tbuckley/cabot-search huggingface dataset:
Abstract 2040: Withaferin A inhibits epithelial-to-mesenchymal transition in non-small lung cell cancer cells via regulation of SMAD and NFkB signaling
Authors: Al Hassan Kyakulaga, Farrukh Aqil, Radha Munagala, Ramesh Gupta
Journal: Cancer Research (2018)

Abstract Background: Metastasis remains the primary cause in lung cancer. Epithelial-to-mesenchyme transition (EMT) has been identified as the hallmark for metastasis in NSCLC, and is being explored for drug targeting. Aberrant signaling mechanisms for cytokines such as TGF-β1 and TNFα are known to induce EMT. In this study we demonstrate the effect and mechanisms of WFA inhibition of EMT in NSCLC cell lines. Objective: The present study was done to determine the effect of WFA on TGF-β1 and TNFα induced EMT, migration and invasion in human NSCLC cells. Furthermore, to determine underlying the mechanisms of WFA inhibition of EMT. Methods: Two human NSCLC cell lines (H1299 and A549) were cultured in DMEM media. To induce the EMT, cells in serum free media were challenged with TGF-β1 (5 ng/mL) or TNFα (5 ng/mL) alone or in combination. To determine the effects of WFA, cells were either pre- or co-treated with different concentrations of WFA for various time points. Western blot analysis, electrophoretic mobility shift assay (EMSA), RT-PCR and immunofluorescence staining were used to determine effects of WFA on Smad2/3 and NFkB activation. Cell adhesion, migration and invasion assays were used to assess in vitro anti-metastatic activity. Results: Our findings indicate that the cytokines TGF-β1 and TNFα cooperate to promote the acquisition of EMT phenotype, migration and invasion of NSCLC cells in vitro. There was a marked increase in the expression of EMT transcription factors Snail, Slug, ZEB and EMT markers such as vimentin and N-cadherin. Cells treated with TGF-β1/TNFα had significantly increased migratory and invasive capacities. WFA treatment significantly inhibited the TGF-β1 induced Smad2/3 activation and TNFα-induced translocation of NFkB into the nucleus. We observed a dose and time dependent inhibition of the phosphorylation of Smad2/3 and NFkB in both cell lines. The cell adhesion, migratory and invasive capacities of both H1299 and A549 cells were greatly diminished by WFA in the presence or absence of cytokines. Conclusion: Based on the current finding, it can be concluded that WFA inhibits EMT via negative regulation of Smad2/3 and NFkB signaling in NSCLC cells. Citation Format: Al Hassan Kyakulaga, Farrukh Aqil, Radha Munagala, Ramesh Gupta. Withaferin A inhibits epithelial-to-mesenchymal transition in non-small lung cell cancer cells via regulation of SMAD and NFkB signaling [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 2040.
Association Between Ambient Air Pollution and Cardiac Morpho-Functional Phenotypes
Authors: Nay Aung, Mihir M. Sanghvi, Filip Zemrak, Aaron M. Lee, Jackie A. Cooper, Jose M. Paiva, Ross J. Thomson, Kenneth Fung, Mohammed Y. Khanji, Elena Lukaschuk, Valentina Carapella, Young Jin Kim, Patricia B. Munroe, Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen
Journal: Circulation (2018)

Background: Exposure to ambient air pollution is strongly associated with increased cardiovascular morbidity and mortality. Little is known about the influence of air pollutants on cardiac structure and function. We aim to investigate the relationship between chronic past exposure to traffic-related pollutants and the cardiac chamber volume, ejection fraction, and left ventricular remodeling patterns after accounting for potential confounders. Methods: Exposure to ambient air pollutants including particulate matter and nitrogen dioxide was estimated from the Land Use Regression models for the years between 2005 and 2010. Cardiac parameters were measured from cardiovascular magnetic resonance imaging studies of 3920 individuals free from pre-existing cardiovascular disease in the UK Biobank population study. The median (interquartile range) duration between the year of exposure estimate and the imaging visit was 5.2 (0.6) years. We fitted multivariable linear regression models to investigate the relationship between cardiac parameters and traffic-related pollutants after adjusting for various confounders. Results: The studied cohort was 62±7 years old, and 46% were men. In fully adjusted models, particulate matter with an aerodynamic diameter &lt;2.5 µm concentration was significantly associated with larger left ventricular end-diastolic volume and end-systolic volume (effect size = 0.82%, 95% CI, 0.09–1.55%, P =0.027; and effect size = 1.28%, 95% CI, 0.15–2.43%, P =0.027, respectively, per interquartile range increment in particulate matter with an aerodynamic diameter &lt;2.5 µm) and right ventricular end-diastolic volume (effect size = 0.85%, 95% CI, 0.12–1.58%, P =0.023, per interquartile range increment in particulate matter with an aerodynamic diameter &lt;2.5 µm). Likewise, higher nitrogen dioxide concentration was associated with larger biventricular volume. Distance from the major roads was the only metric associated with lower left ventricular mass (effect size = −0.74%, 95% CI, −1.3% to −0.18%, P =0.01, per interquartile range increment). Neither left and right atrial phenotypes nor left ventricular geometric remodeling patterns were influenced by the ambient pollutants. Conclusions: In a large asymptomatic population with no prevalent cardiovascular disease, higher past exposure to particulate matter with an aerodynamic diameter &lt;2.5 µm and nitrogen dioxide was associated with cardiac ventricular dilatation, a marker of adverse remodeling that often precedes heart failure development.
Abstract 14896: In Vivo Induction of Regulatory T Cells Delays the Development of Hypertension in Stroke-Prone Spontaneously Hypertensive Rats
Authors: MasatoKatsuki, YoshitakaHirooka, TakuyaKishi, KenjiSunagawa
Journal: Circulation (2014)

Background: T cell activation is implicated in the pathogenesis of hypertension and its complications. In contrast, regulatory T (Treg) cells, which control the immune system, are reported to prevent angiotensin II-induced hypertension and cardiac damage. The precise role of Treg cells in the pathological process of hypertension, however, remains unclear. Recent studies demonstrated that interleukin (IL)-2 and anti-IL-2 monoclonal antibody (IL-2/mAb) complex selectively induces Treg cells in vivo. Here we aimed to determine whether Treg cells are decreased in genetically spontaneously hypertensive rats compared with normotensive rats, and if so, to examine whether administration of IL-2/mAb complex affects the development of hypertension and the progression of cardiac hypertrophy. Methods and Results: We examined Treg cells in stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched normotensive Wistar-Kyoto rats (WKY). CD4+CD25+Foxp3+ cells (Treg cells) in the spleen and peripheral blood were...
Abstract 2209: Lung cancer risk prediction using DNA methylation markers
Authors: Florence Guida, Therese H. Nøst, Caroline Relton, Paul Brennan, Torkjel M. Sandanger, Marc Chadeau-Hyam, Mattias Johansson
Journal: Cancer Research (2018)

Abstract There is an urgent need to improve lung cancer risk assessment as current screening criteria miss a large proportion of cases and result in a high rate of false positives on low-dose CT screening. A fixed effect meta-analyses of 4 epigenome-wide association studies of lung cancer revealed differential DNA methylation at 16 CpG sites (FDR&amp;lt;0.05). The current study aimed to evaluate the extent to which such methylation markers can improve upon smoking-based risk-discrimination among ever smokers. We used data on 662 ever smoking lung cancer case-control pairs from 4 individual prospective cohorts that measured DNA methylation using the Illumina Infinium HumanMethylation450 BeadChip in peripheral blood samples before diagnosis: The Italian part of the European Prospective Investigation into Cancer (EPIC) cohort, the Melbourne Collaborative Cohort (MCCS), the Norwegian Women and Cancer cohort (NOWAC) and the Northern Sweden Health and Disease Study (NSHDS). We adopted a training-testing design where the training was performed on MCCS and NSHDS (N=511 case-control pairs), and the testing on EPIC-Italy and NOWAC (N=151 case-control pairs). Logistic regressions with lasso penalties were performed in the training set to select the best set of CpGs jointly predicting lung cancer. A methylation score was trained by fitting a logistic regression model including the selected CpGs in the training set. A baseline score based on self-reported smoking information (duration, cigarettes/day for current smokers and time since smoking cessation for former smokers) was also developed. The discriminative performances of both scores, as well as integrated model where both smoking and methylation info was incorporated, were assessed by the AUC under the ROC curves in the validation set. The methylation score based on the 9 selected CpG sites yielded an AUC of 0.78 [0.73-0.84] compared to 0.73 [0.68-0.79] for the baseline-smoking score. The model integrating both scores yielded an AUC of 0.79 [0.73-0.84], a notable 0.06-increase in AUC from using the smoking score alone (P=0.008 for difference in AUC). In conclusion, specific methylation biomarkers have a strong potential to improve lung cancer risk assessment and current USPSTF criteria for CT-screening. During the conference, we will present absolute risk estimates based on the integrated risk prediction model. Citation Format: Florence Guida, Therese H. Nøst, Caroline Relton, Paul Brennan, Torkjel M. Sandanger, Marc Chadeau-Hyam, Mattias Johansson. Lung cancer risk prediction using DNA methylation markers [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 2209.
Abstract 16846: Caregiver Symptoms and Burden 3 Weeks and 3 Months After Their Spouse’s Cardiac Surgery
Authors: PaulaSchulz, LaniZimmerman, SueBarnason
Journal: Circulation (2014)

Introduction: Caregivers (CGs) play a major role in cardiac surgery patients’ recovery however, little research has examined the trajectory of burden and symptoms experienced by the CG. Hypothesis: The primary purpose of this longitudinal descriptive pilot study was to describe symptoms (fatigue/inertia, tension/anxiety, depression/dejection, and sleep difficulty) and their relationship to caregiving demand and difficulty in 28 adults caring for their spouses after cardiac surgery. Methods: Data were obtained telephonically 3 weeks and 3 months after surgery using the POMS-SF, Pittsburgh Sleep Quality Index and the Oberst Caregiving Burden Scale. Results: CGs (M = 68.5 ± 6.6 years) were primarily female (92%). In general, mean symptom scores were lower at 3 weeks and increased in severity at 3 months for fatigue/inertia (M = 3.0 ± 2.9 to 3.9 ± 3.6), depression/dejection (M = 1.3 ± 2.3 to 2.2 ± 3.8) and sleep difficulty (M = 3.3 ± 2.1 to 4.1 ± 2.5). Difficulty with caregiving tasks mean scores showed littl...
Abstract 1066: L1CAM as a pivotal mediator for disease progression and prognostic biomarker in gastric cancer patients
Authors: Yoshinaga Okugawa, Yuji Toiyama, Yasuhiko Mohri, Akira Yamamoto, Tsunehiko Shigemori, Chengzeng Yin, Aya Narumi, Shozo Ide, Takahito Kitajima, Hiromi Yasuda, Hiroyuki Fujikawa, Junichiro Hiro, Shigeyuki Yoshiyama, Masaki Ohi, Koji Tanaka, Toshimitsu Araki, Masato Kusunoki
Journal: Cancer Research (2018)

Abstract Background/Aims: Although significant progress has been made in the diagnosis and treatment of Gastric cancer (GC) patients, GC is the second leading cause of cancer-related deaths worldwide. Identification of critical factors driving the progression of metastasis and new prognostic biomarkers are urgently required to improve both early detection of recurrence and prognosis of patients with advanced GC. L1 cell adhesion molecule (L1CAM) has been observed to be highly expressed in several types of tumors, which may play a vital role in tumor progression. The present study investigated the clinical significance of L1CAM, in the development and progression of gastric cancer. Experimental Design: At first, the effects of L1CAM alteration were investigated using proliferation, migration, invasion, and anoikis and xenograft model. Next, we analyzed L1CAM expression in surgical tissue speciemens from 131 gastric cancer patients (Cohort 1) by quantitative real-time reverse transcription-PCR and 309 patients (Cohort 2) by immunohistochemistry. Results: Knockdown of L1CAM using small interfering RNA in GC cell lines resulted in reduced cell proliferation, invasion, migration, and anoikis in gastric cancer cells. Furthermore, Knockdown of L1CAM inhibited metastasis in a xenograft model. Interestingly, L1CAM expression in cancer tissues was significantly higher in patients with lymph node metastasis and distant metastasis. The expression of L1CAM was significantly associated with poor prognosis. Furthermore, L1CAM emerged as an independent prognostic predictor and a predictor of lymph node metastasis in GC patients. Conclusions: Our data highlight that L1CAM appear to play an important role in disease development and L1CAM expression may serve as a novel predictor for the identification of patients who are at high risk for tumor recurrence and strict surveillance in curative GC patients. Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Yasuhiko Mohri, Akira Yamamoto, Tsunehiko Shigemori, Chengzeng Yin, Aya Narumi, Shozo Ide, Takahito Kitajima, Hiromi Yasuda, Hiroyuki Fujikawa, Junichiro Hiro, Shigeyuki Yoshiyama, Masaki Ohi, Koji Tanaka, Toshimitsu Araki, Masato Kusunoki. L1CAM as a pivotal mediator for disease progression and prognostic biomarker in gastric cancer patients [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 1066.
Abstract 1208: Is the decrease in the incidence of large cell carcinoma of the lung due to changes in classification towards adenocarcinoma
Authors: Dana Hashim, Ariana Znaor, William Travis, Paolo Boffetta
Journal: Cancer Research (2018)

Abstract Background: Data from many populations show a decrease in the incidence of large cell carcinoma (LCC) of the lung while incidence of lung adenocarcinoma (AC) is decreasing to a lower rate or even increasing from the 1990s. We compared the changes in incidence of lung LCC and AC worldwide to test the hypothesis that at least part of the decline in LCC incidence was due to classification of these tumors as AC. Methods: We analyzed the annual percent change (APC) in the age-standardized rates (ASRs) of lung LCC and AC incidence between 1996 and 2007 in 78 high-quality cancer registries from Europe, Asia, North America, and South America, using linear regression. Results: Among women, the median APC of LCC incidence was -5.42, and that of AC incidence was -0.96. There was a positive correlation between the two measures (β=0.29; p=0.01). The APC of LCC incidence was negative in 64 populations (82.1%); that of AC incidence was negative in 50 populations (63.3%, p of the χ2 distribution = 0.07). Among women, the median APC for LCC and AC incidence was -5.06 and +2.11, respectively. The correlation between the two measures was 0.17 (p=0.03). The APC of LCC incidence was negative in 59 populations (76.6%); that of AC incidence was negative in 23 populations (29.9%, p of the χ2 distribution = 0.41). Conclusions: The decrease in LCC may be, in part, due to changes in histologic classification and triaging towards a diagnosis of adenocarcinoma. Citation Format: Dana Hashim, Ariana Znaor, William Travis, Paolo Boffetta. Is the decrease in the incidence of large cell carcinoma of the lung due to changes in classification towards adenocarcinoma [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 1208.
Abstract SY01-02: Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis
Authors: Nikolaos Svoronos, Alfredo Perales-Puchalt, Jose R. Conejo-Garcia
Journal: Cancer Research (2018)

Abstract Although the role of estrogen signaling in the progression of breast tumors and a subset of ovarian cancer patients has been underscored by the clinical use of ER antagonists, how estrogens impact the orchestration and maintenance of protective antitumor immunity remains elusive. Here we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to tumor-promoting, expanded myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs) and also the augmentation of their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens had a profound effect on T cell-dependent antitumor immunity and tumor-promoting inflammation, independently of the sensitivity of tumor cells to estrogen signaling. Differences in tumor growth in the presence of estrogen-insensitive tumor cells are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and also upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Consequently, fulvestrant had significant effects in delaying the progression of estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anticancer immunotherapies, which is currently being tested at our institution in breast cancer patients. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathologic, tumor-promoting myelopoiesis. Our work suggests that new antiestrogen drugs that have no agonistic effects (different from tamoxifen) could have benefits to boost protective immunity in a wide range of cancers, while augmented estrogenic activity could contribute to tumor initiation and/or malignant progression. Citation Format: Nikolaos Svoronos, Alfredo Perales-Puchalt, Jose R. Conejo-Garcia. Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis [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 SY01-02.
Extrapulmonary Nontuberculous Mycobacterial Disease Surveillance — Oregon, 2014–2016
Authors: David C. Shih, P. Maureen Cassidy, Kiran M. Perkins, Matthew B. Crist, Paul R. Cieslak, Richard L. Leman
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Nontuberculous mycobacteria (NTM), ubiquitous in soil and water, usually infect immunocompromised persons. However, even healthy persons are susceptible to infection through percutaneous inoculation. Although 77% of NTM diseases manifest as primarily pulmonary illnesses (1), NTM also infect skin, bones, joints, the lymphatic system, and soft tissue. NTM infections can have incubation periods that exceed 5 years (2), often require prolonged treatment, and can lead to sepsis and death. Extrapulmonary NTM outbreaks have been reported in association with contaminated surgical gentian violet (3), nail salon pedicures (4), and tattoos received at tattoo parlors (5), although few surveillance data have been available for estimating the public health burden of NTM.* On January 1, 2014, the Oregon Health Authority designated extrapulmonary NTM disease a reportable condition. To characterize extrapulmonary NTM infection, estimate resources required for surveillance, and assess the usefulness of surveillance in outbreak detection and investigation, 2014-2016 extrapulmonary NTM surveillance data were reviewed, and interviews with stakeholders were conducted. During 2014-2016, 134 extrapulmonary NTM cases (11 per 1 million persons per year) were reported in Oregon. The age distribution was bimodal, with highest incidence among persons aged <10 years (20 per 1 million persons per year) and persons aged 60-69 years (18 per 1 million persons per year). The most frequently reported predisposing factors (occurring within 14-70 days of symptom onset) were soil exposure (41/98; 42%), immunocompromised condition (42/124; 34%), and surgery (32/120; 27%). Overall, 43 (33%) patients were hospitalized, 18 (15%) developed sepsis, and one (0.7%) died. Surveillance detected or helped to control two outbreaks at low cost. Jurisdictions interested in implementing extrapulmonary NTM surveillance can use the Council of State and Territorial Epidemiologists (CSTE) standardized case definition (6) for extrapulmonary NTM reporting or investigative guidelines maintained by the Oregon Health Authority (7).
Response to: ’Early identification of rheumatoid arthritis; the risk of overtreatment in perspective' by Landewé
Authors: Robert B M Landewé
Journal: Annals of the Rheumatic Diseases (2018)

I thank Dr van der Helm-van Mil for critically responding to my Viewpoint1 and for agreeing with most of the ideas I have brought up.2 

The greater part of her argument pertains to the concepts of clinically suspect arthralgia (CSA) and undifferentiated arthritis (UA). She claims that CSA is a research field rather than clinical practice, a view I agree with. I applaud every piece of science that may give us better insight into the pathophysiology of RA. Then she warns that we must await 5 years of outstanding clinical trials before judging clinical relevance, a presumption that I find more problematic, since it implies that ‘her field’ anticipates on a potential future clinical benefit (this is called a ‘frame’). This means there is 5 years more time to further ‘frame’ the concept of CSA as a condition that may be treated pre-emptively, and that any statistically significant benefit after 5 years will be explained as argument pro. It is here that I am a little bit more hesitant than Dr van der Helm-van Mil, who seems to say: ‘The science will speak for itself.’

As said, the concept of CSA confuses risk of disease with presence of disease. In the Viewpoint I took CSA as a risk of rheumatoid arthritis (RA) as one example, but other examples with potential clinical relevance exist and …
Regulation by Differential Development of Th1 and Th2 Cells in Peripheral Tolerance to Cardiac Allograft Induced by Blocking ICAM-1/LFA-1 Adhesion
Authors: MitsuakiIsobe, Jun-ichiSuzuki, SatoshiYamazaki, YoshikazuYazaki, ShiroHorie, YoshioOkubo, KojiMaemura, YoshioYazaki, MorieSekiguchi
Journal: Circulation (1997)

Background Specific immune tolerance to cardiac allografts is induced by anti–ICAM-1 and anti–LFA-1 MAbs. Although the expression of the Th1 cytokines IL-2 and IFN-γ is shown to increase in association with acute rejection, the roles of cytokines in the induction of peripheral tolerance by anti–ICAM-1 and anti–LFA-1 MAbs are not yet known. Methods and Results BALB/c hearts were transplanted into C3H/He mice. The MAbs to ICAM-1 and LFA-1 were injected for 3 days after transplantation in some recipients, and others were treated with FK506. IL-2 concentration in the supernatant of splenocytes from MAb-treated mice that were mix-cultured with donor splenocytes was lower than in normal controls. The expression of Th1 cytokines, detected by Northern blot assay, was enhanced in grafts or spleens of nontreated mice, whereas Th2 cytokines were expressed in the spleens of MAb-treated mice. No cytokine expression was enhanced in mice treated with FK506. Also, the induction of tolerance was prevented by the administr...