tbuckley/cabot-search huggingface dataset:
Abstract P388: Which Obesity-related Indicator is Better for Predicting Incident Hypertension? Results from the population-based cohort study of Japan
Authors: MichikazuNakai, MakotoWatanabe, KunihiroNishimura, MisaTakegami, YoshihiroKokubo, AyaHigashiyama, TomonoriOkamura, YoshihiroMiyamoto
Journal: Circulation (2014)

Objective: Obesity is an established risk factor for hypertension (HT), but it is still controversial which obesity-related indicator is superior in predictability. This study compared the predictability among three indicators, body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR), in the population-based prospective cohort study of Japan, the Suita study. Methods: Participants who had no HT at baseline (1,591 men and 1,973 women) aged 30-84 years were included in this study. The Cox proportional hazard model was used to estimate hazard ratios (HRs) of each indicator for incident HT with the adjustment for age, cigarette smoking and alcohol drinking. Harrell’s C statistics were also estimated for comparison of indicators’ accuracy. Results: During median follow-up of 7.2 years, 1,325 participants (640 men and 685 women) developed HT. HR (95% CI) of BMI, WC and WHtR for incident HT corresponding to a 1 SD increase was 1.25 (1.15-1.35), 1.21 (1.12-1.31) and 1.23 (1.14-1.34) in men...
Induced Pluripotent Stem Cells in Cardiovascular Drug Discovery
Authors: MarkMercola, AlexandreColas, ErikWillems
Journal: Circulation Research (2013)

The unexpected discovery that somatic cells can be reprogrammed to a pluripotent state yielding induced pluripotent stem cells has made it possible to produce cardiovascular cells exhibiting inherited traits and disorders. Use of these cells in high throughput analyses should broaden our insight into fundamental disease mechanisms and provide many benefits for patients, including new therapeutics and individually tailored therapies. Here we review recent progress in generating induced pluripotent stem cell-based models of cardiovascular disease and their multiple applications in drug development.
Abstract 4520: Using SEREX approach to screen and identify the tumor-associated antigens in non-small cell lung cancer
Authors: Lu Pei, Tingting Wang, Peng Wang, Hongchun Liu, Songyun Ouyang, Jianying Zhang, Liping Dai
Journal: Cancer Research (2018)

Abstract Background: Lung cancer is the most common cause of cancer-related deaths worldwide and approximately 85% of lung cancer cases are non-small-cell lung cancer (NSCLC). The average survival and 5-year survival rates of NSCLC patients still remain poor. Autoantibodies against tumor-associated antigens (TAAs) have been shown to be relevant tumor markers. There is an urgent need to better understand the mechanism and to identify useful biomarkers for early immunodiagnosis of NSCLC. Materials and methods: Serological analysis of recombinant tumor cDNA expression libraries (SEREX) was applied to screen the lung cancer tumor-associated antigens (TAAs) with sera from lung cancer patients. Oncomine online database was used to analyze multiple microarray datasets and to identify potential genes in NSCLC progression. Autoantibody responses to TAAs were evaluated by enzyme-linked immunosorbent assay (ELISA) in sera from 196 patients with NSCLC and 196 normal controls. Result: Seventy positive clones had been screened by SEREX approach and 35 genes with known biological function were further identified by mass spectrometry analysis. Ten out of 35 genes were determined to be tested the corresponding autoantibodies since they were consistently over-expressed in NSCLC tissue in three mRNA arrays. The results of ELISA show that the level and positive frequency of the autoantibodies to TOP2A,ACTR3, RPS6KA5 and PSIP1 in sera from NSCLC patients were significantly higher than that in normal control (Ρ&amp;lt;0.05). The sensitivity of the four autoantibodies for diagnosis of NSCLC ranged from 17.4% to 32.1% with the specificity of 90%. The area under curve(AUC)of TOP2A,ACTR3, RPS6KA5 and PSIP1 was 0.758, 0.787, 0.707 and 0.668, respectively. The sensitivity of the panel of this four TAAs was 47.2% and the specificity was 81.5%. Conclusions: TOP2A, ACTR3, PSIP1, RPS6KA5 were tumor-associated antigens and their autoantibodies might be potential biomarkers for immunodiagnosis of NSCLC. Citation Format: Lu Pei, Tingting Wang, Peng Wang, Hongchun Liu, Songyun Ouyang, Jianying Zhang, Liping Dai. Using SEREX approach to screen and identify the tumor-associated antigens in non-small cell lung cancer [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 4520.
Abstract P128: A New Device for Objective Measurement of Sedentary Behavior
Authors: MaryRosenberger, WilliamHaskell, MatthewBuman, BrentLaStofka, LauraCarstensen
Journal: Circulation (2014)

Objective measurement of sedentary behavior with accelerometers is an important part of epidemiological research. Unfortunately, the definition of sedentary behavior includes both “sitting and low levels of energy expenditure”, which are not usually measured by popular activity monitors. Currently, there is only one research device (ActivPAL) that can objectively measure both body posture and activity for sedentary behavior classification. The purpose of this study was to compare the Lumoback device, a commercial accelerometer-based posture monitor, for sedentary measurement during daily activities to the ActivPAL. The Lumoback also has real-time feedback delivered to the user through their mobile device, which may prove to be instrumental in sedentary intervention research. Subjects (N=33) wore the Lumoback and ActivPAL devices simultaneously during waking hours while continuing with their normal activity patterns. Linear regression showed good correlation between sitting minutes (R2=0.89, p < 0.001) and...
Novel Antiplatelet Drug Revacept (Dimeric Glycoprotein VI-Fc) Specifically and Efficiently Inhibited Collagen-Induced Platelet Aggregation Without Affecting General Hemostasis in Humans
Authors: MartinUngerer, KaiRosport, AndreasBültmann, RichardPiechatzek, KerstinUhland, PeterSchlieper, MeinradGawaz, GötzMünch
Journal: Circulation (2011)

Background—Blocking of glycoprotein VI–dependent pathways by interfering in vascular collagen sites is commonly seen as an attractive target for an antiplatelet therapy of acute atherosclerotic diseases such as myocardial infarction or stroke. Revacept (soluble dimeric glycoprotein VI-Fc fusion protein) has been shown to reduce platelet adhesion by blocking vascular collagen in plaques or erosion and to be safe in preclinical studies. A dose-escalating clinical phase I study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of Revacept in humans. Methods and Results—In a first-in-humans study, 30 healthy men received a single intravenous administration of 10, 20, 40, 80, or 160 mg Revacept. The serum concentration–time courses of each dosage of Revacept showed a narrow variation and a concentration and time dependence. Revacept did not significantly affect the bleeding time. Collagen-induced platelet aggregation was dose-dependently inhibited up to 48 hours at lower ...
Abstract P104: Change in Measures of Adiposity in Young Adulthood and Middle-Age Sleep Apnea Risk: The Bogalusa Heart Study
Authors: Tianhu, SuzanneBertisch, WeiChen, JeanetteGustat, LarryWebber, ShengxuLi, KirkPak, SathanurSrinivasan, GeraldBerenson, LydiaBazzano
Journal: Circulation (2014)

Background: Persons with obesity are at high risk of obstructive sleep apnea (OSA); however, the relationship between obesity in young adulthood and future OSA risk is unknown. Methods: We prospectively examined the association between changes in measures of adiposity in young adulthood and subsequent risk of OSA in 857 middle-aged adults free of cardiovascular disease at baseline. Data included at least 2 measures of adiposity (BMI, waist circumference, waist/hip ratio, and waist/height ratio) after 18 years of age. High-risk of OSA was defined as 2 of the following: hypertension, persistent snoring, and persistent daytime sleepiness, based on modified Berlin Questionnaire score, excluding BMI. Persistent snoring was defined as snoring on ≥3 nights/week, snoring louder than talking or very loud, and breathing pauses on ≥3 nights/week. Persistent daytime sleepiness was defined as feeling tired ≥3 days/week after sleeping, feeling tired during time awake ≥3 days/week, and falling asleep while driving. Resu...
Delayed onset of neurosarcoidosis after concurrent ipilimumab/nivolumab therapy
Authors: Irena Tan, Michael Malinzak, April K. S. Salama
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Immune checkpoint inhibitors have transformed the treatment landscape for many cancers, including metastatic melanoma, but have also opened the door for a diverse variety of immune-related adverse effects. <h3>Case presentation</h3> We describe the first reported case of presumed neurosarcoidosis as an immune-related adverse effect that developed nearly a year after discontinuation of treatment with combination ipilimumab and nivolumab for recurrent metastatic melanoma. The patient was noted to develop clinical signs consistent with systemic sarcoidosis shortly after the initiation of treatment and underwent a biopsy of hilar lymphadenopathy that confirmed sarcoidosis and after which immunotherapy was discontinued. His melanoma remained stable on surveillance imaging for the next year after which time he developed neurological symptoms and was found to have MRI brain abnormalities without evidence of intracranial metastatic disease, consistent with probable neurosarcoidosis given biopsy-proven systemic sarcoidosis and lack of evidence of CNS infection or malignancy. He underwent treatment with high dose steroids, followed by infliximab, and then methotrexate with both clinical and radiographic improvement within 4&nbsp;months of starting treatment. <h3>Conclusions</h3> Immune-related adverse effects often occur within 3–6&nbsp;months of receiving immune checkpoint inhibitor therapy, with some reports of late toxicity. This report highlights a case of probable neurosarcoidosis nearly a year after discontinuation of immune checkpoint therapy. The potential for durable responses after discontinuation of therapy also likely underscores a potential for late toxicity. In patients presenting with new or unexplained symptoms after checkpoint inhibitor therapy, the index of suspicion for an immune-related adverse effect should remain high, irrespective of timing.
Depression and 18-Month Prognosis After Myocardial Infarction
Authors: NancyFrasure-Smith, FrançoisLespérance, MarioTalajic
Journal: Circulation (1995)

Background We previously reported that major depression in patients in the hospital after a myocardial infarction (MI) substantially increases the risk of mortality during the first 6 months. We examined the impact of depression over 18 months and present additional evidence concerning potential mechanisms linking depression and mortality. Methods and Results Two-hundred twenty-two patients responded to a modified version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) for a major depressive episode at approximately 7 days after MI. The Beck Depression Inventory (BDI), which measures depressive symptomatology, was also completed by 218 of the patients. All patients and/or families were contacted at 18 months to determine survival status. Thirty-five patients met the modified DIS criteria for major in-hospital depression after the MI. Sixty-eight had BDI scores ≥10, indicative of mild to moderate symptoms of depression. There were 21 deaths during the follow-up period, includ...
Abstract 2325: Protein homeostasis adaptation to Hsp70 inhibition in cancer
Authors: Sara Sannino, Christopher J. Guerriero, Amit J. Sabnis, Trever G. Bivona, Jeffrey L. Brodsky
Journal: Cancer Research (2018)

Abstract Cancer cells experience acute stress conditions due to their increased proliferation rate and synthesis of misfolded proteins. However, by modulating the mechanisms that control protein-folding, cancer cells avoid cell death. Thus, it is perhaps not surprising that molecular chaperones, like Hsp70, are upregulated in cancer cells compared to their normal counterparts. These data suggest that these chaperones are potential targets for cancer therapy. Previous work in our lab demonstrated the dependence of patient-driven rhabdomyosarcoma cell survival on cytoplasmic Hsp70 activity, thanks to the use of a specific Hsp70 inhibitor, MAL3-101. In particular, we discovered that treatment of on RMS13 cell line with an Hsp70 inhibitor, known as MAL3-101, activates the PERK driven unfolded protein response that results in CHOP-dependent cell death (Sabinis et al., 2016). Nevertheless, the mechanism underlying how Hsp70 inhibition triggered apoptosis was poorly understood. By taking advantage of a MAL3-101-resistant cell line (RMS13-R), we have now determined which compensatory mechanism alters MAL3-101-driven cell death. We found that both endoplasmic reticulum-associated degradation (ERAD) and autophagy are upregulated in RMS13-R cells, underlying the increased demand on two protein degradation pathways upon inhibition of Hsp70. Specifically, autophagy related genes were upregulated, and increased conversion of LC3BI to LC3BII and accumulation of LC3BII was detected in RMS13-R cells. Further experiments demonstrated that autophagy was further induced by MAL3-101 treatment in RMS13-R cells, as evidenced by an increase in the messages and proteins corresponding to key autophagy components. Finally, we discovered that only autophagy inhibition—but not inhibition of ERAD—re-sensitized RMS13-R cells to Hsp70 inhibition, which was apparent from an induction of apoptotic markers and cell death. These data highlight a pro-survival role for autophagy induction upon exposure to an Hsp70 inhibitor in cancer, and provide a link between Hsp70, proteasomal degradation, the unfolded protein response, and autophagy in rhabdomyosarcoma. Citation Format: Sara Sannino, Christopher J. Guerriero, Amit J. Sabnis, Trever G. Bivona, Jeffrey L. Brodsky. Protein homeostasis adaptation to Hsp70 inhibition in cancer [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 2325.
Abstract LB-399: Aspirin reduces doxorubicin-induced senescence and early-aging in mice
Authors: Mingxiao Feng, Minsub Shim
Journal: Cancer Research (2018)

Abstract Survivors of childhood cancers are often associated with the adverse late effects of earlier cancer treatments, including hearing loss, early menopause, osteoporosis, hypoplasia, fatigue, and infertility. While an accumulating body of evidence supports the hypothesis that cancer treatment is associated with accelerated aging, the mechanisms that lead to a functional decline or frailty remain elusive. Expression of cyclooxygenase-2 (COX2), a key enzyme in prostaglandin biosynthesis, is known to be increased in the tissues of aged humans and mice. We have previously found that transgenic expression of COX2 causes premature aging phenotypes in mice. Since it is well-known that COX2 expression is highly induced by various chemotherapeutic agents, we further investigated the possible link between COX2 and the late effects of chemotherapy. Treatment of juvenile mice with doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, resulted in increased cellular senescence and premature aging in adult mice. Interestingly, tissue expression of COX2 persisted even at 11 weeks after cessation of DOX treatment. In addition, aspirin, a classical non-steroidal anti-inflammatory drug (NSAID), alleviated cellular senescence and early aging phenotypes in DOX-treated mice. Moreover, NSAIDs, either a selective or non-selective COX2 inhibitors, reduced the viability of senescent cells and down-regulated the levels of Bcl-xL and LC3b. Our results suggest that chemotherapy-induced COX2 may play an important role in the late effects of chemotherapy by inducing cellular senescence and further aging. Citation Format: Mingxiao Feng, Minsub Shim. Aspirin reduces doxorubicin-induced senescence and early-aging in mice [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 LB-399.
Abstract 5071: The functional relevance of Atypical Chemokine Receptor 1 (ACKR1/DARC) genetic isoforms in breast cancer
Authors: Brittany D. Jenkins, Rachel N. Martini, Inasia Brown, Melissa B. Davis
Journal: Cancer Research (2018)

Abstract Chemokines and their receptors can interact to affect the host's anti-tumor response by influencing the migration of host immune cells indirectly via a chemokine gradient. The regulation and function of these receptors is paramount in ensuring an appropriate immune response to an inflammatory stimulus, especially in the case of cancer. One such receptor, Atypical Chemokine Receptor 1 (ACKR1/DARC), is a genetically diverse transmembrane GPCR that can buffer pro-inflammatory CXC- and CC- chemokine activity in circulation and within tissues, influencing leukocyte migration. While the basic immunological function of this receptor is known, the specific function of its two genetic isoforms, A and B, is not. These isoforms are produced by two alternative promoters and distinct mRNA splicing events. Isoform A is not split by introns, even in the untranslated regions, and offers homology to CXCL8. The alternative splice variant, Isoform B, does contain an intron, and follows the GT-AG splicing rule, including a novel exon coding for an additional 7 amino acids. This localizes to the N-terminus, making up part of the extracellular binding region of the receptor. We aim to determine if the two major ACKR1 isoforms have distinct functional abilities to bind or sequester pro-inflammatory chemokines in epithelial breast cell lines. By creating isoform specific overexpression and knockout constructs, and transiently transfecting the DNA into our subtype specific cell lines, we can use an ELISA assay to determine chemokine concentration in the media, and measure differences based on isoform specificity. Using immunofluorescence, we first show that ACKR1 and our two proinflammatory chemokines, CCL2 and CXCL8, are expressed on the surface of epithelial cells and colocalize. We then indicate that there is an isoform specific difference in chemokine concentration between different breast cancer subtypes, in addition to differences seen in overexpression and knockout cell lines. Determining the functionality of these two isoforms can help us better understand ACKR1's role in the immune system, and its potential role as a prognostic marker in breast cancer. Citation Format: Brittany D. Jenkins, Rachel N. Martini, Inasia Brown, Melissa B. Davis. The functional relevance of Atypical Chemokine Receptor 1 (ACKR1/DARC) genetic isoforms in breast cancer [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 5071.
Inhibition of Restenosis in Femoropopliteal Arteries
Authors: MichaelWerk, SoenkeLangner, BiankaReinkensmeier, Hans-FrankBoettcher, GunnarTepe, UlrichDietz, NorbertHosten, BerndHamm, UlrichSpeck, JensRicke
Journal: Circulation (2008)

Background— The success of percutaneous intervention in peripheral arterial disease is limited by restenosis. The aim of the present pilot study was to evaluate a novel method of local drug delivery. Methods and Results— This randomized multicenter study with blinded reading enrolled 87 patients in Rutherford class 1 to 4 with occlusion or hemodynamically relevant stenosis, restenosis, or in-stent restenosis of femoropopliteal arteries. Treatment was performed by either conventional uncoated or paclitaxel-coated balloon catheters. The primary end point was late lumen loss at 6 months. Secondary end points included restenosis rate, ankle brachial index, Rutherford class, target lesion revascularization, and tolerance up to >18 months. Before intervention, there were no significant differences in lesion characteristics such as reference diameter (5.3±1.1 versus 5.2±1.0 mm), degree of stenosis (84±11% versus 84±16%), proportion of restenotic lesions (36% versus 33%), and mean lesion length (5.7 cm [0.8 to 22...
Abstract 1445: Metastasis-resistant fatty liver induced by a choline-deficient diet
Authors: Miki Nakamura, Atsushi Suetsugu, Tomoyuki Satake, Kosuke Hasegawa, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman
Journal: Cancer Research (2018)

Abstract Background: Fatty liver disease is increasing worldwide. The differences of the liver metastasis between fatty liver and normal liver remain unclear. We established the EL4-RFP lymphoma models in mice with fatty liver induced by a choline-deficient-diet (CDD) comparing the frequency of liver-metastasis of this tumor in mice with fatty and normal livers. Material and method: C57BL/6-GFP transgenic mice were fed with a CDD in order to establish a fatty liver model. EL4-RFP malignant lymphoma cells were injected in the spleen of fatty-liver mice and normal mice. Using the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope, metastases in mice with fatty liver or normal liver were imaged. Results: EL4-RFP tumors were observed to metastasize to the liver and bone marrow as well as form ascites. Fewer metastases in the fatty liver were observed than in the normal liver. Similarly, fewer cancer-associated fibroblasts (CAFs) were observed in the fatty liver. Conclusion: The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty liver. The fatty liver may not be a suitable environment for CAFs which may be due to re-programmed methionine metabolism which may have occurred during the time the animals were on the CDD. Citation Format: Miki Nakamura, Atsushi Suetsugu, Tomoyuki Satake, Kosuke Hasegawa, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman. Metastasis-resistant fatty liver induced by a choline-deficient diet [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 1445.