tbuckley/cabot-search huggingface dataset:
Abstract 175: Atypical PKC knockdown alters TGFβ signaling potential
Authors: Adrian Gunaratne, Gianni Di Guglielmo
Journal: Cancer Research (2012)

Abstract Transforming growth factor beta (TGFβ) regulates many important cellular processes including growth control and cell migration. In epithelial tumor cells, TGFβ signaling is fundamentally altered and induces epithelial to mesenchymal transition (EMT) leading to increased migratory potential. We have recently reported that the inhibition of atypical PKC isoforms (aPKC) extends TGFβ induced Smad signaling by altering receptor trafficking. Here we report that siRNA targeting of aPKC in A549 lung adenocarcinoma cells extends temporal P-Smad2 signaling but does not alter the transcript levels of Snail and Slug, as assessed by qPCR analysis. Interestingly, TGFβ was not observed to have as robust an increase in MMP9 and PAI-1 levels in aPKC-silenced cells compared to cells transfected with control siRNA. To further analyze the functional consequences, we assessed EMT by immunofluorescence microscopy analysis as well as immunoblotting for epithelial and mesenchymal cell markers. We found that TGFβ-dependent EMT was significantly reduced in aPKC silenced cells. We also uncovered that in addition to increased P-Smad2 signaling, P38 MAPK phosphorylation was increased and extended in aPKC silenced cells. Finally, we discovered that aPKC phosphorylates Par6 on a conserved serine residue that has been shown to regulate EMT and metastasis in breast cancer. Taken together, we believe that aPKC regulates several aspects of TGFβ signaling, including P-Smad2, P-P38 and P-Par6 levels. Consequently, convergence of these signals in aPKC silenced cells leads to reduced EMT and migratory potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 175. doi:1538-7445.AM2012-175
PMO-024 A qualitative exploration of inflammatory bowel disease patient attitudes towards self management and new modes of care delivery
Authors: K Kemp, J Griffiths, S Campbell, K Lovell
Journal: Gut (2012)

<h3>Introduction</h3> Equity and excellence: Liberating the NHS (2010) states that new modes of care delivery must be explored for patients with long term conditions (LTCs). Increasing the proportion of people with a LTC to self care is a Quality Indicator and High Level Outcome in the Health and Well Being Strategy. The increasing focus on self care and reduction in inappropriate outpatient appointments are key priorities in commissioning services. The role of self management in IBD has been established but patient perceptions of self management programmes need to be addressed when implementing new modes of care delivery. <h3>Methods</h3> The aim of this study was explore patient perceptions of self management as part of a follow-up care model. 24 in depth qualitative interviews were conducted, 18 patients had Crohn9s Disease, six ulcerative colitis, age range 27–72 yrs. Disease duration range was 2–40 years. Patients were asked about self management, participation in self management programmes, open access appointments and the value of their hospital appointments when well. Thematic analysis of interviews was undertaken using NVivo 9.0. <h3>Results</h3> No patients were enrolled into a self management programme. Only two had heard of self management. Four clear groups of patients perspectives of self management emerged: (1) patients who embraced the concept of self management and questioned why they had not heard of it prior to the interview; (2) patients who dismissed self management and could perceive no advantages to it, would not take “responsibility for their body”; (3) patients who were willing to embark on a programme with the caveat that if they could not manage, they could revert back to the traditional care system; and (4) patients who required more knowledge about their illness and body response before considering self management. All patients were concerned about open—access and a fear of not “getting in” when needed. This led to an unwillingness to accept this yet all but one of the 24 patients stated that, when well, their hospital appointment was often a waste of their time and the healthcare professionals9 time. <h3>Conclusion</h3> Integrated care pathways for patients with inflammatory bowel disease should be responsive to their clinical needs, be feasible and acceptable to those delivering and receiving care. When designing new modes of care delivery, consideration must be given to the group of patients that will not, or cannot self manage. Patients also appear to lack confidence in new modes of care delivery. Re-building this confidence is vital to the successful implementation of integrated care pathways where there is an element of self management.
Abstract 5178: Smad7 is integrated mediator for the proteolysis of Myc.
Authors: Jin-Muk Kang, Ja-Shil Hyun, Bona Lee, Ja-Kyung Kim, Ji-Hee Lee, Seong-Jin Kim, Tae-Aug Kim
Journal: Cancer Research (2013)

Abstract Myc, a pleiotropic transcription factor, plays a prominent role in human cancer progression. The regulation of Myc stability, therefore, is critical to understand the molecular mechanism of tumorigenesis in various cancers. Myc stability is tightly regulated by the activity of ubiqutin ligases, Skp2 and Fbw7. However, a key mediator of this process has not been addressed yet. Here, we have identified Smad7 as an intermediary regulating Myc stability by recruiting F-box protein, Skp2. Microarray analysis using the cell lines stably expressed Smad7, indicates that Smad7 markedly inhibits transcription of, c-myc-target genes including Id1, Id2, and Id3 without affecting c-myc gene expression. The expression of Myc protein, however, is down-regulated by induction of Smad7 in vitro, and in vivo, Smad7 transgene inducible system in primary epidermal keratinocyte. Conversely, the loss of Smad7 is implicated in the increase of endogenous Myc and Id2 expression, indicating that Smad7 is involved in post-translational regulation of Myc. Indeed, Smad7 ubiquitylates Myc through Smad7 PY motif, showing that mutation or deletion on PY motif diminishes the ubiquitylation of Myc. Treatment of proteasome inhibitor abates Smad7-mediated Myc degradation in HaCaT cell line that conditionally express level of human c-myc. Mapping of Smad7 interactions with Myc and Skp2 indicates that c-terminus, MH2 domain, of Smad7 binds to 3LRR/7LRR domain (aa142-390) of Skp2, and also interacts with Fbw7. Furthermore, intermediate domain (aa 162-236) of Myc has been identified to interact with c-terminus of Smad7. In the presence of Skp2 and Fbw7, Smad7 facilitated the degradation of Myc, thus impairing Myc stability. Smad7 also markedly represses Myc-mediated transcriptional activity and its target gene expression. These findings provide a new insight of Smad7 functions as a key mediator for the proteolysis of Myc proto-oncoprotein. Citation Format: Jin-Muk Kang, Ja-Shil Hyun, Bona Lee, Ja-Kyung Kim, Ji-Hee Lee, Seong-Jin Kim, Tae-Aug Kim. Smad7 is integrated mediator for the proteolysis of Myc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5178. doi:10.1158/1538-7445.AM2013-5178
Surgical Relief for Tracheal Obstruction from a Vascular Ring
Authors: Robert E. Gross
Journal: New England Journal of Medicine (1945)

IN 1931, I performed an autopsy on a five-month-old baby who had had wheezing respirations since birth and had recently developed difficulty in swallowing. At this examination a ring of blood vessels was found encircling the intrathoracic portion of the esophagus and trachea in such a way that the esophagus was indented from behind, whereas the trachea was compressed on its anterior surface. The pathological findings at once suggested that a division of some part of the so-called "vascular ring" during life would probably have relieved the pressure on the constricted esophagus and trachea.The above-mentioned case aroused my curiosity, . . .
A3.32 Efficacy of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis
Authors: Lindsay Lally, Robert Lebovics, Wei-Ti Huang, Robert F Spiera
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> Otolaryngologic (ENT) involvement is the most prevalent manifestation of Granulomatosis with Polyangiitis (GPA) and correlates with permanent damage and decreased quality of life. Although prior studies have evaluated the efficacy of rituximab (RTX) for granulomatous features of GCA, none have evaluated its efficacy solely for ENT manifestations. We compared the efficacy of RTX to other therapies for the ENT manifestations of GPA. <h3>Methods</h3> A retrospective analysis of 975 visits from 99 GPA patients seen at a tertiary care ENT practice between 2003 and 2013. At each visit subjects had complete ENT exam with ENT activity assessed by a single expert otolaryngologist. ENT disease activity at each visit in subjects on RTX was compared to those on all other therapy. <h3>Results</h3> 48 subjects never received RTX and 51 received RTX at least once. There was no active ENT disease at 92.4% of visits for subjects on RTX compared to 53.7% of visits for subjects not receiving RTX (OR 11.0; 95% CI 5.5–22.0, p&lt;0.0001). Subjects on RTX compared to methotrexate, azathioprine, cyclophosphamide or trimethoprim-sulfamethoxazole were significantly more likely to be in ENT remission, p&lt;0.0001 for each comparison. <h3>Conclusion</h3> RTX is an effective treatment for ENT manifestations of GPA. Subjects treated with RTX were significantly less likely to have active ENT disease compared to those not on RTX. Patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies.
Abstract P6-08-01: Perceptions of breast cancer risk, psychological adjustment and behaviors in adolescent girls at high-risk and population-risk for breast cancer
Authors: AR Bradbury, L Patrick-Miller, B Egleston, L Schwartz, L Tuchman, C Moore, P Rauch, C Sands, R Shorter, B Rowan, S Malhotra, S van Decker, H Schmidheiser, P Sicilia, L Bealin, M Daly
Journal: Cancer Research (2012)

Abstract BACKGROUND: Preliminary evidence suggests that many girls from breast cancer (BC) families are aware of their increased risk for BC. How this awareness impacts their psychosocial adjustment and health behaviors remains unknown. METHODS: 11–19 YO girls at high-risk (HR) or population-risk (PR) for BC completed self-administered quantitative surveys informed by the Self-Regulation Theory of Health Behavior. Girls with a first or second-degree relative with BC were classified as HR. For hypothesis testing, we used simple linear and logistic regressions. To account for correlation of responses within families, we used robust (cluster-corrected) standard errors or Generalized Estimating Equations. RESULTS: 47 PR and 89 HR girls have completed surveys. Age did not differ between groups (Mage = 15.6; SD=2.4). 30% of HR girls have a mother with BC. 67% of HR girls vs. 30% of PR girls reported self-perceived risk for adult BC to be “higher than other girls my age,” (p = &amp;lt;0.01, Table 1). Perceived risk was associated with an increasing number of first and second-degree relatives with BC (p = 0.002) and older age (p = 0.01). There was no evidence that the relationship between perceived risk and age was moderated by risk status (p = 0.740 for interaction terms). The majority of both HR and PR girls reported that there are things women and girls their age can do to prevent BC. (table 1) Perceived controllability of BC did not differ significantly by age or risk status. HR girls reported higher general anxiety (p = 0.07), but not depression than PR girls. HR girls more frequently reported tobacco use than PR girls (p = 0.05). HR girls also reported greater alcohol use, more frequent performance of self-breast exams and less frequent physical activity than PR girls, although these differences were not significant. CONCLUSION: Girls from BC families are more likely to perceive themselves to be at increased risk for BC, to experience more general anxiety, and to have engaged more frequently in risk behaviors, particularly tobacco use. The majority of girls perceive BC to be preventable both for women in general and for themselves, suggesting a potential “teachable moment” among adolescents that might be sustainable across the lifespan. Further research evaluating knowledge and perceptions of breast cancer risk throughout adolescent development and differences among subgroups could inform strategies to optimize adolescent psychosocial responses to hereditary cancer risk and promote preventive health behaviors among both HR and PR girls. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-08-01.
Endorphins and the Control of Breathing
Authors: Teodoro V. Santiago, Carlos Remolina, Vincent Scoles, Norman H. Edelman
Journal: New England Journal of Medicine (1981)

Since narcotic drugs profoundly depress breathing, we tested whether endogenous opioids influenced control of breathing in chronic obstructive pulmonary disease (COPD), reasoning that the stress of chronic dyspnea might cause elaboration of "endorphins." In 14 patients with COPD (but without respiratory failure) and eight normal controls, we measured ventilation, mechanical lung function, respiratory sensitivity to carbon dioxide, and the increase in respiratory effort elicited by an increase in resistance to breathing; each measurement was performed before and after administration of the opiate antagonist naloxone. Before naloxone, increased resistance to breathing enhanced respiratory effort in all controls, but seven of 14 patients with COPD had no response. After naloxone, these seven patients had load responses. Furthermore, the respiratory effort elicited by the resistance also increased after the drug was given to the patients who had had a response. These data suggest that endorphin elaboration minimizes the stress of chronic airway obstruction. (N Engl J Med. 1981; 304:1190–5.)
Abstract LB-465: The miRNA cluster 424/503 is an integral part of the TGFb-mediated cytostatic response in human mammary epithelial cells
Authors: David Llobet Navas
Journal: Cancer Research (2012)

Abstract TGF-beta plays a major role during development and normal tissue homeostasis. Indeed and focusing in mammary tissue biology TGF-beta has been unmasked as a key component during epithelium cell proliferation, lactancy and involution. However, and despite most of the TGF-beta actions are well known for decades, its dichotomic effects depending on cell type, context and disease states and the mechanisms that lie underneath are still not fully understood. In this study we uncover a novel player in the mechanism through which TGF-beta induces cell cycle arrest in mammary epithelial cells. Using microRNA array expression profile we found a strong correlation between the expression of miRs 424 and 503 and TGF-beta treatment in MCF10A cells. Interestingly, this microRNAs are located clustered in the long arm of the X chromosome, regulated by a region located upstream containing a canonical SMAD3/4 binding site and expressed as a policistronic pri-miRNA. Ectopic upregulation of miR-424/503 induces cell cycle arrest at G1 phase mimicking TGF-beta actions. Our mechanistic studies have unveiled that this miRNA cluster exerts its function by modulating the expression of CDC25A through binding to its 3′UTR. Altogether our results point to miRs 424/503 as a new player in the cytostatic program mediated by TGF-beta in mammary epithelial cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-465. doi:1538-7445.AM2012-LB-465
EDUCATION LEVEL IS ASSOCIATED WITH CARDIOVASCULAR RISK FACTORS, SYSTEMIC INFLAMMATION, ARTERIAL STIFFNESS AND OXIDATIVE STRESS
Authors: Heval Mohamed Kelli, Mosaab Awad, Muhammad Hammadah, Moosa Haider, Hina Ahmed, Matthew Topel, Salim Hayek, Keyur Patel, Brandon Gray, Kareem Mohammed, Priscilla Pemu, Tene Lewis, Sandra Dunbar, Laurence Sperling, Viola Vaccarino, Gary Gibbons, Arshed Quyyumi
Journal: Journal of the American College of Cardiology (2016)
THU0220 Rituximab for anca associated vasculitis: A systematic review
Authors: L. Silva, R. Blanco, V. Martínez-Taboada, E. Loza, S. Muñoz-Fernández, J.M. Pego, I. Rúa-Figueroa
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Cyclophosphamide (CYC) and corticosteroids (CS) are widely used in the treatment of ANCA-associated vasculitis (AAV). However, not all patients achieve remission and these drugs are associated with serious adverse events. New treatments like rituximab (RTX) have been proposed. <h3>Objectives</h3> To systematically review the efficacy and safety of RTX in AAV. <h3>Methods</h3> We systematically searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials up to October 2011 using a comprehensive search strategy for RTX, AAV, efficacy and safety (mesh terms and text words). Selection criteria were predefined by protocol. We selected meta-analysis, systematic literature reviews, clinical trials (CT), cohort studies and case series with &gt;3 cases, that included &gt;18 year-old patients with AAV on RTX. Studies including patients with Behçet disease, cryoglobulinemia, large vessel and secondary vasculitis, and basic science studies were excluded. Title and abstract selection and subsequent detailed review of selected articles were independently performed by two reviewers. The included studies quality was graded using the Oxford Levels of Evidence Scale, and results expressed as level of evidence (LE), recommendation grade (RG). <h3>Results</h3> The search strategy identified 2,762 potentially relevant articles, of which 80 were selected for full paper review. Twenty-three articles were eventually included in the analysis and 2 identified by handsearch. The selection included 3 randomized CT, 2 open trials and 20 case series, which analyzed 638 patients. Main characteristics and results of the CT and the open studies are shown in the table. More than 70% of the 359 patients of the case series achieved remission after RTX treatment. <h3>Conclusions</h3> RTX is not inferior to CYC regarding to the induction of remission in AAV (LE 1b; GR A), might be superior in relapsing disease (LE 1b; GR A), but showed no differences in sustained renal remission (LE 1b; GR A). Treatment with RTX leads to a safe CS tapering (LE 1b; GR A). RTX adverse events in AVV patients did not differ from those reported in other rheumatic diseases. <h3>Disclosure of Interest</h3> None Declared
Abstract 4988: FOXP3, a critical mediator of regulatory T-cell function, is expressed in subsets of myeloid cells.
Authors: Sudheer Kumar Gara, Yanli Pang, Christine Hollander, Li Yang
Journal: Cancer Research (2013)

Abstract Forkhead box P3 (FOXP3) is a well-known molecular marker for regulatory T cells (Tregs) and is considered as a master regulatory transcription factor for the development, maturation and function of Tregs. Mutations in FOXP3 lead to severe immune deficiencies and cancer in human and mice. Administration of Foxp3-expressing Tregs drastically reduced the disease severity in animal models of diabetes, asthma and multiple sclerosis giving rise to hope for therapeutic options. It is not clear whether cell types other than Treg express FOXP3. While investigating TGFβ-mediated signaling in the myeloid lineage, we discovered a subset of myeloid derived suppressor cells (Gr-1+CD11b+ cells or MDSCs) that express FOXP3. Indeed these cells were CD3 negative suggesting that they are not of T cell lineage. Upon further investigation, we observed that these FOXP3 expressing myeloid cells are present in different tissues of mouse. Moreover, we found that they are elevated under pathological conditions. We are currently identifying the molecular function and mechanisms of Foxp3 expression in the myeloid subsets. Our work will provide new insight into the FOXP3 research area beyond regulatory T cells, and might reveal its role in regulating the immunosuppressive activity of MDSCs. Citation Format: Sudheer Kumar Gara, Yanli Pang, Christine Hollander, Li Yang. FOXP3, a critical mediator of regulatory T-cell function, is expressed in subsets of myeloid cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4988. doi:10.1158/1538-7445.AM2013-4988
The many faces of gastrointestinal T-cell lymphoma manifest simultaneously in the same patient
Authors: N. Thosani, A. Quesada, D. Kulkarni, D. Wolf
Journal: Endoscopy (2013)

A 50-year-old man with a history of AIDS presented with complaints of dyspnea on exertion, anemia, and melena. Seven years prior to the current presentation, he presented with intussusception, underwent right hemicolectomy, and was diagnosed with a cecal mass consistent with T-cell lymphoma. He was noncompliant with his medication regime and was lost to follow-up until the current admission. He underwent esophagogastroduodenoscopy and colonoscopy for further evaluation of iron-deficiency anemia and melena. Upper gastrointestinal endoscopy revealed: (1) multiple concentric rings in the lower esophagus, (2) a small (4-mm) nodule in gastric cardia, and (3) a nodule with central ulceration in the gastric body ([Fig. 1]). Colonoscopy showed: (1) a large mass protruding from the small intestine into the ileocolonic anastomosis, (2) ulceration within the blind loop at the anastomosis, and (3) a sessile polyp in the sigmoid colon ([Fig. 2]). Pathology review of specimens from all of these sites revealed a high-grade peripheral T-cell lymphoma positive for T-cell markers CD4 and patchy for CD3. Immunostaining was negative for CD7 and CD8 ([Fig. 3]). The patient was started on appropriate highly active antiretroviral therapy (HAART) therapy and chemotherapy.