tbuckley/cabot-search huggingface dataset:
Abstract 14844: Ampk is Required for Maintaining Atrial Metabolism and Oxidative Stress
Authors: Yina Ma, Xiaohong Wu, Xiaoyue Hu, Gary Cline, Fadi G Akar, Lawrence H Young
Journal: Circulation (2020)

Background: AMP-activated kinase (AMPK) has a critical role in cellular substrate and energy metabolism, regulating fatty acid oxidation, stimulating glucose transport and glycolysis. AMPK is crucial in the LV, preventing ischemic injury and heart failure. Atrial AMPK depletion induces atrial fibrillation in mice, but the role of AMPK in regulating atrial metabolism and oxidative stress is unknown. Methods: Atrial AMPK was selectively depleted in mice, utilizing sarcolipin-Cre mediated deletion of floxed α1 and α2 catalytic subunits (AMPKdKO). Floxed littermate mice were controls (CON). Microarray, immunoblotting, liquid chromatography-mass spectrometry (LC-MS), and electron microscope (EM) were used to access the gene, protein, metabolism, and mitochondria changes. Results: Pathway analysis of microarray data showed that fatty acid metabolism was downregulated in the AMPKdKO vs. CON atria (n=4 per group, p&lt;0.0001). PGC1-α and downstream genes regulating fatty acid metabolism, including acyl-CoA thioesterase (ACOT), long-chain fatty acid-CoA ligase (ACSL), carnitine palmitoyltransferase 2 (CPT2), and fatty acid binding protein (FABP) were reduced in the AMPKdKO vs. CON atria (at 1 week of age). Atrial long-chain fatty acyl-CoA and acyl-carnitine levels were decreased (by LC-MS) in the AMPKdKO vs. CON atria (at 4 and 8 weeks of age) (n=3-4 per group, p&lt;0.05). EM images showed evidence of swollen, broken and degraded mitochondrial in AMPKdKO atria (at 8 weeks age). Atrial expression of antioxidant enzymes, including SOD2 and PRDX3, was reduced (by immunoblotting) in AMPKdKO vs. CON atria (n=3-4, p&lt;0.05). Conclusion: AMPK regulates critical mechanisms regulating atrial fatty acid metabolism and oxidative stress. Loss of atrial AMPK reduces the concentration of critical fatty acid intermediates for oxidative mitochondrial metabolism. These metabolic alterations may contribute to structural and electrical remodeling, and ensuing atrial fibrillation, that results from the loss of AMPK in the atria.
INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a multicenter prospective observational study (INVIDIa-2)
Authors: Melissa Bersanelli, Diana Giannarelli, Ugo De Giorgi, Sandro Pignata, Massimo Di Maio, Alberto Clemente, Elena Verzoni, Raffaele Giusti, Marilena Di Napoli, Giuseppe Aprile, Paola Ermacora, Annamaria Catino, Vieri Scotti, Francesca Mazzoni, Pamela Francesca Guglielmini, Antonello Veccia, Marco Maruzzo, Ernesto Rossi, Francesco Grossi, Chiara Casadei, Corrado Ficorella, Vincenzo Montesarchio, Francesco Verderame, Mimma Rizzo, Giorgia Guaitoli, Lucia Fratino, Caterina Accettura, Manlio Mencoboni, Fable Zustovich, Cinzia Baldessari, Saverio Cinieri, Andrea Camerini, Letizia Laera, Mariella Sorarù, Paolo Andrea Zucali, Valentina Guadalupi, Francesco Leonardi, Marcello Tiseo, Michele Tognetto, Francesco Di Costanzo, Carmine Pinto, Giorgia Negrini, Antonio Russo, Maria R Migliorino, Marco Filetti, Sebastiano Buti
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Until now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs). Methods The prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety. Results The study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p&lt;0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p&lt;0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% vs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1–2). Conclusion The INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.
GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice
Authors: Ricardo J. Samms, Michael E. Christe, Kyla A.L. Collins, Valentina Pirro, Brian A. Droz, Adrienne K. Holland, Jessica L. Friedrich, Samantha Wojnicki, Debra L. Konkol, Richard Cosgrove, Ellen P.S. Conceição Furber, Xiaoping Ruan, Libbey S. O’Farrell, Annie M. Long, Mridula Dogra, Jill A. Willency, Yanzhu Lin, Liyun Ding, Christine C. Cheng, Over Cabrera, Daniel A. Briere, Jorge Alsina-Fernandez, Ruth E. Gimeno, Julie S. Moyers, Tamer Coskun, Matthew P. Coghlan, Kyle W. Sloop, William C. Roell
Journal: Journal of Clinical Investigation (2021)

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r–null mice. In the absence of GLP-1R–induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Analysis of major histocompatibility complex class I expression on Reed- Sternberg cells in relation to the cytotoxic T-cell response in Epstein- Barr virus-positive and -negative Hodgkin's disease
Authors: JJ Oudejans, NM Jiwa, JA Kummer, A Horstman, W Vos, JP Baak, PM Kluin, P van der Valk, JM Walboomers, CJ Meijer
Journal: Blood (1996)
Abstract P139: The Impact Of Inpatient Diet Orders On Patient Nutrition And Dietary Behaviors Post Discharge
Authors: Lily N Dastmalchi, Ishaan Dharia, Leigh A Frame, Allen J Solomon
Journal: Circulation (2021)

Introduction: Suboptimal nutrition is a known contributor to the development of cardiovascular disease. In the past decade, focus has been on improving the quality of hospital food with nutrition and policy science initiating programs, e.g. Healthy Food in Health Care. Little has been studied on the impact of these improvements on diet choices after discharge. To our knowledge, this is the first study to evaluate if inpatient diet orders play a role in nutrition after discharge. Methods: Patients ≥18 years of age admitted to the medicine service with either a regular or cardiac diet order were recruited. Exclusion criteria were the following dietary parameters—fluid restriction, low potassium, diabetic, gluten free, or vegan diets. Patients were given a baseline questionnaire using a Lickert scale to assess dietary behaviors, nutrition counseling during admission, and demographics. One month post-discharge, a follow-up questionnaire was given to reassess their dietary choices. Results: In this preliminary analysis, 70 subjects were enrolled: 57.1% (n= 40) regular diet and 42.0% (n=30) cardiac diet. 38.6% (n=27) believed diet orders during admission were part of the their medical treatment. At follow-up, 55 patients remained and included in the final analysis. 50 with identifiable subject IDs: 57.4% (n= 27) regular diet and 42.5% (n=20) cardiac diet. 15 were lost to follow up: 1 deceased, 2 declined to participate, 2 were readmitted to the hospital, and the remaining were not reachable. Diet was reported as always important to overall health 50.0% (n=35) at baseline vs 72.7% (n=40, p= 0.642) at follow up. 22.8% (n=16) of subjects stated never reading nutrition labels in comparison to follow-up 12.7% (n=7, p= 0.019). Never monitoring salt intake was reported among 23.6% (n=9) patients at baseline and 12.7% at follow-up (n=6, p=0.043). Subjects reported that nutrition education was never received during their inpatient or outpatient follow up period (30% (n=21) vs 76.3% (n=42), p=0.0002). Conclusions: To-date, our pilot study shows inpatient diet orders having the potential to influence dietary behaviors with significant changes in food label reading and monitoring salt intake after discharge. Nutrition education was significantly never given in both inpatient and outpatient settings. However, most patients believe nutrition is important to their overall health, further supporting receptivity to nutrition education during inpatient and outpatient follow-up education.
Platelet-associated anti-GPIIb-IIIa autoantibodies in chronic ITP mainly recognize cation-dependent conformations: Comparison with the epitopes of serum autoantibodies.
Authors: Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Honda S, Tadokoro S, Kanakura Y, Kurata Y, Matsuzawa Y
Journal: Blood (1995)
Abstract #429: Dependence on PI3K and RAS-RAF pathways drives the activity of the combination of everolimus (RAD001) and RAF265, a novel inhibitor of the RAF-MAPK pathway, in vitro and in vivo
Authors: Pierre Mordant, Yohann Loriot, Céline Leteur, Yungan Tao, Jean Bourhis, Jean-Charles Soria, Eric Deutsch
Journal: Cancer Research (2009)

Background. PI3K-Akt and Ras-Raf activation can induce cellular immortalisation, proliferation and resistance to anticancer therapeutics such as EGFR inhibitors or chemotherapy. Our goal was to assess the consequences of the inhibition of these two pathways in tumor cells with activation of either Ras-Raf, PI3K-Akt, or both pathways. We investigated whether the combination of a novel Raf/VEGFR2 inhibitor, RAF265, with an mTOR inhibitor, RAD001, could lead to enhanced antitumoral effects in vitro and in vivo. Material and methods. We used A549 (Kras mutant, low pTEN), HCT116 (Kras, PI3KCA mutant), HT29 (Braf V599E mutant), and MDAMB231 (Kras, BRAF G463V mutant) cell lines. Immunobloting was performed to evaluate inhibitor activity. Cell proliferation was assessed by clonogenic assay. MTT assay and Bliss additivism model was used to classify the effect of the combination on cell viability. Subcutaneous xenografts were used to assess the activity of the combination in vivo. Results. A decrease in pS6 and pMEK was found after treatment of all the cell lines with RAD001 and RAF265, respectively. In HCT116, HT-29 and MDAMB231 cells, RAD001 alone (0,1 - 10 nM) failed to decrease cell viability while in A549 cells, RAD001 alone achieved a decrease of 30% in cell viability. In HT29 and MDAMB231 cells, RAF265 alone showed significant activity with IC50 values of 5 to 10 \#956;M while in A549 and HCT116 cells, IC50 was not reached at concentrations of RAF265 up to 10 \#956;M. However, in the presence of 1 nM RAD001, the IC50 for RAF265 was 5 \#956;M in A549 cells, and 10 \#956;M in HCT116 cells. The effect of the combination was found to be additive in A549 cells and synergistic in HCT116 cells. In HCT116 cells, RAF265 exposure led to a marked decrease in phosphorylation of mTOR downstream effectors, such as S6 and 4EBP1. The combination showed no additional activity in HT29 and HCT116 cells. In clonogenic assay, A549 and HCT116 colonies were smaller with the combination than with either drug alone, suggesting increased inhibition of cell proliferation. In vivo, the combination showed no additional activity in A549 and MDAMB231 cells, but induced an additive tumoral growth delay compared to each compound given alone in HCT116 cells. Conclusion. Combination of the RAF inhibitor with mTOR inhibitor is an effective strategy to enhance antitumoral effects on cells with deregulation of both, Ras-Raf and PI3K-PTEN. In vitro, the combination is additive in A549 cells and synergistic in HCT116 cells, possibly through a cross-inhibition of 4EBP1 and S6, mTOR downstream effectors. In vivo, the combination is additive in HCT116 cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 429.
急性非代償性心不全患者に対するカルペリチド(hANP)治療の長期的予後における効果
Authors: Hata N, Seino Y, Tsutamoto T, Suzuki H, Hiramitsu S, Yoshikawa T, Yokoyama H, Tanaka K, Mizuno K, Nejima J, Kinoshita M
Journal: Circulation (2006)
Heart Failure With Targeted Cancer Therapies
Authors: Virginia S. Hahn, Kathleen W. Zhang, Lova Sun, Vivek Narayan, Daniel J. Lenihan, Bonnie Ky
Journal: Circulation Research (2021)

Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.
Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer
Authors: Daryl Jin Tai Tay, Yangyang Song, Boya Peng, Tan Boon Toh, Lissa Hooi, Desiree-Faye Kaixin Toh, HuiQi Hong, Sze Jing Tang, Jian Han, Wei Liang Gan, Tim Hon Man Chan, Manchugondanahalli S. Krishna, Kiran M. Patil, Manikantha Maraswami, Teck Peng Loh, Yock Young Dan, Lei Zhou, Glenn Kunnath Bonney, Pierce Kah-Hoe Chow, Gang Chen, Edward Kai-Hua Chow, Minh T.N. Le, Leilei Chen
Journal: Molecular Therapy (2021)

Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3′ end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2′-O-methyl (2′-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types. Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3′ end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2′-O-methyl (2′-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.
Abstract 15576: Cardiovascular Disease in Elderly Familial Hypercholesterolemia Individuals Attending a Cascade Screening Program
Authors: elaine coutinho, Marcio H Miname, Viviane Z Rocha, Marcio S Bittencourt, Cinthia Jannes, Alexandre Pereira, Jose E Krieger, Raul D Santos
Journal: Circulation (2020)

Introduction: Familial hypercholesterolemia (FH) is associated with early onset of cardiovascular disease (CVD) and mortality. Lipid lowering treatment (LLT) may change the natural history of FH, however there is scant information about elderly individuals (older than 60 years) with FH. This study describes characteristics of elderly FH individuals presenting or not CVD. Hypothesis: Monogenic defects are important markers of CVD risk and initiation and long-term use of lipid lowering therapy (LLT) is relevant to minimize this risk. Methods: Cross-sectional analysis of clinical and laboratory of molecularly proven elderly FH (FH+) and non-affected (FH-) individuals attending a cascade screening program. FH+ were divided in those presenting or not CVD (defined as previous myocardial infarction or ischemic stroke, carotid or coronary revascularization and angina with stenosis ≥50% on angiography). Results: From 4,111 genotyped individuals, 462 (11.2%) elders were included (198 FH+ and 264 FH-). There was predominance of females in either groups, however with more men in FH+ 37.4% vs. 24.2%, p=0.002. No differences were seen between FH+ and FH- regarding age, [median (%25;75%)] 66 (62;71) and 66 (63;71) years, p=0.68; use of LLT 88.5% vs. 91.5%, p=0.29 and high intensity LLT 61.7 % vs. 55.8%, p=0.20, respectively. Despite longer LLT duration in FH+ 11(7;20) vs. 7 (3;13) years, p&lt;0.001, in either groups LLT was started late, at 54 (47;61) and 59 (52;64) years, p &lt;0.001, respectively in FH+ and FH-. FH+ had higher LDL-C at diagnosis, 243 (179;302) vs. 228 (209;251) mg/dL, p=0.013, as well as greater frequencies of previous CVD 40.9% vs. 27.3%, p=0.002, and early CVD 22.2% vs. 9.0%, p&lt;0.001. In FH+, male sex [OR (95%CI)] 5.29 (2.25-12.45), p&lt;0.001, and use of high intensity LLT 2.51 (1.08-5.87), p=0.03, were independently associated with CVD. Conclusions: The genetic diagnosis of FH was associated with higher rates of CVD and early CVD vs. FH- hypercholesterolemics. Elders with FH+ who survived despite late LLT initiation have a worse CVD history than FH- elders, emphasizing the relevance of a monogenic defect as cause of long-lasting hypercholesterolemia and CVD risk, particularly in men.
방사선 투시하의 경피적 배액술로 치료된 감염된 거대 간낭종 1예
Authors: 김희진(Hee Jin Kim), 이정일(Joung Il Lee), 박경분(Kyoung Bun Park), 동석호(Seok Ho Dong), 김효종(Hyo Jong kim), 김병호(Byung Ho Kim), 장영운(Young Woon Chang), 장린(Rin Chang)
Journal: Clinical and Molecular Hepatology (1999)

Symptomatic hepatic cysts are infrequently seen. A 82-year-old woman was admitted because of growing abdominal mass and pain. On admission, the mass was palpated on right upper quadrant of the abdomen. Ultrasonography and computed tomography disclosed a huge cystic lesion of the liver. It measured 22.5 x 19.0 x 18.0 cm and had a thick wall that was irregular. Because of the patient's symptoms and the radiologic findings, the decision was made to aspirate the cyst percutaneously under fluoroscopic guidance. Percutaneous drainage yielded approximately 3300 cc of yellow brownish fluid. A cytologic evaluation of the fluid was negative for malignant cells, and a fluid analysis was described as predominantly inflammatory in nature. Cultures revealed a growth of Klebsiella oxytoca. After drainage of the cystic fluid, we instilled contrast medium. No communication between the cyst and bile ducts was seen. Seven days later, the patient was discharged. Four months after treatment, no reaccumulated fluid was observed by ultrasonography. Ten months after treatment, the patient is healthy without abdominal discomfort. We report a case of the infected huge hepatic cyst successfully treated with fluoroscopic-guided percutaneous drainage. (Korean J Hepatol 1999;5:142－147)
Abstract 16127: Peripheral Artery Disease Guideline Operative With Patient-Reported Outcomes (PAD GO PRO): A Report From the PAD GO PRO Quality Program
Authors: Matthew C Bunte, Sravanthi Vupputuri
Journal: Circulation (2020)

Introduction: Peripheral artery disease (PAD) is a public health epidemic, driven by surging rates of diabetes and an aging population. Poor disease recognition and inconsistent medical care account for suboptimal outcomes. Methods: Using an administrative code algorithm, patients over age 40 years evaluated during an ambulatory visit were screened for diagnostic codes indicating PAD. Patients with PAD were assessed for optimal medical care (OMC) per 2016 American Heart Association Guidelines on the Management of Patients with Lower Extremity PAD, including (1) antiplatelets, (2) statins, (3) antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and (4) tobacco abstention. OMC was defined as achieving all 4 quality metrics at first visit. Rates for a composite endpoint of all-cause mortality, myocardial infarction, and stroke (MACE) were compared between OMC and non-OMC groups. Cox proportional hazard modeling was used to assess the relationship between OMC and outcomes. Results: In a population of 353,738 unique ambulatory patients, 15,690 had PAD (4.4%). Among those with PAD, the mean (SD) age was 72.5+/-11.0 years, 46.2% were female, and 11.2% used tobacco. Patients with PAD receiving OMC (n=4,371), compared to those with non-OMC (n=11,319), had a significantly reduced rate of the composite endpoint (19.9% vs 26.9%; hazard ratio (HR): 0.65; [95% confidence interval (CI), 0.60-0.71]; p&lt;0.001) during a mean 26.7 months follow-up (Figure). The benefits of OMC on MACE was driven by a reduction in all-cause death (7.1% vs 15.5%; HR: 0.41, [95% CI, 0.36-0.46]; p&lt;0.001). Rates of myocardial infarction (12.5% vs 15.41%; HR 0.96 [95% CI, 0.86-1.08]; p=0.532) and stroke (3.3% vs 3.8%; HR 1.06 [95% CI, 0.87-1.30]; p=0.556) were not significantly reduced. Conclusions: In a large, real-world cohort of patients identified to have PAD, guideline-directed OMC significantly reduces all-cause death and MACE.