tbuckley/cabot-search huggingface dataset:
Abstract 985: BAC Transgenic Analysis of the Smooth Muscle Calponin Gene
Authors: Xiaochun Long, Mary A Georger, Vivian Liu, Joseph M Miano
Journal: Circulation (2007)

Regulatory elements controlling gene expression are often found in separate, sometimes remote, regions around gene loci. Artificial chromosomes offer a means to capture all regulatory elements for study of gene regulation in a near-correct genomic context. The smooth muscle calponin gene (CNN1) encodes for a multifunctional protein involved in signaling, contractile force generation, and growth regulation. While CNN1’s physiology has been studied extensively, its transcriptional regulation has proven to be intractable to conventional in vivo assays. Four evolutionarily-conserved serum response factor (SRF) binding sites (called CArG boxes) are present in the first intron of CNN1 and appear to be required for full transcriptional competence of CNN1 in cultured smooth muscle cells (SMC). To assess the functionality of CNN1 CArG elements in vivo , we exploited a 103-kb bacterial artificial chromosome (BAC) containing the human CNN1 locus shown previously to completely recapitulate endogenous mouse CNN1 expression in vivo . We now show similar SMC-restricted expression of human CNN1 from only 38-kb of BAC sequence. BAC recombineering studies in which the first intron (containing four CArG elements) of CNN1 is replaced with a bacterial selection gene ( galK ) reveal complete loss of human CNN1 expression in vascular SMC, with residual expression in some visceral SMC-containing tissues such as bladder. Transgenic mice carrying the 38-kb BAC with point mutations in all four intronic CArG elements show similar findings suggesting that SRF directly mediates in vivo expression of CNN1 primarily through intronic CArG elements. Bioinformatic, luciferase, and ChIP assays reveal the presence of distal, conserved CArG elements, including a previously unrecognized one located more than 3-kb upstream of the CNN1 transcription start site. The latter CArG-like element is responsive to the SRF coactivator myocardin and is essential for full CNN1 promoter activity in vitro . Moreover, this distal CArG-like element is embedded in a cis regulatory module with conserved binding sites to other distinct transcription factors. We propose that full in vivo CNN1 gene expression requires multiple elements, including five CArG boxes, spread over 14-kb of genomic sequence.
Abstract 364: Cardioprotective Effects Of Carbon Monoxide Mediated By Hypoxia-inducible Factor (HIF) 1-alpha
Authors: Takanori Hayasaki, Hui Liao, Matthew C. Hyman, David J. Pinsky
Journal: Circulation (2008)

Until recently, carbon monoxide (CO) was thought of a toxic gaseous waste product of heme catabolism. Although recent evidence following left anterior descending artery (LAD) ligation in rats has suggested a potential cardioprotective effect of low dose inhaled CO, the molecular mechanism underlying this protection are obscure. The purpose of this study was to elucidate the mechanistic basis for this effect. Myocardial ischemia-reperfusion injury (LAD ligation) was performed in mice which were exposed to room air (RA) or low dose CO (250 ppm) 24 hrs before ischemia. Myocardial infarct size was significantly diminished (by 38%; p&lt;0.01, n=6) in the CO group compared with the RA group. As one pathway of ischemic preconditioning is believed to be mediated by cycloxygenase (COX)-2, we hypothesized that CO might upregulate COX-2 to elicit ischemic cardioprotection. CO increased COX-2 expression in the hearts of mice in a time-dependent manner, peaking at 24 hrs with 4.8-fold protein induction. Additional experiments, done to test a potential separate mechanism of ischemic cardioprotection by CO, showed that CO increased HIF-1α 5.2 fold. The expression of HIF-1α and COX-2 were also higher in CO-exposed cardiomyocytes (HL-1 cells) compared with RA-exposed HL-1 cells. Treatment of HL-1 cells with the COX-2 specific inhibitor (NS398) and prostaglandin (PGE2) had no effect on HIF-1α mRNA levels. However, NS398 significantly abrogated (by 62%, p&lt;0.05, n=3) the increase of HIF-1α expression induced by CO, and PGE2 significantly increased (by 34%, P&lt;0.05, n=3) the HIF-1α expression of RA-exposed inhaled HL-1 cells. Moreover, treatment of mice with NS398 almost completely abolished the cardioprotective effect of CO against ischemia-reperfusion injury. This finding suggests that CO stabilizes HIF-1α via COX-2 activation of prostaglandin E2 synthesis in the heart, and implies that CO protects the heart in ischemia-reperfusion injury via stabilization of HIF-1α.
672P Real-world study of cabozantinib in patients with advanced renal cell carcinoma (aRCC) after VEGF-targeted therapy (CASSIOPE): Interim data for patients who had received prior nivolumab
Authors: G. Procopio, P. Hamberg, P. Bigot, C. Suarez Rodriguez, P. Barthelemy, J-C. Eymard, C. Masini, P. Gajate Borau, P. Dutailly, V. Perrot, M. Staehler
Journal: Annals of Oncology (2021)
Fat mass and response to TNFα blockers in early axial spondyloarthritis: an analysis of the DESIR cohort
Authors: Anna Molto, Solange Tang, Bernard Combe, Maxime Dougados, Pascal Richette
Journal: Annals of the Rheumatic Diseases (2021)

Some studies have showed that obesity, as determined by a body mass index (BMI) ≥30 kg/m2, hampers treatment response to tumour necrosis factor-alpha blockers (TNFb) in patients with axial spondyloarthritis (axSpA).1 However, no study has specifically determined the impact of abdominal adiposity as assessed by waist circumference (WC), on treatment response to TNFb in early axSpA. As compared with BMI, WC is more strongly associated with the metabolic disturbances thought to underlie many of the obesity‐related conditions. Notably, it is associated with low-grade inflammation and all-cause and cardiovascular mortality with or without adjustment for BMI.2 Therefore, we hypothesise that WC could be also an independent factor for TNF b response.

We conducted an analysis to assess the impact of abdominal adiposity on the treatment effect of TNFb in real life in an early axSpA population. Devenir des Spondylarthropathies Indifferenciees Recentes cohort3 is a multicenter, observational, prospective cohort of 708 patients with early (<3 years) inflammatory back pain suggestive of axSpA. Demographics (weight, height, BMI and WC) and disease characteristics (including treatment) were collected every 6 months. Patients receiving a TNFb for the first 2 years of following were matched to their nearest neighbour (according to their propensity score value) to patients receiving any other treatment (usual care, …
Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
Authors: Jorge C. Correia, Yildiz Kelahmetoglu, Paulo R. Jannig, Christoph Schweingruber, Dasha Shvaikovskaya, Liu Zhengye, Igor Cervenka, Naveen Khan, Michael Stec, Mariana Oliveira, Jik Nijssen, Vicente Martínez-Redondo, Serge Ducommun, Michele Azzolini, Johanna T. Lanner, Sandra Kleiner, Eva Hedlund, Jorge L. Ruas
Journal: Cell Metabolism (2021)

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1ɑ1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.
Intratumoral VEGF nanotrapper reduces gliobastoma vascularization and tumor cell mass
Authors: Flávia Sousa, Ana Isabel Costa-Pereira, Andrea Cruz, Fábio Júnio Ferreira, Marcos Gouveia, José Bessa, Bruno Sarmento, Rui D.M. Travasso, Inês Mendes Pinto
Journal: Journal of Controlled Release (2021)
Adding a New Medication Versus Maximizing Dose to Intensify Hypertension Treatment in Older Adults
Authors: Carole E. Aubert, Jeremy B. Sussman, Timothy P. Hofer, William C. Cushman, Jin-Kyung Ha, Lillian Min
Journal: Annals of Internal Medicine (2021)

Background: There are 2 approaches to intensifying antihypertensive treatment when target blood pressure is not reached, adding a new medication and maximizing dose. Which strategy is better is unknown. Objective: To assess the frequency of intensification by adding a new medication versus maximizing dose, as well as the association of each method with intensification sustainability and follow-up systolic blood pressure (SBP). Design: Large-scale, population-based, retrospective cohort study. Observational data were used to emulate a target trial with 2 groups, new medication and maximizing dose, who underwent intensification of their drug regimen. Setting: Veterans Health Administration (2011 to 2013). Patients: Veterans aged 65 years or older with hypertension, an SBP of 130 mm Hg or higher, and at least 1 antihypertensive medication at less than the maximum dose. Measurements: The following 2 intensification approaches were emulated: adding a new medication, defined as a total dose increase with new medication, and maximizing dose, defined as a total dose increase without new medication. Inverse probability weighting was used to assess the observational effectiveness of the intensification approach on sustainability of intensified treatment and follow-up SBP at 3 and 12 months. Results: Among 178 562 patients, 45 575 (25.5%) had intensification by adding a new medication and 132 987 (74.5%) by maximizing dose. Compared with maximizing dose, adding a new medication was associated with less intensification sustainability (average treatment effect, −15.2% [95% CI, −15.7% to −14.6%] at 3 months and −15.1% [CI, −15.6% to −14.5%] at 12 months) but a slightly larger reduction in mean SBP (−0.8 mm Hg [CI, −1.2 to −0.4 mm Hg] at 3 months and −1.1 mm Hg [CI, −1.6 to −0.6 mm Hg] at 12 months). Limitation: Observational data; largely male population. Conclusion: Adding a new antihypertensive medication was less frequent and was associated with less intensification sustainability but slightly larger reductions in SBP. Trials would provide the most definitive support for our findings. Primary Funding Source: National Institute on Aging and Veterans Health Administration.
205P Immunomodulation in early triple-negative breast cancer (TNBC): Analysis of soluble markers as predictive biomarkers to neoadjuvant chemotherapy in TNBC
Authors: M. Nunez Abad, S. Torres Martínez, C. Ferriol Martinez, E. Escorihuela, C. Garcia Gonzalez, M.M. Franco de la Rosa, L. Montagud Inza, J.Á. García García, V. Gumbau Puchol, C. Castañer Puga, P. Matoses Ortiz, I. Barreres Moll, M.J. Godes Sanz de Bremond, S. Calabuig-Fariñas, C. Caballero Díaz, A. Blasco Cordellat, C.J. Camps, V. Iranzo
Journal: Annals of Oncology (2021)
Abstract 11489: Coffee Consumption Affects the Impact of Weight Loss over a One-Year Period on Lipid Metabolism
Authors: Aiko Sakamoto, Yuko Ishizaka, Minoru Yamakado, Ryozo Nagai, Nobukazu Ishizaka
Journal: Circulation (2012)

Objective: There remains a controversy over whether coffee consumption is favorable for lipid metabolism and future cardiovascular risks. We investigated the association between body mass index (BM...
1275P Mutational landscape of non-small cell lung carcinoma in patients with different types of premalignant bronchial lesions
Authors: T.S. Gerashchenko, A.A. Schegoleva, A.A. Khozyainova, R.S. Vorobiev, E.O. Rodionov, O.V. Pankova, V.M. Perelmuter, E.V. Denisov
Journal: Annals of Oncology (2021)
The Role of Cost-effectiveness Analysis in Health and Medicine
Authors: Louise B. Russell
Journal: JAMA (1996)

<h3>Objective.</h3> —To develop consensus-based recommendations guiding the conduct of cost-effectiveness analysis (CEA) to improve the comparability and quality of studies. The recommendations apply to analyses intended to inform the allocation of health care resources across a broad range of conditions and interventions. This article, first in a 3-part series, discusses how this goal affects the conduct and use of analyses. The remaining articles will outline methodological and reporting recommendations, respectively. <h3>Participants.</h3> —The Panel on Cost-Effectiveness in Health and Medicine, a nonfederal panel with expertise in CEA, clinical medicine, ethics, and health outcomes measurement, was convened by the US Public Health Service (PHS). <h3>Evidence.</h3> —The panel reviewed the theoretical foundations of CEA, current practices, and alternative procedures for measuring and assigning values to resource use and health outcomes. <h3>Consensus Process.</h3> —The panel met 11 times during 21/2 years with PHS staff and methodologists from federal agencies. Working groups brought issues and preliminary recommendations to the full panel for discussion. Draft recommendations were circulated to outside experts and the federal agencies prior to finalization. <h3>Conclusions.</h3> —The panel's recommendations define a "reference case" costeffectiveness analysis, a standard set of methods to serve as a point of comparison across studies. The reference case analysis is conducted from the societal perspective and accounts for benefits, harms, and costs to all parties. Although CEA does not reflect every element of importance in health care decisions, the information it provides is critical to informing decisions about the allocation of health care resources.
Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies
Authors: Carlos A Garcia-Prieto, Lorea Villanueva, Alberto Bueno-Costa, Veronica Davalos, Europa Azucena González-Navarro, Manel Juan, Álvaro Urbano-Ispizua, Julio Delgado, Valentín Ortiz-Maldonado, Francesca del Bufalo, Franco Locatelli, Concetta Quintarelli, Matilde Sinibaldi, Marta Soler, Manuel Castro de Moura, Gerardo Ferrer, Rocio G Urdinguio, Agustin F Fernandez, Mario F Fraga, Diana Bar, Amilia Meir, Orit Itzhaki, Michal J Besser, Abraham Avigdor, Elad Jacoby, Manel Esteller
Journal: JNCI Journal of the National Cancer Institute (2021)

Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course.We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided.We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02).We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.
Characterization of Outcomes by Surgical Management of Lung Neuroendocrine Tumors Associated With Cushing Syndrome
Authors: Kenneth P. Seastedt, George A. Alyateem, Karthik Pittala, Seth M. Steinberg, David S. Schrump, Lynnette K. Nieman, Chuong D. Hoang
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Ectopic adrenocorticotropic hormone secretion from lung tumors causing Cushing syndrome are associated with high rates of morbidity. Optimal management remains obscure because knowledge is based on rare reports with few patients. <h3>Objective</h3> To characterize the outcomes of lung neuroendocrine tumors associated with Cushing syndrome. <h3>Design, Setting, and Participants</h3> An observational case series review from 1982 to 2020 was conducted in a single institution referral center. Kaplan-Meier analysis estimated disease-free survival (DFS). Participants underwent curative-intent surgery for a lung neuroendocrine tumor causing Cushing syndrome. <h3>Exposures</h3> Lobectomy or pneumonectomy vs sublobar resection. <h3>Main Outcomes and Measures</h3> Disease-free survival, disease persistence/recurrence. <h3>Results</h3> Of the 68 patients, the median age was 41 years (range, 17-80 years), 42.6% (29 of 68) were male, 81.8% (54 of 66) were White, with a mean follow-up after surgery was 16 months (range, 0.1-341 months). Lobectomy was the most common procedure (48 of 68 [70.6%]), followed by wedge resection (16 of 68 [23.5%]) and segmentectomy (3 of 68 [4.4%]). Video-assisted thoracoscopic surgery was performed in 19 of 68 (27.9%) of patients. Surgical morbidity was 19.1% (13 of 68), and perioperative mortality was 1.5% (1 of 68). Lymph node positivity was 37% (22 of 59) when evaluable. The overall incidence of persistence/recurrence was 16.2% (11 of 68) with a median time to recurrence of 55 months (range, 18-152 months). The median DFS was reached in 12.7 years (0.1-334 months). There were no statistical differences in DFS based on tumor size, stage (8th edition TNM), whether full systematic lymphadenectomy was performed or not, nodal status, or surgical approach. <h3>Conclusions and Relevance</h3> In this case series study, neuroendocrine pulmonary tumors associated with Cushing syndrome had increased nodal metastasis, higher recurrence, and lower DFS than quiescent bronchopulmonary carcinoid tumors, but many patients experienced favorable outcomes. This observation is underscored by the discordance of TNM-stage classifications vs prognosis. Observing no difference in surgical techniques, the implication may be that a lung-sparing approach could suffice. These results may reflect the intrinsic importance of the hormone physiology instead of the carcinoid biologic factors.
Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT
Authors: Prakriti Gaba, Deepak L. Bhatt, Robert P. Giugliano, Ph. Gabriel Steg, Michael Miller, Eliot A. Brinton, Terry A. Jacobson, Steven B. Ketchum, Rebecca A. Juliano, Lixia Jiao, Ralph T. Doyle, Craig Granowitz, Jean-Claude Tardif, Christie M. Ballantyne, Duane S. Pinto, Matthew J. Budoff, C. Michael Gibson
Journal: Journal of the American College of Cardiology (2021)

REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. The purpose of this study was to determine the effects of IPE on investigator-reported events. Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361)
475P A phase Ib study of NUC-3373, a targeted inhibitor of thymidylate synthase, in combination with standard therapies in patients with advanced colorectal cancer (NuTide:302)
Authors: J. Berlin, A.L. Coveler, K.K. Ciombor, F. Kazmi, J. Graham, M.L. Peters, J.W. Clark, M. Myers, A. De Gramont, T.R.J. Evans, S. Blagden
Journal: Annals of Oncology (2021)
1010P Intratumorally administered CV8102 in patients with advanced solid tumors: Preliminary results from completed dose escalation in study 008
Authors: T. Eigentler, L. Heinzerling, J. Krauss, C. Weishaupt, S. Ochsenreither, C. Lebbe, P. Mohr, M. Oliva, H.K. Oberoi, P. Terheyden, J.M. Trigo Perez, C. Robert, F-G. Bauernfeind, M. Fluck, E. Richtig, A. Soria, S-K. Kays, B. Schmitt-Bormann, M. Falk, U.S. Gnad-Vogt
Journal: Annals of Oncology (2021)
275P A phase II study of LAG525 in combination with spartalizumab (PDR001), PDR001 and carboplatin (Carbo), or Carbo, as first- or second-line therapy in patients (Pts) with advanced (Adv) triple-negative breast cancer (tnbc)
Authors: L.A. Carey, J-Y. Pierga, S. Kümmel, G. Jerusalem, M. De Laurentiis, M. Miller, Z. Li, M. Kaper, F. Su, S. Loi
Journal: Annals of Oncology (2021)