tbuckley/cabot-search huggingface dataset:
Abstract 13964: A Microtubule-Connexin-43 Feed-Forward Loop Suppresses Arrhythmias in Duchenne Muscular Dystrophy Mice
Authors: Julie Nouet, Eric Himelman, Mauricio Lillo, Chong Alexander, Xander H Wehrens, George G Rodney, Lai-hua Xie, Natalia Shirokova, Jorge E Contreras, Diego Fraidenraich
Journal: Circulation (2021)

Dilated cardiomyopathy is the leading cause of death in patients with Duchenne muscular dystrophy (DMD), a lethal neuromuscular disorder that affects 1 in 5,000 males. We identified pathological remodeling of gap-junction protein Connexin-43 (Cx43) is a strong contributor towards DMD-related cardiomyopathy, which occurs primarily through a reduction in post-translational phosphorylation of Cx43 serine residues 325/328/330. We hypothesized that the organization of the microtubules (MTs) regulates the phospho-status of Cx43, and that the phospho-status of Cx43 regulates the organization of the MTs. To study a potential regulation of Cx43 by MTs, we delivered colchicine (Colch), a MT-regulator that reduces oxidative stress and corrects MT organization, into the DMD mouse model (mdx) and in Cx43-phosphorylation-deficient mdx mice (mdxS3A). We found that, while Colch treatment prevented the formation and aberrant activity of remodeled Cx43 in the hearts of mdx mice, it did not prevent aberrant activities in the hearts of mdxS3A mice. Thereby, Colch treatment did not prevent severe cardiac conduction in Isoproterenol-stressed mdxS3A mice, while it protected against Isoproterenol-induced arrhythmias in mdx mice. To study a potential regulation of MTs by Cx43, we evaluated the MT cytoskeleton in Cx43-phospho-mimicking mdx mice (mdxS3E). We found that the MT organization of mdxS3E isolated cardiomyocytes resembled that of wild-type. Lastly, to assess the potency of S3E in rescuing fibrosis in severe models of DMD-cardiomyopathy, we studied mdxS3E mice with partial absence of utrophin (utr). We found that S3E conferred protection against fibrosis in mdxutr(+/-)S3E relative to mdxutr(+/-) mice. In sum, Cx43-triplet phosphorylation depends on proper organization of the MT cytoskeleton, and the organization of the MT cytoskeleton depends on Cx43-triplet phosphorylation. This dual dependency creates a feed-forward mechanistic loop, which is disrupted in DMD-cardiomyopathy leading to MT disarray, arrhythmias and long-term fibrosis. The pathology is prevented either by forcing corrections in the MTs with Colch or in Cx43 with S3E. Thus, the impactful intersection between MTs and Cx43 can be harnessed for future cardiovascular disease studies.
Abstract 13203: Exercise Decreases Stress-Associated Neural Activity Predominantly by Upregulating Regulatory Medial Prefrontal Cortical Activity
Authors: Hadil Zureigat, Shady Abohashem, Charbel Gharios, Kenechukwu Mezue, Taimur Abbasi, Alexander Cardeiro, Lisa Shin, Aaron L Baggish, Zahi A Fayad, Michael Osborne, Ahmed A Tawakol
Journal: Circulation (2021)

Introduction: Exercise associates with dose-dependent decreases in stress-associated neural activity (SNA) which, in part, mediate exercise’s beneficial impact on major adverse cardiovascular event (MACE) risk. SNA can be assessed as a ratio of the resting metabolic activity of the brain’s fear centers (i.e., the amygdala [Amyg]), to that of regulatory centers (i.e., the medial prefrontal cortex [PFC]). However, it is unknown whether exercise reduces SNA by impacting the activity of Amyg, mPFC, or both. Hypothesis: We tested whether exercise reduces SNA primarily through enhancing the activity of the mPFC. We further hypothesize that it is the regulatory effect of the mPFC on SNA that contributes to MACE risk reduction. Methods: Self-reported physical activity data were obtained from Partners Biobank participants and total metabolic equivalents-minutes per week (MET-min/wk) were calculated. In a subset with clinical 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, Amyg and mPFC activity were measured and corrected by whole cerebrum activity. SNA was calculated (Amyg/mPFC activity). MACE and cardiovascular risk factors were obtained using International Classification of Diseases codes. Results: Out of 684 subjects with both physical activity and imaging data (median age 68 years [IQR 60,75]), 275 (40.2%) developed MACE. Physical activity (as tertiles) associated with a dose-dependent increase in mPFC activity (Figure 1A; standardized β [95% CI]: 0.087 [0.002,0.036], p=0.025). Moreover, while SNA predicted MACE in adjusted analysis, the activities of the Amyg or PFC alone did not (Figure 1B). Conclusions: Exercise associates with dose dependent increases in mPFC activity. This effect does not directly reduce MACE risk; however, it may reduce MACE risk via its regulatory action on SNA. These observations may also have relevance in the impact of exercise on depression/anxiety disorders and cognitive function.
Triple Post-Transplant Cyclophosphamide (PTCY) Based Gvhd Prophylaxis for HLA Matched or HLA Haploidentical Transplants
Authors: Eugenio Galli, Elisabetta Metafuni, Sabrina Giammarco, Maria Assunta Limongiello, Idanna Innocenti, Francesco Autore, Luca Laurenti, Patrizia Chiusolo, Federica Sorà, Andrea Bacigalupo, Simona Sica
Journal: Blood (2021)
Extracellular vesicles in kidney transplantation: a state-of-the-art review
Authors: James Ashcroft, Philippa Leighton, Tegwen R. Elliott, Sarah A. Hosgood, Michael L. Nicholson, Vasilis Kosmoliaptsis
Journal: Kidney International (2021)

Kidney transplantation is the optimal treatment for patients with kidney failure; however, early detection and timely treatment of graft injury remain a challenge. Precise and noninvasive techniques of graft assessment and innovative therapeutics are required to improve kidney transplantation outcomes. Extracellular vesicles (EVs) are lipid bilayer-delimited particles with unique biosignatures and immunomodulatory potential, functioning as intermediaries of cell signalling. Promising evidence exists for the potential of EVs to develop precision diagnostics of graft dysfunction, and prognostic biomarkers for clinician decision making. The inherent targeting characteristics of EVs and their low immunogenic and toxicity profiles combined with their potential as vehicles for drug delivery make them ideal targets for development of therapeutics to improve kidney transplant outcomes. In this review, we summarize the current evidence for EVs in kidney transplantation, discuss common methodological principles of EV isolation and characterization, explore upcoming innovative approaches in EV research, and discuss challenges and opportunities to enable translation of research findings into clinical practice.
DDRE-44. TIRABRUTINIB MONOTHERAPY FOR RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: HIGH RESPONSE RATE, COMMON SKIN-RELATED DISORDERS, AND DURABLE REMISSION IN A SUBSET OF PATIENTS
Authors: Nobuyoshi Sasaki, Keiichi Kobayashi, Kuniaki Saito, Ryo Onoda, Yousuke Seiya, Yuki Yamagishi, Saki Suzuki, Hirofumi Nakatomi, Yoshiaki Shiokawa, Motoo Nagane
Journal: Neuro-Oncology (2021)

Abstract BACKGROUNDS Prognosis of relapsed primary central nervous system lymphoma (rPCNSL) is poor ranging between 2.2 and 16 months, and the optimal treatment strategy has not been established. Tirabrutinib is a second generation Bruton’s tyrosine kinase (BTK) inhibitor, approved by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) for relapsed and refractory (r/r) PCNSL in March 2020. While an overall response rate (ORR) of 64% and progression-free survival (PFS) of 2.9 months was reported in a phase 1/2 study, the real-world treatment results of rPCNSL treated with tirabrutinib have not been investigated yet. METHODS Treatment results of rPCNSL patients treated with tirabrutinib at the author’s institution including response rate, PFS, overall survival (OS), and toxicity profiles were retrospectively analyzed. RESULTS Eleven patients were identified (median age: 73 [range: 50-83], median PFS: 70 [range: 40-90]). Response was CR in four (36.4%), PR in five (45.4%), PD in two (18.2%) patients, providing with an ORR of 81.8%. At a median follow up of 25.7 months, relapse was observed in seven patients (63.6%), and median PFS was 3.0 months. Durable remission of more than six months was obtained in four patients (36.4%). As for toxicities, six patients (54.5%) had skin-related disorders, which lead to tirabrutinib interruption in two (18.2%), dose reduction in three (27.3%), and discontinuation in two patients (18.2%). Grade 3/4 hematological toxicities were grade 4 neutropenia in one, and grade 3 lymphopenia in five patients (45.4%). No deaths have been observed. DISCUSSION Tirabrutinib monotherapy achieved a high response rate in rPCNSL, while skin-related disorders appeared to be the major obstacle leading to treatment interruption or discontinuation. Overall median PFS was in line with the phase 1/2 study. A subset of patients achieved durable remission, suggesting its strong benefit in certain patients. Further investigation of predictive biomarkers for response to tirabrutinib is warranted.
Abstract 12113: Deletion of Extracellular Signal-Regulated Kinases 2 Using SM22α-Cre Driver Causes Cardiac Failure and Vascular Dysfunction
Authors: Kazuki Kagami, Yusuke Yumita, Midori Iwashita, Ishinoda Yuki, Takayuki Namba, Takumi Toya, Yukinori Ikegami, Risako Yasuda, Nobuyuki Masaki, Yasuo Ido, Yuji Nagatomo, Takeshi Adachi
Journal: Circulation (2021)

Background: Extracellular signal-regulated kinases 1/2 (ERK1/2) play significant roles in proliferation, migration, and cell death. Tyrosine kinase inhibitors (TKIs) have a serious concern for card...
Abstract 10599: The Effects of Gestational Age and Size on Management Strategies and Outcomes in Neonatal Tetralogy of Fallot
Authors: Leanne Duhaney, Martina A Steurer, Rebecca Baer, Christina Chambers, Satish Rajagopal, Laura M Mercer-rosa, V. Mohan Reddy, Laura L Jelliffe-Pawlowski, Shabnam Peyvandi
Journal: Circulation (2021)

Introduction: Data suggests there are benefits to both staged (SR) and complete repair (CR) for neonatal Tetralogy of Fallot (nTOF), though data is lacking on whether high-risk groups would benefit from one strategy over another. In a large state with variable practice patterns, we studied the impact of gestational age (GA) and weight by GA (birth weight z-score: BWz) at birth on surgical strategy and outcomes in nTOF, hypothesizing that GA and BWz would influence these outcomes. Methods: Population-based cohort study (2011-2017) of infants with nTOF (defined as catheter or surgical intervention prior to 44 weeks corrected GA) was performed. BWz was categorized as appropriate, small or large for GA. Surgical strategy and timing were compared by GA ( &lt; 36 weeks preterm (n= 96), 37-38 weeks early term (n= 97), &gt; 38 weeks full term (n= 152)) and BWz. Multivariable (MV) models were constructed to evaluate composite outcome of mortality or significant morbidity (BPD, IVH, NEC, PVL etc.) at 1 year and total number of hospital days in first year of life. Results: There were 345 patients included (SR= 194; CR= 151). Surgical strategy did not differ by GA or BWz. Within CR group, full term and early term neonates underwent surgery 20 (95%CI: -27.1, -14.1; p&lt;0.001) and 15 days (95%CI: -22.1, -8.2; p&lt;0.001) sooner than preterm neonates. BWz was not associated with surgical timing. A stratified analysis trended toward lower survival probability among preterm neonates undergoing CR vs. SR (p= 0.1). In a MV model including GA, BWz, surgical approach and DOL surgery, only GA was associated with the composite outcome. The odds of a poor outcome was 0.45 (95%CI:0.24,0.86) times lower in full term vs. preterm neonates, p= 0.02. The adjusted total burden of hospital days in the first year was 32 (95%CI: -47.7,-16.9; p&lt;0.001) and 22 (95%CI: -36.5,-7.7; p= 0.003) days less in early term and full term compared to preterm neonates. Conclusions: In nTOF, GA and BWz were not associated with surgical strategy though premature neonates were more likely to wait longer for their initial intervention. One-year outcomes appear to be strongly influenced by GA and not surgical strategy; however, there was a trend to suggest that SR may result in better survival probability among premature neonates.
만성 B형간염에서 간 조직내 TGF-p1과 a-SMA 단백질의 발현정도와 인터페론 치료효과와의 상관관계
Authors: 김배영(Bai Young Kim), 안희정(hee Jeong Ahn), 오성욱(Seong Wook Oh), 정은미(Oun Mi Jeong), 최유정(Yu Jeong Choi), 국진환(Jin Hwan Kook), 김경철(Kyung Chul Kim), 홍성표(Sung Pyo Hong), 황성규(Seong Gyu Hwang), 박필원(Pil Won Park), 임규성(Kyu Sung Rim)
Journal: Clinical and Molecular Hepatology (1998)

Backg round/Aims : The aim of this study was to evaluate the effect of α- interferon (IFN) on liver histology as well as on activation of hepatic stellate cell ( HSC) and trans for ming growth fact or β- 1 (TGF β- 1) expression. We had also investigated the clinical usefulness of  TGFβ- 1 and α- smooth muscle actin (α- SMA) expression in liver tissue for predicting a response toα- IFN therapy in chronic hepat it is B. Methods : We studied the expression of  TGFβ-1 and α- SMA in liver biopsys pecimens from 51 chronic hepatitis B pat ients . Using immunohistochemical staining and a semiquant it ative scoring met hod, we also evaluated TGF- β1 and α- SMA expression in liver stellate cells before and after α- IFN therapy in liver tissue from rebiopsys pecimen of  the 12 chronic hepatitis B pat ients . Recombinant  IFN α- 2b (Intron A) in doses of 6 MU/ d was given to patients intramus cularly three times per week for 6 months ( total doses , 432 MU). The patients were divided into two groups according to serum alanine aminotransferase levels as well as HBV- DNA and HBeAg s eroconversion stat e. Histological grading and staging scores were according to modified Histological Activity Index (HAI) gradingsys tems of  Ishak ( 1995).  Results : The index of portal inflammation and total scores of  HAI grading significantly decreased in biopsies afterα - IFN t reat ment, but the scores of fibrosis staging showed no significant change in biopsies after IFN t reat ment. A significant decrease in α- SMA expression, especially in periportal area, was found, but the change of  TGFβ- 1 expression was not significant. The immunoreactivity of α- S MA was significantly lower in responders than in non-res ponders , whereas the diffference of immun or eactivity of  TGFβ - 1 between these two groups was not found. Conclusions : These findings suggest that α- IFN therapy may reduce the necroinflammatory activity in liver tissues of chronic B viral hepatitis and that the degree of - S MA ex pression before treatment may be employed as a pottent predicting indicat or for the therapeutic efficacy of  IFN- alfa.(Korean J Hepatol 1998;4:317 329)
Abstract 11071: Increased Circulating Raas Activity is Related to Functionally Significant Coronary Artery Disease as Defined by Ffr and [ <sup>15</sup> O]h2o Pet Perfusion as Well as Vulnerable Plaque Characteristics on CT Angiography
Authors: Ruurt Jukema, Ruben de Winter, Pepijn van Diemen, Roel Driessen, Jan H Danser, Ingrid Garrelds, Pieter Raijmakers, Peter van de Ven, Paul Knaapen, Ibrahim Danad, Guus De Waard
Journal: Circulation (2021)

Introduction: Renin-angiotensin-aldosterone-system (RAAS) activity has been linked to coronary artery disease (CAD) and coronary microvascular dysfunction (CMD), opening potential frontiers for treatment. In this study we investigated if increased RAAS activation is related to CAD, high risk plaque (HRP), myocardial perfusion, and CMD in chest pain patients. Methods: Renin as a measure for RAAS activation, was quantified by immunoradiometric assay in 205 patients (64% men; age 58 ± 9 years) with suspected CAD. Patients underwent 256-slice coronary CT angiography for (quantitative) plaque analysis and coronary artery calcium (CAC) scoring, [ 15 O]H2O PET perfusion imaging and invasive FFR measurements in all coronary arteries. A total of 585 vessels were stratified upon four categories based on [ 15 O]H2O PET perfusion and invasive pressure measurements. Vessels with a FFR &gt;0.80 but with an ischemic hyperemic MBF below 2.3 ml/min/g were defined as CMD. Results: In univariable analysis, renin associated positively with the CAC score, total plaque volume (TPV) and impaired perfusion (p&lt;0.01 for all). Patients with HRP displayed higher levels of renin (p=0.04). As expected, renin (p&lt;0.01) was elevated in males. After correction for baseline characteristics including sex, renin associated positively with CAC score and TPV (p&lt;0.01 and p=0.03), but not with HRP and perfusion (p=0.14 and p=0.40). Figure 1 shows that vessels with a significant flow limiting stenosis (FFR+, PET+; p=0.04) occur in patient with elevated renin levels, while vessels defined as CMD (FFR-, PET+) do not, except for patient without RAAS inhibition. Conclusion: RAAS activation is associated with CAD defined by FFR and [ 15 O]H2O PET and HRP. Future studies should clarify whether RAAS activation and CAD are causally related and represent modifiable targets. Figure 1. Intergroup p values are depicted for significant p values only. The upper and lower whiskers represent the 10 th and 90 th percentile.
Abstract 11891: Greater Rates of Readmission and Length of Stay Among Heart Failure Patients With Cardiac Amyloidosis Than Those Without
Authors: Abdallah F Masri, Umair Jabbar, Mukunthan Murthi, Saurabh Malhotra
Journal: Circulation (2021)

Introduction: Cardiac amyloidosis (CA) portends a poor prognosis in heart failure (HF) patients. While CA is being diagnosed with an increasing frequency, it is not known whether the knowledge of a diagnosis of CA influences HF readmissions or hospital length of stay (LOS). Methods: Data on HF readmission and hospital LOS was collected for patients undergoing Technetium pyrophosphate (PYP) imaging for CA between January 2018 to December 2020 from our institution’s Business Intelligence reports. CA was confirmed by a combination of PYP imaging and assessment of monoclonal proteins. Number of readmissions per patient per year and the mean cumulative LOS per year were calculated for those with and without confirmed CA. Date of confirmatory testing was used as a cut-off for comparison of HF readmission and LOS prior to and after diagnosis of CA. Results: A total of 112 patients underwent PYP imaging during the study period, of which 30 (27%) had CA (transthyretin=26; light-chain=4). Patients with CA were similar in proportion of African Americans (90%) and gender (57% women) compared to those without CA, but were older on average (76.7 vs 69.4 years, p=0.002). Patients with CA had more frequent HF readmissions prior to and after their diagnosis compared to those without CA (Figure). While both had similar LOS prior to confirmatory testing, LOS was significantly higher in CA patients following diagnosis. Patients without CA saw a significant decline in HF readmission and LOS after performance of confirmatory testing, contrasting with CA patients whose readmissions rates and LOS remained unchanged before and after confirmation of the diagnosis. Conclusions: Patients with CA have more frequent HF readmissions and a higher annual LOS when compared to those without CA. Confirmation of CA diagnosis has no effect on these outcomes. Patients with CA may require more tailored interventions to reduce their acute care healthcare utilization.
Abstract 13408: Generating Human Engineered Heart Tissue Containing the Major 4 Cardiac Cell Types, Each Color-Coded and Differentiated From Pluripotent Stem Cells
Authors: Marc N Hirt, Tessa Werner, Justus Stenzig, Kristoffer Riecken, Boris Fehse, Arne Hansen, Thomas Eschenhagen
Journal: Circulation (2018)

Introduction: We have previously shown that engineered heart tissue (EHT) from neonatal rat heart cells responds to sustained mechanical or pharmacological stress stimuli similarly as hearts in viv...
Abstract 11599: Elevated Interleukin-6 and <i>TMPRSS6</i> Genotype Are Associated with Worse Cardiovascular Outcomes
Authors: Ian Barrows, Richard Amdur
Journal: Circulation (2021)

Introduction: Elevated levels of plasma interleukin-6 (IL-6) and impaired iron homeostasis are associated with cardiovascular disease. IL-6 and matriptase-2, which is encoded by the TMPRSS6 gene, help regulate iron homeostasis. A nonsynonymous V736A substitution (rs855791) reduces the ability of matriptase-2 to inhibit hepcidin transcription, leading to iron-deficiency anemia that is refractory to iron administration. We assessed the hypothesis that patients with chronic kidney disease and elevated IL-6 and the rs855791 genotype have poorer cardiovascular outcomes. Methods: We used the clinical, genetic and biomarker data from 3031 Chronic Renal Insufficiency Cohort (CRIC) study participants with follow-up over 10 years. The genotype data was extracted from genome-wide association studies. The primary outcome of interest was all-cause mortality and a composite of myocardial infarction (MI), stroke, congestive heart failure (CHF) and peripheral arterial disease (PAD). We used a separate logistic regression model for each outcome, with covariates for genotype and IL-6 quintile, and the genotype x IL-6 interaction. These models were adjusted for the Pooled Cohort Equation 10-year atherosclerotic cardiovascular disease probability estimate, race, BMI, baseline eGFR and baseline albuminuria. Results: Among the study participants, 1569 (52%) and 1122 (37%) were homozygous for GG and AA alleles, and 1122 (37%) were heterozygous (AG). The rs855791 genotype and plasma level of IL-6 were significantly associated with lower hemoglobin levels, all-cause mortality and cardiovascular outcomes. In the adjusted model that included the rs855791 genotype, IL-6 remained significantly associated with all-cause mortality (1.36 (1.26-1.45), p&lt;0.001) and the CVD composite (1.27 (1.19-1.36), p&lt;0.001). The interaction of IL-6 quintile x rs855791 genotype was not significantly associated with outcomes. Conclusion: In conclusion, elevated plasma levels of IL-6 and the rs855791 genotype are both independently associated with anemia, all cause mortality and cardiovascular outcomes in patients with kidney disease.
Abstract 11945: A Paradox of Medical Cost and Outcomes: A Comparison of Acute Heart Failure Outcomes in the United States vs. Japan
Authors: Benjamin Bates, Nobuyuki Enzan, Takeshi Tohyama, Poonam Gandhi, Shouji Matsushima, Hiroyuki Tsutsui, Tomomi Ide, Soko Setoguchi
Journal: Circulation (2021)

Background: Despite advances in therapy, the burden of heart failure (HF) has not declined in the US. Comparing HF between nations may provide hypothesis generating research to improve outcomes and decrease costs. We directly compared characteristics, management, cost, and outcomes of acute HF hospitalization in the US vs. Japan. Methods: We identified acute HF patients (age &gt;65) in US Medicare Part A, B, and D data and Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter registry in 2013. We described patient characteristics, length of stay (LOS), cost paid, post-discharge follow-up (f/u), CV medications, death, and CV readmission. Results: We identified 11,193 Japanese and 120,289 US patients hospitalized for acute HF. While similar in age and gender, US patients were more likely to have multiple comorbidities (Table). Japanese patients had a 3-fold longer median LOS, a 3-fold lower median per-day hospital cost paid, more than 10-fold likely to receive cardiac rehab, and were more likely to receive CV medications. While inpatient mortality was higher in Japan (8.6% vs 3.2%), overall mortality after HF admission and CV readmission was 1.5-2-fold higher in US patients (Figure). US patients had higher physician f/u within 14 days but overall f/u rate was higher in Japan. Conclusion: Despite longer LOS with lower hospital costs, Japanese HF patients had high inpatient cardiac rehab participation, more CV medications, higher f/u rate with a physician, and better survival. Further studies may assess potential interventions (e.g. inpatient cardiac rehab, prevention of premature discharge) to improve outcomes in US HF patients.