bluuebunny/crossref_metadata_2025 huggingface dataset:
Processing Method of Missing Data in Dam Safety Monitoring
Authors: Wei Wei , Gu Chongshi , Fu Xiao
Published: July 2021

A large amount of data obtained by dam safety monitoring provides the basis to evaluate the dam operation state. Due to the interference caused by equipment failure and human error, it is common or even inevitable to suffer the loss of measurement data. Most of the traditional data processing methods for dam monitoring ignore the actual correlation between different measurement points, which brings difficulties to the objective diagnosis of dam safety and even leads to misdiagnosis. Therefore, it is necessary to conduct further study on how to process the missing data in dam safety monitoring. In this study, a data processing method based on partial distance combining fuzzy C-means with long short-term memory (PDS-FCM-LSTM) was proposed to deal with the data missing from dam monitoring. Based on the fuzzy clustering performed for the measurement points of the same category deployed on the dam, the membership degree of each measurement point to cluster center was described by using the fuzzy C-means clustering algorithm based on partial distance (PDS-FCM), so as to determine the clustering results and preprocess the missing data of corresponding measurement points. Then, the bidirectional long short-term memory (LSTM) network was applied to explore the pattern of changes of measurement values under identical clustering conditions, thus processing the data missing from monitoring effectively.
The Size Effect and Microstructure Changes of Granite after Heat Treatment
Authors: Guo Zhongping , Li Jian , Song Yongqi , He Chengqian , Zhang Fuyu
Published: July 2021

High temperature can change the mechanical properties of granite, with significant nonlinear characteristics, and at the same time change its microstructure. Therefore, two kinds of granites are used in this paper: one is normal temperature granite and the other is granite treated at 600°C, and a detailed comparative study is made. The fracture toughness of two kinds of rocks was tested by fracture tests, and the results were analyzed by a nonlinear fracture mechanics model (SEL). At the same time, in order to understand the influence of high temperature on the mineral composition and microstructure of granite, XRD, optical microscope, and SEM were used to observe the mineral composition, microcracks, and fracture morphology of granite. The results show the following: (1) high temperature significantly changes the fracture mechanics parameters of granite. The fracture toughness of granite treated at 600°C is significantly lower than that of untreated granite, which is reduced by more than 60%. (2) No obvious size effect was found in the untreated granite, while the size effect of the granite after treatment at 600°C was significant. (3) The granite after high‐temperature treatment showed strong nonlinear characteristics, and the SEL can reasonably describe and explain its nonlinear fracture characteristics. (4) The brittleness of the granite treated at 600°C decreased and the ductility increased. The microscopic morphology of the fracture was rough, with obvious steps and rivers. The microcracks and porosity had increased significantly, but the main components did not change significantly.
An Enhanced Half‐Quasi‐Z‐Source Inverter for Wind Energy Conversion System with D‐PMSG
Authors: Zhang Yang , Cheng Zhun , Chen Qing , Li Qingmei
Published: July 2021

To solve the problem of the traditional quasi‐Z‐source inverters with low voltage gain, an enhanced half‐quasi‐Z‐source inverter (E‐HQZSI) is proposed and applied to direct‐drive permanent‐magnet wind power generation systems in this paper. The expression of the boosting factor is deduced, which shows that E‐HQZSI has higher voltage gain compared with the QZSI and HQZSI. However, the higher voltage gain of the E‐HQZSI will lead to the large distortion of the generator stator current necessarily. In this paper, a periodic shoot‐through duty ratio control scheme is proposed to reduce the stator current harmonics for E‐HQZSI. According to the change rule of the single‐phase stator current, the shoot‐through duty ratio is compromised to make that the three‐phase stator currents are as close as possible to the sine wave. Finally, the correctness of the theoretical analysis is verified by simulation and experiment.
KDM1A Promotes Immunosuppression in Hepatocellular Carcinoma by Regulating PD-L1 through Demethylating MEF2D
Authors: Wang Yonglan , Cao Kun
Published: July 2021

Background. Immune checkpoint inhibitor therapy targeting antiprogrammed cell death-1 (anti-PD-1) or its ligand (anti-PD-L1) is effective in the treatment of some hepatocellular carcinomas (HCC). Hence, further identification of biological targets related to PD-L1 regulation in HCC is beneficial to improve the clinical efficacy of immunotherapy. Some HCC cells express lysine-specific demethylase 1A (KDM1A), which is implicated in the reduced survival time of patients. Here, we studied whether the level of PD-L1 and the immunosuppression are regulated by KDM1A and its miRNA in HCC cells. Methods. In the present study, we studied clinical data from The Cancer Genome Atlas (TCGA) database. We performed qPCR and western blotting assays to measure the expression level of genes of interest. PD-L1 expression was also analyzed by FACS. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 was used to generate gene knockout cells to investigate the relationships of genes of interest. We also developed a reporter gene assay (RGA) to explore the changes in T cell-induced antitumor immunity relative to PD-L1 expression in HCC cells. The binding between proteins and promoters or miRNAs and their target genes was explored by luciferase reporter assays. Results. The results showed that PD-L1 and KDM1A were increased in HCC patients and cells, and KDM1A promoted the expression of PD-L1 in HCC cells. Our findings showed that the enhancement of PD-L1 expression was not attributed to mitochondrial dysfunction caused by increases in KDM1A in HCC cells. Furthermore, we observed a lower level of MEF2D methylation in HCC cells than in normal human liver cells. Demethylated MEF2D could bind to the promoter of PD-L1 and activate its expression, while KDM1A interacted with MEF2D and acted as a demethylase to reduce its methylation. Moreover, a new miRNA, miR-329-3p, targeting KDM1A was found to regulate the PD-L1 expression profile in HCC cells. In the xenograft model, the tumors treated with miR-329-3p showed growth inhibition. Conclusions. Mechanistically, miR-329-3p inhibits tumor cellular immunosuppression and reinforces the response of tumor cells to T cell-induced cytotoxic effect by targeting KDM1A mRNA and downregulating its expression, which contributed to MEF2D demethylation and activation of PD-L1 expression.
Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma
Authors: Li Chuan , Lin Wen-Yang , Rizvi Hira , Cai Hongchen , McFarland Christopher D. , Rogers Zoe N. , Yousefi Maryam , Winters Ian P. , Rudin Charles M. , Petrov Dmitri A. , Winslow Monte M.
Published: July 2021

The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here, we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1-mutant lung tumors to platinum therapy, was validated using a large patient response data set. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies.

Significance:

An experimental and analytical framework to generate in vivo pharmacogenomic maps that relate tumor genotypes to therapeutic responses reveals a surprisingly complex map of genotype-specific resistance and sensitivity.
The Ratio of Toxic-to-Nontoxic miRNAs Predicts Platinum Sensitivity in Ovarian Cancer
Authors: Patel Monal , Wang Yinu , Bartom Elizabeth T. , Dhir Rohin , Nephew Kenneth P. , Matei Daniela , Murmann Andrea E. , Lengyel Ernst , Peter Marcus E.
Published: July 2021

Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2–7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3′ untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses.

Significance:

These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.
Effects of Exercise on Cancer Treatment Efficacy: A Systematic Review of Preclinical and Clinical Studies
Authors: Yang Lin , Morielli Andria R. , Heer Emily , Kirkham Amy A. , Cheung Winson Y. , Usmani Nawaid , Friedenreich Christine M. , Courneya Kerry S.
Published: July 2021

We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.
SENTI-101, a Preparation of Mesenchymal Stromal Cells Engineered to Express IL12 and IL21, Induces Localized and Durable Antitumor Immunity in Preclinical Models of Peritoneal Solid Tumors
Authors: Gonzalez-Junca Alba , Liu Frances D. , Nagaraja Archana S. , Mullenix Alyssa , Lee Chen-Ting , Gordley Russell M. , Frimannsson Daniel O. , Maller Ori , Garrison Brian S. , Iyer Dharini , Benabbas Anissa , Truong Tiffany A. , Quach Allison , Tian Mengxi , Martinez Rowena , Savur Rishi , Perry-McNamara Alyssa , Nguyen Denny , Almudhfar Niran , Blanco Carmina , Huynh Christina , Nand Asish , Lay Yu-An E. , Magal Ashita , Mangalampalli Sravani , Lee Philip J. , Lu Timothy K. , Lee Gary
Published: July 2021

Advanced peritoneal carcinomatosis including high-grade ovarian cancer has poor prognoses and a poor response rate to current checkpoint inhibitor immunotherapies; thus, there is an unmet need for effective therapeutics that would provide benefit to these patients. Here we present the preclinical development of SENTI-101, a cell preparation of bone marrow-derived mesenchymal stromal (also known as stem) cells (MSC), which are engineered to express two potent immune-modulatory cytokines, IL12 and IL21. Intraperitoneal administration of SENTI-101 results in selective tumor-homing and localized and sustained cytokine production in murine models of peritoneal cancer. SENTI-101 has extended half-life, reduced systemic distribution, and improved antitumor activity when compared with recombinant cytokines, suggesting that it is more effective and has lower risk of systemic immunotoxicities. Treatment of tumor-bearing immune-competent mice with a murine surrogate of SENTI-101 (mSENTI-101) results in a potent and localized immune response consistent with increased number and activation of antigen presenting cells, T cells and B cells, which leads to antitumor response and memory-induced long-term immunity. Consistent with this mechanism of action, co-administration of mSENTI-101 with checkpoint inhibitors leads to synergistic improvement in antitumor response. Collectively, these data warrant potential clinical development of SENTI-101 for patients with peritoneal carcinomatosis and high-grade ovarian cancer.

Graphical abstract: SENTI-101 schematic and mechanism of action

SENTI-101 is a novel cell-based immunotherapeutic consisting of bone marrow–derived mesenchymal stromal cells (BM-MSC) engineered to express IL12 and IL21 intended for the treatment of peritoneal carcinomatosis including high-grade serous ovarian cancer. Upon intraperitoneal administration, SENTI-101 homes to peritoneal solid tumors and secretes IL12 and IL21 in a localized and sustained fashion. The expression of these two potent cytokines drives tumor infiltration and engagement of multiple components of the immune system: antigen-presenting cells, T cells, and B cells, resulting in durable antitumor immunity in preclinical models of cancer.
The Effect of Different Administration Time and Dosage of Vitamin D Supplementation in Patients with Multiple Sclerosis: A Meta-Analysis of Randomized Controlled Trials
Authors: Yuan Xiaofan , Guo Lei , Jiang Chuan , Yang Xu , Huang Jie
Published: July 2021

Background: Despite the vitamin D treatment in patients with multiple sclerosis (MS), there continues to be controversial discrepancy in outcomes according to the current research. Many systematic reviews have evaluated the effect of vitamin D as an adjuvant treatment in patients with MS; however, there is no consensus on the optimum administration time and dosage of vitamin D intake. A meta-analysis for exploring the different administration time and dosage of vitamin D is warranted. Methods: Randomized controlled trials (RCTs) on the effect of different administration time and dosage of vitamin D in patients with MS were recorded within 7 databases. This meta-analysis was performed with 2 clinical outcomes: EDSS (Expanded Disability Status Scale) and relapses during research. Results: The pooled results indicated that receiving different administration time and dosage of vitamin D as an adjuvant treatment had no significant therapeutic effect on MS according to the EDSS scores and relapses during research. Conclusion: According to our meta-analysis, the administration of vitamin D in different dosages (ranging from 2,857 to 14,007 IU/day) and treatment period (ranging from 6 to 24 months) did not affect the clinical outcomes (EDSS and relapses during research) in patients with MS. Additional RCTs should be conducted to explore whether a longer duration and a larger dosage of vitamin D without serious adverse effects might produce therapeutic effects in patients with MS.
Vulnerabilidade à contaminação das águas superficiais da Bacia Hidrográfica do Rio Pirapó, Paraná
Authors: Graça Carlos Henrique da , Silveira Hélio
Published: July 2021

A água é um dos recursos mais importantes para a sobrevivência dos seres vivos, devendo ser muito bem gerida, de modo a não comprometer a qualidade de vida das gerações futuras. Um dos maiores desafios é diminuir os efeitos da carência e contaminação da água. O objetivo desse trabalho é estabelecer uma classificação da vulnerabilidade à contaminação das águas superficiais, visando contribuir com a gestão mais efetiva da bacia hidrográfica do rio Pirapó – Paraná. Para isso foi aplicado o modelo semi-empírico de Morgan, Morgan e Fenney (MMF – modificado). Os resultados mostram que vulnerabilidade à contaminação das águas superficiais apresentou maior porcentagem ligada à vulnerabilidade média, corresponde cerca de 63% da área da bacia. Essa classificação, está relacionada a ocorrência de solos profundos (Latossolos e Nitossolos) e resistentes ao desprendimento de partículas, com valores mais baixos de escoamento superficial influenciados pela redução na intensidade da precipitação, além de estar sobre áreas de declividade moderadas, com predomino de classes ente 6 e 15%. Assim, considera-se que o estudo possa contribuir no desenvolvimento ações favoráveis a proteção das águas superficiais da bacia, priorizando áreas específicas de proteção para o monitoramento de suas águas.
Prognosis After the Implantation of an Intra-Aortic Balloon Pump in Cardiac Surgery Calculated With a New Score
Authors: Hausmann Harald , Potapov Evgenij V. , Koster Andreas , Krabatsch Thomas , Stein Julia , Yeter Ruhi , Kukucka Marian , Sodian Ralf , Kuppe Hermann , Hetzer Roland
Published: July 2021

Background

Over the past decade, the use of a ventricular-assist device (VAD) in patients with postcardiotomy cardiogenic shock has resulted in hospital discharge rates of 25% to 40% and is improving. Nevertheless, indications for and timing of the implantation of a VAD in patients who have received an intra-aortic balloon pump (IABP) remain unclear.

Methods and Results

From July 1996 to March 2000, 391 patients with cardiac low-output syndrome who underwent open-heart surgery and had an IABP implanted were analyzed in a retrospective pilot study. The perioperative mortality was 34% (133 patients). Clinical parameters were analyzed 1 hour after IABP support began. Statistical multivariate analysis showed that patients with an adrenaline requirement higher than 0.5 μg · kg
−1
· min
−1
, a left atrial pressure >15 mm Hg, urine output <100 mL/h, and mixed venous saturation (S
v
O
2
) <60% had poor outcomes. Using this data, we developed an IABP score (0 to 5 points) to predict survival early after IABP implantation in cardiac surgery. We evaluated our score by monitoring another 101 patients as a control group prospectively. Additionally, 210 patients who received coronary artery bypass grafting (CABG) exclusively were analyzed. All investigations confirmed the validity of the score.

Conclusions

The IABP score can predict survival early after IABP implantation. In patients with a high IABP score, implantation of a VAD should be considered.
Treatment of Thrombus Formation Associated With the MicroMed DeBakey VAD Using Recombinant Tissue Plasminogen Activator
Authors: Rothenburger Markus , Wilhelm Markus J. , Hammel Dieter , Schmidt Christoph , Tjan Tonny D. T. , Böcker Dirk , Scheld Hans H. , Schmid Christof
Published: July 2021

Background

The latest generation of left ventricular assist devices consists of nonpulsatile impeller pumps. In these small pumps, thrombus formation inside the device does not lead to thromboembolic end-organ dysfunction but may dramatically impair pump flow. We report on our experience with thrombus-related pump dysfunctions of the MicroMed DeBakey left ventricular assist device and its treatment.

Methods

Eight of 22 patients with a MicroMed DeBakey VAD presented with a critically reduced pump flow. In 7 cases, an increased power demand indicative of progressive thrombus formation associated with the device was evident, whereas 1 case presented with thrombus formation within the inflow conduit associated with a very low power demand. Brief spontaneously resolving pump stops had been noted in 6 patients. All 8 patients were treated with 100 mg of recombinant tissue plasminogen activator (rt-PA), administered via an IV line.

Results

Rt-PA lysis led to an increase of pump flow along with a reduction of power demand within a short time in all patients. No severe bleeding complications occurred. However, 4 patients experienced transient epistaxis. All patients could be discharged from intensive care immediately after discontinuation of thrombolytic therapy.

Conclusion

Rt-PA lysis is a very effective tool for thrombus-related pump dysfunction in patients with impeller pumps, which renders emergency surgical exchange unnecessary in most cases.
Effects of pH Management During Deep Hypothermic Bypass on Cerebral Microcirculation: Alpha-Stat Versus pH-Stat
Authors: Duebener Lennart F. , Hagino Ikuo , Sakamoto Takahiko , Mime Lotfi Ben , Stamm Christof , Zurakowski David , Schäfers Hans-Joachim , Jonas Richard A.
Published: July 2021

Objective

There is controversy regarding the optimal pH strategy during deep hypothermic bypass in children. We directly visualized the effects of the pH-stat and alpha-stat strategy on cerebral microcirculation (including leukocyte/endothelial cell interactions) in a piglet model using intravital fluorescence microscopy.

Methods

Two groups of 5 piglets (mean weight 9.6±1.3 kg) with a cranial window over parietal cerebral cortex underwent 10-minute normothermic bypass, 40-minute cooling on cardiopulmonary bypass ([CPB] Hct 30%, 100 mL/kg/min), 60-minute circulatory arrest at 15°C, and 40-minute rewarming with alpha-stat (group alpha) or pH-stat (group pH). Plasma was labeled with fluorescein-ITC-dextran for assessment of microvascular diameter. Circulating leukocytes were labeled and observed in postcapillary venules for adhesion before and up to 120 minutes after CPB. Cerebral tissue oxygenation was evaluated by quantification of NADH autofluorescence, which increases during ischemia.

Results

At the end of normothermic bypass diameter of cerebrocortical microvessels increased to 116±9% (alpha) versus 119±10% (pH) of pre-CPB baseline values. During cooling microvascular diameter decreased in group alpha and significantly increased in group pH (89±11% (alpha) versus 132±13% (pH) at the end of cooling;
P
<0.001). During the first 10 minutes of rewarming, the cerebral microvascular diameter was significantly larger when the pH stat strategy was used. Tissue oxygenation at the end of cooling was significantly greater in the pH-stat group (
P
=0.008). On reperfusion, the pH-stat strategy resulted in significantly more rapid return of tissue oxygenation toward baseline although at the end of rewarming the metabolic recovery was complete in both groups. The whole body lactate during early rewarming was significantly less with the pH stat strategy. There was no significant difference between the groups regarding the number of adherent leukocytes throughout the time course of the experiment.

Conclusions

pH-stat management increases tissue oxygenation during deep hypothermic bypass and after circulatory arrest. Leukocyte/endothelial cell interactions during hypothermic bypass are mild with both alpha-stat and pH-stat.
Abstract 119: Nebivolol Suppresses Hypoxic-Induced Rat Thoracic Aortic Smooth Muscle Cell Apoptosis by a Mechanism Involving Nitric Oxide Production, HSP70 Upregulation and Inhibition of P53 Phosphorylation
Authors: Tsoporis James , Rizos Ioannis K , Toumpoulis Ioannis K , Salpeas Vasileos , Izhar Shehla , Parker Thomas G
Published: July 2021

Aneurysmal degeneration of the ascending aortic artery is a common and frequently lethal disease process. Localized hypoxic-induced aortic smooth muscle cell (SMC) apoptosis, a factor amenable to medical intervention, has been reported to participate in the pathogenesis of ascending aortic aneurysm formation (ASAA. β-adrenergic blockers are the drugs most commonly used in the treatment of ASAA. The aim of this study was to investigate the effects of the new third-generation β-blocker nebivolol (NB) on hypoxic-induced smooth muscle cell apoptosis and to characterize the mechanisms activated in this NB action. Treatment of cultured rat thoracic aortic SMC, with NB (10 μM) compared to diluent (100 μM Ascorbic acid) (AA) for 1 hr attenuated hypoxic (5%C02/95%N2) apoptosis as measured by decreases in TUNEL positive staining (15.3+2.3 (AA) vs 5.6+1.2 (NB) % apoptotic nuclei, p<0.05), caspase-3 activity (91.3+2.4 (AA) vs 72.1+0.8 (NB) μmol/mL, p<0.05), the apoptotic ratio of bax/bcl-2 mRNA expression (1.37+0.14 (AA) vs 0.82+0.11 (NB) fold-change, p<0.05), pro-apoptotic miR1 (2.9+0.35 (AA) vs 1.18+0.22 (NB) fold change, p<0.05), and increased anti-apoptotic miR133A (0.74+0.17 (AA) vs 2.3+0.42 (NB) fold change, p<0.05), n=8-10/group. The NB-induced decrease in hypoxic SMC apoptosis was associated with a 5.5 fold increase in nitric oxide (NO) production as quantified by the ratio of Nitrate/Nitrite, a 2.5-3.2 fold increase in Hsp70 mRNA and protein as measured by RT-PCR and Western analysis respectively, and an attenuation of p53 phosphorylation. Blockade of NO production by L-NAME, or siRNA HSP70 knock down, resulted in an increase in p53 phosphorylation and prevented the NB-induced antiapoptotic response of hypoxic SMC. The beneficial pro-survival response of NB in hypoxic thoracic aortic SMCs makes this novel β-blocker clinically relevant in the treatment of ASAA.
Abstract 636: Gut Microflora Influences Pathology in the Kawasaki Disease (KD) Vasculitis Mouse Model
Authors: Wakita Daiko , Kurashima Yosuke , Takasato Yoshihiro , Lee Youngho , Shimada Kenichi , Chen Shuang , Crother Timothy R , Lehman Thomas J , Fishbein Michael C , Kiyono Hiroshi , Arditi Moshe
Published: July 2021

Background:
KD is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated.

Objective:
To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model.

Methods and Results:
We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal bacteria and/or fungi, and determined whether altered microorganism burden in this KD mouse model contributes to disease severity. To deplete bacteria and/or fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to antibiotics cocktail (Abx) or antifungal drug (fluconazole; Fluc) in their drinking water for 5 wks and induced KD. The mice treated with Abx or Fluc had significantly reduced coronary arteritis and AAA compared to controls. The Abx plus Fluc administration showed marked decrease of KD vasculitis.

Conclusions:
We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that both bacteria and fungi in the intestinal microbiota may control the induction and severity of KD vasculitis. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.
Abstract 10: Endothelial FGF Protects Against Pulmonary Hypertension
Authors: Woo Kel Vin , Weinheimer Carla , Kovacs Attila , Ornitz David
Published: July 2021

Pulmonary hypertension (PH) is a debilitating disease where 1 in 4 patients will die within five years of diagnosis. Pathologic changes of endothelial cell function, together with smooth muscle and adventitial hyperplasia increase pulmonary vascular resistance. Consequent elevation in right ventricular pressure ultimately causes right heart failure.

Expression of Fibroblast Growth Factor Receptors (FGFRs), FGFR1 and FGFR2, are elevated in lung samples from PH patients; however, the impact of these receptors on endothelial cell function, and endothelial to smooth muscle interaction is poorly understood.

We hypothesize that activation of endothelial FGFR1 and FGFR2 promotes endothelial cell survival, elaborating signals that protect against pulmonary hypertension via inhibition of smooth muscle cell recruitment.

We used the
Tie2-Cre
transgene to conditionally inactivate
Fgfr1
and
Fgfr2
in endothelial cells. Experimental mice with genotype

Tie2-Cre; Fgfr1
f/f
; Fgfr2
f/f

(DCKO) and control

Fgfr1
f/f
; Fgfr2
f/f

(DFF) were challenged with 10% hypoxia for 2 weeks. At the end, right ventricular pressure (RVp) was measured by cardiac catheterization. Compared to mice in normoxia, control littermates in hypoxia demonstrated significant increases in RVp, and RV to left ventricle + septum (LV+S) weight ratio, consistent with development of PH. DCKO mice demonstrate further elevation in RVp and an increase in the RV to LV+S weight ratio, demonstrating worsening PH. We also observed formation of plexiform lesions in DCKO mice, suggestive of a severe pathology. We found a previously unreported involvement of FGF10 in pulmonary hypertension. FGF10 expression was decreased in hypoxia-challenged DCKO mice as compared to both DCKO littermates on room air, and to hypoxia challenged DFF control mice.

Our data suggests that endothelial FGFR1 and FGFR2 activation may protect against pulmonary hypertension. Further studies are underway to elucidate the role of FGF10 and its mechanism in the pathology. We will also further identify associated FGF ligands, associated signaling mechanisms, and endothelial to smooth muscle interactions.
Abstract 101: Dipeptidylpeptidase-iv Inhibition Using MK626 Attenuates BAPB/AT2 Induced Murine Aneurysm
Authors: Byrne John S , Chen Emily , Husain Mansoor , Ouzounian Maral , Robbins Clint , Lindsay Thomas
Published: July 2021

The dearth of effective treatments to diminish aneurysm progression is a recognized clinical challenge. Modulation of the glucagon-like peptide-1 (GLP-1) pathway is a recent addition to anti-diabetic management regimes, and has pleiotropic effects to inhibit arterial wall macrophage infiltration, a key pathological event in aneurysmal disease. We therefore hypothesized that inhibition of endogenous breakdown of GLP-1, using the dipeptidylpeptidase-IV inhibitor MK626, would attenuate BAPN/AT2 induced murine aneurysm.

Eight-week-old C57/Bl6 mice received two weeks of oral beta-aminopropriononitrile (BAPN) and four weeks of angiotensin-2 (AT2) via mini-osmotic pump. MK626 3mg/kg in methylcellulose vehicle was administered daily and compared to control methylcellulose vehicle. At four weeks, whole aortas were dissected and photomicrographed. Cross sections of aorta were stained using H&E and EVG.

Compared to wild-type, BAPN/AT2 caused dilatation of the aorta from the ascending to the suprarenal segment (p<0.002) with infrarenal sparing (p=0.77). Focal aneurysmal dilatation reproducibly occurred in the suprarenal aorta (wild-type diameter 0.93±0.03mm, n=8; BAPN/AT2 diameter 2.26±0.12, n=8; p<0.0001). Treatment with MK626 attenuated dilatation of the descending aorta compared to controls (BAPN/AT2 control 1.26±0.05mm, n=8; MK626 1.07±0.05mm, n=10; p=0.03). The focal suprarenal aneurysmal dilatation was significantly reduced by treatment with MK626 (BAPN AT2 control 2.26±0.34mm, n=8; MK626 1.66±0.32mm, n=10; p=0.0001). BAPN/AT2 induced aortic aneurysm was associated with excess matrix deposition, increased medial thickness, and elastic fibre fragmentation.

Modulation of the GLP pathway using the dipeptidylpeptidase-IV inhibitor MK626 attenuates aneurysm in a BAPN/AT2 induced murine model.
Abstract 122: Supervised Exercise Therapy for Claudication Modulates Global Profiles of Plasma Lipid Mediators
Authors: Small Aeron , Borokowski Kamil , Ratcliffe Sarah , Englund Erin , Arany Zoltan , Newman John , Floyd Thomas , Mohler Emile , Damrauer Scott
Published: July 2021

Background:
Lipid mediators are complex molecules that demonstrate an association to inflammatory states including atherosclerotic vascular disease. Peripheral artery disease (PAD) is an atherosclerotic disease of the distal aorta and lower extremity arteries. Supervised walking therapy (SWT) is the mainstay of treatment for PAD and is hypothesized to improve claudication by suppressing inflammatory activation.

Objectives:
We sought to examine how lipid mediators were impacted by treadmill testing in PAD, and to identify lipid mediators that were altered by SWT.

Methods:
Plasma samples were collected before and after Gardner treadmill testing (GTT) in individuals with PAD; participants underwent 12 weeks of SWT and were retested. Lipid mediators were isolated using Ostro Sample Preparation Plates (Waters; Milford, MA) and quantified by UPLC-MS/MS.

Results:
Thirty-six participants had complete sets of plasma for analysis. The median age was 67 years (IQR: 62 - 71); there were 55 men (73%) and the median ABI was 0.64 (IQR: 0.55 - 0.76). The median peak walking time prior to SWT was 7.4 min (IQR: 4.8 - 10.3 min), which increased to 11.9 min (IQR: 8.4 - 17.1) after SWT (p < 10
-4
). Discriminant analysis showed clear separation of pre- and post- GTT and pre- and post- SWT samples based on global lipid profiles (Figure 1). Cluster analysis demonstrated 13 distinct clusters of lipid mediators; those clusters containing carbon and arachidonic acid epoxides, and vicinal diols were significantly (FDR <5%) impacted by the interaction between SWT and GTT.

Conclusions:
Lipid mediator profiles manifested unique response patterns to treadmill testing and were modified by supervised walking therapy. These data suggest that lipid mediators play an active role in the biology underlying improvements in lower extremity symptoms associated with SWT and may offer a novel target for therapeutic manipulation.
Abstract 126: Diabetes Influences Circulating FAS in Patients With Carotid Artery Stenosis
Authors: Zayed Mohamed A , Darwish Malik , Naim Uzma , Sanchez Luis A , Semenkovich Clay F
Published: July 2021

Plasma lipid abnormalities associated with diabetes are thought to contribute to atherogenesis and overall cardiovascular morbidity. Fatty Acid Synthase (FAS), an essential multiunit enzyme that catalyzes the synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA, was recently found to circulate in the plasma (pFAS). Since FAS is essential for the lipogenic functions of the liver and adipose tissue, and its tissue expression is altered in the setting of diabetes, we sought to evaluate whether pFAS is a biomarker for arterial occlusive disease in diabetic patients. To test this hypothesis, we compared the activity of pFAS in the fasting serum in a relatively homogenous group of 15 diabetic (DM) and 15 non-diabetic (NDM) patients who are undergoing carotid endarterectomy (CEA). We also evaluated pFAS in 15 additional control patients who have no evidence of arterial occlusive disease. Among selected patients, DM patients were more likely to have hypertension and receive metformin compared to NDM patients (P<0.05). Control patients who have no evidence of arterial occlusive disease were all <60 years old, and none had cardiovascular morbidities. DM patients undergoing CEA demonstrated a 39% increase in pFAS activity compared to NDM patients undergoing CEA (P=0.04), and a 91% increase compared to control patients (P<0.001). Similarly, on Western blot analysis DM patients demonstrated an average 27% increase compared to control patients (P=0.4). pFAS did not correlate with fasting plasma glucose, LDL, HDL, or total cholesterol, but demonstrated a modest correlation with fasting plasma triglycerides (R
2
=0.4, P=0.03). These findings suggest pFAS activity is altered in DM patients with carotid artery stenosis, and correlates with specific plasma lipid profiles suggestive of overall cardiovascular morbidity.
Abstract 141: Inhibition of Coagulation Factor Xa Attenuates Myocardial Ischemia Reperfusion Injury in Mice
Authors: Posma Jens , Posthuma Jelle , Van Oerle Rene , Heitmeier Stefan , Ten Cate Hugo , Spronk Henri
Published: July 2021

Background:
Ischemic/reperfusion (I/R) injury substantially effects the outcome of myocardial infarction (MI). Current reperfusion therapy does not sufficiently prevent injury caused by microvascular thrombo-inflammation. Coagulation proteases mediate inflammation via protease activated receptors. FXa induced thrombin generation is the key step in the coagulation cascade. We
hypothesize
that inhibition of FXa by rivaroxaban attenuates I/R injury after MI.

Methods:
Male WT c57BL/6 mice (age 8-9 weeks, n=8 per group) underwent surgical ligation of the left anterior descending coronary artery 7 days prior to experimentation. Next, the ligature was tightened for 1h to induce ischemia and loosened either at 4h (early), or at 4 weeks (late), to allow reperfusion. The intervention consisted of 2 rivaroxaban (1.6 mg/kg) i.v.-injections or placebo (0.9%NaCl) after 15min of ischemia and 5min of reperfusion. In the early model. the area at risk (AAR) was visualized through Evans blue and differentiated from the area of infarction (AOI) through triphenyl tetrazolium chloride staining. Plasma cardiovascular markers were quantified using Luminex Multiplex. In the late model, LVEF was measured 10min pre-ischemia and 4 weeks’ post-reperfusion utilizing echocardiography.

Results:
The rivaroxaban treatment group showed signs of diminished myocardial damage as indicated by reduced median AOI/AAR (41%[IQR34-48] vs. control 62%[IQR52-67] p<0.001). This was supported by a better preserved LVEF after 4 weeks of reperfusion (25%[IQR19-31] vs. control (16%[IQR12-21]). Although not significantly different, plasma E-Selectin, PECAM-1, PAI-1, proMMP9, and thrombomodulin showed a trend to increased levels upon treatment with rivaroxaban.

Conclusion:
FXa inhibition by rivaroxaban significantly reduces myocardial I/R injury in mice and may provide long term preservation of LVEF. Raised cardiovascular markers suggest increased tissue remodeling and phenotypical alteration of endothelial cells after rivaroxaban treatment. These results suggest that coagulation proteases (i.e. FXa) play a relevant role in I/R injury during MI, most likely through activation of protease activated receptors.
Abstract 142: Biomimetic Recombinant Thrombomodulin Conjugate and Its Anticoagulant Activity
Authors: Wang Lin , Jiang Rui , Sun Xue-Long
Published: July 2021

Thrombomodulin (TM) is an endothelial cell membrane protein that acts as a major cofactor in the protein C (PC) anticoagulant pathway. To closely mimic membrane protein structural feature of TM, we proposed a membrane-mimetic re-expression of recombinant TM onto liposome. The EGF-like domains 4-6 of TM (TM
456
) are essential for PC activation. A recombinant TM containing TM
456
and an azidohomoalanine at C-terminus was expressed in
E. coli
. The biomimetic liposomal recombinant TM conjugate was prepared by conjugation of the recombinant TM
456
-azide with liposome
via
orthogonal chemistry and confirmed with Western blotting and PC activation activity. The liposomal recombinant TM
456
conjugate showed a 2-fold higher PC activation activity than that of the recombinant TM
456
alone
,
which indicated that the lipid membrane has a beneficiary effect on the recombinant TM
456
’s activity. Also, the liposomal recombinant TM
456
conjugate showed higher stability and longer plasma half-life than TM
456
. Moreover, the liposomal recombinant TM
456
conjugate showed
in vivo
anticoagulant activity by decreasing the mortality in a thrombin-induced thromboembolism mouse model. The reported liposomal TM
456
conjugate mimics endothelial TM structure and anticoagulant activity and may serve as an anticoagulant agent candidate for future development.
Abstract 143: Bridging the Gender Gap: Sex Differences in Von Willebrand Factor Aptamer Inhibition Across Species
Authors: Dornbos David L , Wheeler Debra G , Green Jeanne , Venetos Nicholas , Huttinger Allyson , Talentino Spencer , Musgrave Nicholas , Jones Cheyenne , Zweier Jay L , Nimjee Shahid M
Published: July 2021

Introduction:
A gender gap exists in stroke, with increased morbidity and mortality in women. The underlying mechanisms remain unknown, although differences in platelet biology may play a role. Inhibition of the interaction between VWF and GP 1B-IX-V has demonstrated thrombolytic efficacy.

Hypothesis:
We hypothesized that sex differences in reperfusion after stroke were attributable to the VWF-GP IB-IX-V axis, and inhibition of this interaction would yield clear discrepancies.

Methods:
Adult wild-type (C57BL/6J) mice were anesthetized, the right carotid artery exposed and baseline carotid flow obtained by Doppler. Thrombosis was induced with a FeCl
3
patch. After 20-minute stabilization, mice were intravenously administered vehicle (n, male=12, female=8) or VWF aptamer. Aptamer (0.5 mg/kg) administration was assessed using a bolus (5 min; n, male=5, female=8) method. Given the minimal observed thrombolytic effect in females, a continuous infusion (45 min; n, female=5) was also attempted.

Next, blood from male (n=8) and female (n=8) adult wild-type beagles was mixed with VWF aptamer (control, 6.25 nM, 12.5 nM, 25 nM, and 100 nM), and platelet reactivity was assessed (Platelet Function Analyser-100). Statistical analysis was performed using a two-way ANOVA with multiple comparisons.

Results:
Bolus VWF aptamer restored carotid blood flow in male mice (Figure 1), compared to females (p<0.001) and vehicle (p<0.01). With continuous infusion, reperfusion in female mice was significantly higher than vehicle (p<0.01).

Male canines (264.3 ± 70.3 s) demonstrated significantly more platelet inhibition (p<0.01) than females (175.3 ± 83.2 s) at the 12.5 nM VWF aptamer concentration.

Conclusions:
Following VWF inhibition,
in vivo
thrombolytic efficacy in mice is gender dependent, while
ex vivo
platelet activity varies in canines. The mechanisms underlying these differences in platelet biology are unclear, but this indicates that the VWF-GP IB-IX-V axis plays a role.
Abstract 168: Role of Beta-Carotene Conversion to Vitamin a in Atherosclerosis
Authors: Amengual Jaume , Zhou Felix , Barrett Tessa J , von Lintig Johannes , Fisher Edward A
Published: July 2021

Beta-carotene (BC) is the natural precursor of vitamin A, a potent gene regulator involved in cellular homeostasis and immune system. Vitamin A is formed by the action of the enzyme BC oxygenase 1 (BCO1), which is mostly expressed in the intestine and the liver. Whereas ingested BC is present in large amounts in human plasma and tissues, wild-type mice do not accumulate BC in significant amounts. To study the role of circulating BC and its conversion to vitamin A in atherosclerosis, we crossed

Ldlr
-/-

mice with

Bco1
-/-

mice. When compared to

Ldlr
-/-

mice,

Ldlr
-/-

/

Bco1
-/-

mice fed a Western Diet containing BC (WD-BC) accumulate large amounts of BC in plasma, liver, and in atherosclerotic lesions. To study the role of BCO1 in the conversion BC to vitamin A in myeloid cells, as well as in plaque macrophages, we performed bone marrow transplant experiments (BMTs) using wild-type or

Bco1
-/-

mice as a donor, and

Ldlr
-/-

/

Bco1
-/-

as a recipient mice. After BMTs, recipient mice were fed WD-BC for 16 weeks. Gene expression analyses on circulating monocytes and T-cells of mice receiving

Bco1
-/-

myeloid cells showed a pro-inflammatory phenotype in comparison to those that received wild-type cells (monocytes; IL-1β ˜ 1.5 fold increase, T-cells; FoxP3 ˜ 1 fold decrease). Overall, these results indicate that BCO1 regulates the inflammatory status of myeloid cells through the conversion of circulating BC to vitamin A.
Abstract 170: Glucose Oxidation by Pyruvate Dehydrogenase Ameliorates Cradiomyocytes Contractility in Response to Hypoxic Stress
Authors: Chu Dongyang , Rousselle Thomas , Cates Courtney , Li Ji
Published: July 2021

Introduction:
Pyruvate dehydrogenase (PDH) plays a key role in aerobic energy metabolism and occupies a central crossroad between glycolysis and the tricarboxylic acid cycle. Dichloroacetate (DCA), a PDH activator, has been revealed to increase glucose oxidation and reduce myocardial infarct size during ischemia and reperfusion.

Hypothesis:
Cardiac PDH activation plays a critical role in modulation of cardiomyocytes contractility and calcium signaling in response to hypoxia.

Methods:
Mechanical properties and intracellular Ca
2+
homeostasis were measured in isolated cardiomyocytes by IonOptix system. The stress signaling was evaluated using immunoblotting and immunoprecipitation analysis.

Results:
PDH activator DCA treatment significantly protects cardiomyocytes from hypoxia-induced contractile dysfunction as measured by maximal velocity of shortening (+dL/dt) and relengthening (–dL/dt), peak height and peak shortening (PS) amplitude, time-to-90% relengthening (TR90) in cardiomyocytes. However, DCA treatment did not show any protective effects on contractile functions of isolated cardiomyocytes from the cardiomyocyte specific PDH KO mouse hearts under hypoxic conditions. Intriguingly, the rise of intracellular Ca
2+
levels and intracellular ATP levels have no significant difference among wild type (WT) and PDH KO cardiomyocytes with and without DCA treatment. The results demonstrated that cardiomyocyte PDH KO does not affect cardiomyocyte contractility under normal physiological conditions, but significantly impaired the contractile functions of isolated cardiomyocytes under hypoxic conditions. Furthermore, the immunoblotting results showed that hypoxia triggered phosphorylation of AMP-activated protein kinase (AMPK) in isolated cardiomyocytes, but the AMPK phosphorylation was significantly impaired in PDH KO cardiomyocytes. DCA treatment clearly augmented ischemic AMPK phosphorylation in the isolated wild type (WT) but not in PDH KO cardiomyocytes.

Conclusions:
The glucose oxidation by pyruvate dehydrogenase (PDH) plays a critical role in cardiomyocyte contractility in response to hypoxic stress. PDH agonist DCA could be used for improve contractile function of cardiomyocytes under hypoxic insults.