatic tests. Next we characterized chosen non-canonical pathways and downstream effectors in the CRISPR KO's through Western Blot analysis and qPCR respectively. The Second aim of this study was to characterize the non-canonical pathways In-vivo. Using human tumor tissue samples, we examined the expression and activation of the different pathways via Western Blot analysis and checked for correlation with clinical parameters. Results: KO cells showed significantly lower migration and invasion capabilities compared to Wild Type (WT) cells. Our results show a decrease in the activation of ERK1/2, JNK1 and JNK2 in the TβRI variant 1 KO in ES-2 cells (p=0.058, p=0.002 and p&amp;lt;0.0001 respectively). The downstream effectors SNAIL and TWIST show significantly higher levels in the KO compared to WT cells. Of the pathways examined, p-AKT was found to be higher in post chemotherapy samples (p=0.029) and JNK1 was higher in effusions from patients with poor chemotherapy response (p=0.045). Site-related findings show that p85 (PI3K), AKT and p-AKT were highest in metastasis, medium in solid ovarian carcinoma and lowest in effusions (p&amp;lt;0.0001, p=0.0024 and p=0.0021 respectively). Closing statement: These findings provide new insight on the importance of TGFβ‘s role in the progression of OC, and is, as far as we know, is the first study done on the metastatic roles of the receptor variants. Citation Format: Liora Jacobs Catane, Claes G. Trope, Ben Davidson, Reuven Reich. The noncanonical pathways of transforming growth factor β in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2031.
A Bibliometric Analysis of the Landscape of Cancer Rehabilitation Research (1992–2016)
Authors: Nicole L Stout, Catherine M Alfano, Christopher W Belter, Ralph Nitkin, Alison Cernich, Karen Lohmann Siegel, Leighton Chan
Journal: JNCI Journal of the National Cancer Institute (2018)

Cancer rehabilitation research has accelerated as great attention has focused on improving survivorship care. Recent expert consensus has attempted to prioritize research needs and suggests greater focus on studying physical functioning of survivors. However, no analysis of the publication landscape has substantiated these proposed needs. This manuscript provides an analysis of PubMed indexed articles related to cancer rehabilitation published between 1992 and 2017. A total of 22 171 publications were analyzed using machine learning and text analysis to assess publication metrics, topic areas of emphasis, and their interrelationships through topic similarity networks. Publications have increased at a rate of 136 articles per year. Approximately 10% of publications were funded by the National Institutes of Health institutes and centers, with the National Cancer Institute being the most prominent funder. The greatest volume and rate of publication increase were in the topics of Cognitive and Behavioral Therapies and Psychological Interventions, followed by Depression and Exercise Therapy. Four research topic similarity networks were identified and provide insight on areas of robust publication and notable deficits. Findings suggest that publication emphasis has strongly supported cognitive, behavioral, and psychological therapies; however, studies of functional morbidity and physical rehabilitation research are lacking. Three areas of publication deficits are noted: research on populations outside of breast, prostate, and lung cancers; methods for integrating physical rehabilitation services with cancer care, specifically regarding functional screening and assessment; and physical rehabilitation interventions. These deficits align with the needs identified by expert consensus and support the supposition that future research should emphasize a focus on physical rehabilitation.
Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction
Authors: Bruno Levy, Raphael Clere-Jehl, Annick Legras, Tristan Morichau-Beauchant, Marc Leone, Ganster Frederique, Jean-Pierre Quenot, Antoine Kimmoun, Alain Cariou, Johan Lassus, Veli-Pekka Harjola, Ferhat Meziani, Guillaume Louis, Patrick Rossignol, Kevin Duarte, Nicolas Girerd, Alexandre Mebazaa, Philippe Vignon, Mathieu Mattei, Carine Thivilier, Pierre Perez, Thomas Auchet, Caroline Fritz, Julie Boisrame-Helme, Emmanuelle Mercier, Denis Garot, Jessica Perny, Sebastien Gette, Emmanuelle Hammad, Coralie Vigne, Auguste Dargent, Pascal Andreu, Philippe Guiot
Journal: Journal of the American College of Cardiology (2018)
Abstract 3811: Targeted Interleukin 2 and synergy with immune check-point inhibitors
Authors: Cornelia Deborah Hutmacher-Berndt, Dario Neri
Journal: Cancer Research (2018)

Abstract Systemic high-dose Interleukin 2 (IL2) is able to elicit complete responses in patients suffering from metastatic melanoma. However, the majority of patients cannot receive the whole treatment dose due to severe toxicities. Other approved drugs for the treatment of metastatic melanoma include chemotherapeutics (e.g. Dacarbazine), a protein kinase B-raf inhibitor (Vemurafenib) and an immune check-point inhibitor (Ipilimumab, an anti CTLA-4 antibody). These drugs provide a clear benefit to patients, but cancer cures are still rare. Targeting IL2 to the site of disease represents a promising strategy to circumvent the toxicity and maximize the efficacy of this immunomodulatory payload. Various formats of targeted IL2 fusion proteins are currently in clinical development. Furthermore, recent successful approaches in the field of immunotherapy focus on the inhibition of check-point pathways, aiming to release the immunosuppressive brakes of the immune system. To explore the possibility of improving therapeutic efficacy of the single agents, a targeted version of IL2 (namely F8-IL2, where the F8 antibody recognizes the alternatively-spliced extra-domain A of fibronectin) was investigated in combination with an anti PD-1, anti PD-L1, or anti CTLA-4 antibody in an immunocompetent mouse model of CT26 colon carcinoma. In a first study, the combination of F8-IL2 and CTLA-4 blockade led to significant tumor growth retardation (curing 3/ 5 mice). Increasing the dose of F8-IL2 from 30 to 45 µg led to a 100 % cure rate with no signs of toxicity (body weight loss &amp;lt;5 %). Moreover, all cured mice acquired protective long-term immunity, which prevented tumor growth upon subsequent rechallenge with CT26 colon carcinoma cells. Furthermore, high dose F8-IL2 combined with the anti PD-1 antibody showed better therapeutic results than the respective monotherapies. In contrast, combination of F8-IL2 with the anti PD-L1 antibody did not improve the therapeutic outcome. Taken together, these data provide a strong rationale for the clinical use of targeted IL2 in combination with Ipilimumab. Citation Format: Cornelia Deborah Hutmacher-Berndt, Dario Neri. Targeted Interleukin 2 and synergy with immune check-point inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3811.
DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia
Authors: Darren C. Johnson, Cornelius Y. Taabazuing, Marian C. Okondo, Ashley J. Chui, Sahana D. Rao, Fiona C. Brown, Casie Reed, Elizabeth Peguero, Elisa de Stanchina, Alex Kentsis, Daniel A. Bachovchin
Journal: Nature Medicine (2018)
Screening for Osteoporosis to Prevent Fractures
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens, Michael J. Barry, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Maureen G. Phipps, Michael Pignone, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2018)

<h3>Importance</h3> By 2020, approximately 12.3 million individuals in the United States older than 50 years are expected to have osteoporosis. Osteoporotic fractures, particularly hip fractures, are associated with limitations in ambulation, chronic pain and disability, loss of independence, and decreased quality of life, and 21% to 30% of patients who experience a hip fracture die within 1 year. The prevalence of primary osteoporosis (ie, osteoporosis without underlying disease) increases with age and differs by race/ethnicity. With the aging of the US population, the potential preventable burden is likely to increase in future years. <h3>Objective</h3> To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on screening for and treatment of osteoporotic fractures in men and women, as well as risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The screening population was postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. <h3>Findings</h3> The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. <h3>Conclusions and Recommendation</h3> The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement)
Abstract 1768: An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile
Authors: Yu-an Yang, Srividya Vasu, Howard Yang, Maxwell P. Lee, Sushil Rane, Amer M. Mirza, Lalage M. Wakefield
Journal: Cancer Research (2018)

Abstract TGF-β family members are overexpressed in many advanced cancers and correlate with metastasis and poor prognosis. Based on encouraging preclinical data, therapeutics that target the TGF-β pathway are now in early phase clinical trials in oncology. While the three isoforms of TGF-β have essentially identical activities in vitro, there is relatively little known about how they might differ in vivo. Using a panel of twelve mouse allograft models of metastatic breast cancer, we showed that while TGF-β1 protein was consistently up-regulated in mammary tumors compared with normal mammary gland, the opposite was true for TGF-β3. Furthermore, in human breast cancer high TGF-β3 mRNA or protein expression was associated with better outcome, particularly in estrogen-receptor positive breast cancers. Collectively the data suggest that TGF-β1 and TGF-β3 may have opposing effects on breast cancer progression. Using an antibody that selectively neutralizes only TGF-β1 and TGF-β2, we explored the effect of sparing TGF-β3 on therapeutic outcome in the 4T1 and TSAE1 models of metastatic breast cancer. While the TGFβ1,2 antibody and two pan-TGF-β antibodies had similar efficacy against the metastasis endpoint in these very aggressive models, transcriptomic analysis of primary tumors after two weeks of antibody therapy suggested that sparing TGF-β3 might have positive effects on the metabolic profile of treated animals. To address this issue directly, we showed that mice without tumors had a significantly improved glucose tolerance following treatment with anti-TGF-β1/2 antibodies for 2-3 weeks when compared with mice treated with pan-TGF-β antibodies. Addressing potential human relevance, we showed that high expression of transcripts that were selectively upregulated in the primary tumors when TGF-β3 was spared correlated with good outcome in human breast cancer. The data suggest that use of isoform-selective TGF-β antagonists may offer advantages over the use of pan-TGF-β blocking agents for the treatment of breast cancer. Citation Format: Yu-an Yang, Srividya Vasu, Howard Yang, Maxwell P. Lee, Sushil Rane, Amer M. Mirza, Lalage M. Wakefield. An anti-TGF-β1/2 antibody that spares TGF-β3 retains full anti-tumor efficacy and generates an improved metabolic profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1768.
UK medical school places must double, says Royal College of Physicians
Authors: Abi Rimmer
Journal: BMJ (2018)

The Royal College of Physicians (RCP) has urged the government to double the number of UK medical school places from 7500 to 15 000.

Speaking at the RCP’s annual conference in London on 25 June the college’s president, Jane Dacre, said that the UK needed 2840 more medical school places just to be able to train enough consultant physicians.

“What’s more, physicians make up a third of doctors working in hospitals—what happens when we add on …