bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcutaneous Carbon Dioxide Decreases Immunosuppressive Factors in Squamous Cell Carcinoma In Vivo
Authors: Yatagai Nanae , Hasegawa Takumi , Amano Rika , Saito Izumi , Arimoto Satomi , Takeda Daisuke , Kakei Yasumasa , Akashi Masaya
Published: July 2021

Introduction. In recent years, the tumour immunosuppressive mechanism has attracted attention as a cause of tumour chemoresistance. Although chemoresistance and immunosuppression of tumours have been reported to be associated with a hypoxic environment, effective treatments to improve hypoxia in tumours have not yet been established. We have previously applied carbon dioxide (CO2) to squamous cell carcinoma and have shown that improvement in local oxygenation has an antitumour effect. However, the effects of local CO2 administration on tumour immunosuppression, chemoresistance, and combination with chemotherapy are unknown. In this study, we investigated the effects of local CO2 administration on squamous cell carcinoma and the effects of combined use with chemotherapy, focusing on the effects on tumour immunosuppressive factors. Methods. Human oral squamous cell carcinoma (HSC‐3) was transplanted subcutaneously into the back of a nude mouse, and CO2 and cisplatin were administered. After administration twice a week for a total of 4 times, tumours were collected and the expression of tumour immunosuppressive factors (PD‐L1, PD‐L2, and galectin‐9) was evaluated using real‐time polymerase chain reaction and immunostaining. Results. Compared with the control group, a significant decrease in the mRNA expression of PD‐L1 was observed in both, CO2‐treated and combination groups. Similarly, the expression of PD‐L2 and galectin‐9 decreased in the CO2‐treated and combination groups. Furthermore, immunostaining also showed a significant decrease in the protein expression of tumour immunosuppressive factors in the CO2‐treated and combination groups. Conclusion. It was confirmed that the tumour immunosuppressive factors decreased due to local CO2 administration to the mouse model. CO2 administration has the potential to improve the hypoxic environment in tumours, and combined use with chemotherapy may also improve tumour immunosuppression.
Management of Airways through Rapid Tracheostomy in a Severely Burnt Patient Attended to via Helicopter
Authors: Filippelli Orazio Stefano Giovanni , Giglio Anna Maria , Tiburzi Simona Paola , Archinà Maria Teresa , Barozzi Ercole , Maglio Pietro , Candido Stefano , Viotti Roberta , Riccelli Umberto , Pezzi Mario , Romano Carmelo , Scozzafava Anna Maria , Guzzo Maria Laura
Published: July 2021

In Catanzaro, Italy, an adult male with severe burns all over his body and in a state of coma was promptly rescued by the medical team at the air ambulance service (HEMS), who provided airway safety through laryngeal mask placement (LMA). The patient was subsequently transferred to the nearest Hub center, where an emergency tracheostomy was performed to ensure better airway management during the flight to the nearest available major burn center. This is the first documented case at regional level of a patient undergoing rapid tracheostomy through an imminent transfer with air ambulance.
Angiosarcoma of the Face: A Case Study and Literature Review of Local and Metastatic Angiosarcoma
Authors: Lara-Martinez Hugo , Weinberg Molly , Baratam Praneeth , Horn Jeffrey , Ward Kristine , Styler Michael
Published: July 2021

Angiosarcomas are vascular malignancies with a tendency to spread extensively both locally and systemically. We report a case of cutaneous angiosarcoma of the face in a 53-year-old man that was originally misdiagnosed as an abscess. Initially small, the lesion enlarged over a four-to-six-month period and began to bleed. Two shave biopsies were performed that returned a diagnosis of angiosarcoma. The patient underwent radical resection and lymph node dissection, which revealed positive margins and ten of forty-six positive lymph nodes. The patient was treated with paclitaxel and concurrent radiation therapy (RT). Restaging scans showed a new sclerotic lesion of the T10 vertebra, three hepatic lesions, and an adrenal lesion, all concerning for metastasis. Biopsy of one of the hepatic lesions was consistent with metastatic angiosarcoma. In this review, we discuss the presentation of cutaneous angiosarcoma, the importance of early diagnosis, and the treatment options available for metastatic disease that has failed first-line chemotherapy.
The Principle of Intelligent Switch Composition and Algorithm of the Built-In Electronic Voltage Transformer
Authors: Cao Xinhui , Dong Yuting , Li Zhongzheng , Li Juan , Liang Gang , Zhou Honglian
Published: July 2021

With the rapid development of the social economy, people’s demand for energy is increasing. Global warming has made people pay more attention to the importance of energy saving and emission reduction. The power grid is the system responsible for the transmission and distribution of electric energy. Therefore, in the context of energy saving and emission reduction, there are higher requirements for substations in the power grid. For this reason, an intelligent switch with built-in electronic voltage transformer is designed. The concept and key technical characteristics of the electronic voltage transformer intelligent switch are introduced; the overall design scheme of the built-in electronic voltage transformer intelligent switch is expounded; the hardware and software system of the device is designed; the management and control strategy of the design device is such as transformer tangent control, voltage and reactive control; and the operating system is ported. Finally, the simulation test of the system proves that the system has high effectiveness and stability. The research can provide reference for the realization of efficient, economic, stable, safe, and environmentally friendly distribution of power in a power grid.
Nivolumab and Ipilimumab Combination Immunotherapy for Patients with Metastatic Collecting Duct Carcinoma
Authors: Danno Tetsuya , Iwata Shohei , Niimi Fusako , Honda Sachi , Okada Haruka , Azuma Takeshi
Published: July 2021

Collecting duct carcinoma (CDC) is a rare, extremely aggressive form of renal cancer. Recently, immune checkpoint inhibitors (ICI), anti-programmed death-1 (PD-1) antibody, and anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody were approved for use against metastatic renal cell carcinoma. We herein described two cases of metastatic renal collecting duct carcinoma treated with a combination immunotherapy consisting of nivolumab and ipilimumab. In the first case, which included a bone metastasis, the best response achieved was stable disease (SD) for one year. In the second case, which was accompanied by a lung metastasis, the best response achieved was a partial response. The outcome of these cases suggested that the combination of nivolumab and ipilimumab is effective against renal collecting duct carcinoma.
Role of PI3K/AKT Signaling Pathway in Nucleus Pulposus Cells
Authors: Xiao Quan , Teng Yun , Xu Changming , Pan Wei , Yang Hanshi , Zhao Jiali , Zhou Quan
Published: July 2021

Objective. To investigate the role of PI3K/AKT signaling pathway in nucleus pulposus (NP) cells. Methods. Nucleus pulposus (NP) cells were isolated from SD rat, and thereafter, passage three (P3) NP cells were divided into the following experimental groups: control, PI3K/AKT agonist IGF‐1 (25 ng/ml, 50 ng/ml, and 100 ng/ml), and PI3K/AKT inhibitor LY294002 (5 μM, 10 μM, and 20 μM). Flow cytometry and BrdU cell proliferation assays were performed to assess apoptosis and the proliferation rate of NP cells. Western blot analysis was performed to examine the protein expression level of Col II, Col X, Aggrecan, and MMP13. Results. PI3K/AKT inhibitor LY294002 increased the rate of apoptosis in NP cells when compared to the control and decreased the proliferation rate when compared to control. Moreover, LY294002 decreased the protein expression level of Col‐II and Aggrecan in NP cells. At the same time, LY294002 increased the protein expression level of MMP13 and Col‐X in NP cells. Through activating PI3K/AKT, IGF‐1 increased the proliferation rate when compared to control and decreased the rate of apoptosis when compared to control. Additionally, IGF‐1 decreased the protein expression level of MMP13 and Col‐X and increased Col‐II and Aggrecan in NP cells. Conclusion. The inhibition of PI3K/AKT signaling pathway accelerated the apoptosis of NP cells and facilitated the extracellular matrix degradation. However, the activation of PI3K/AKT pathway partly prevented the NP cell from apoptosis and promoted their proliferation. Meanwhile, its activation also delayed the loss of extracellular matrix.
Memory Augmented Neural Network-Based Intelligent Adaptive Fault Tolerant Control for a Class of Launch Vehicles Using Second-Order Disturbance Observer
Authors: Chen Haipeng , Chen Kang , Fu Wenxing
Published: July 2021

This paper focuses on the MANN-based intelligent adaptive fault tolerant control for a class of launch vehicles. Firstly, the attitude dynamic model of the launch vehicles suffering from the actuator faults and disturbances has been formulated. Secondly, the second-order disturbance observer has been designed for the launch vehicle to achieve the exact estimation and compensation of the time-varying disturbances. Meanwhile, the MANN has been introduced as online approximator, suppressing the adverse influence of the unknown nonlinearities. Moreover, several adaptive laws have been proposed to achieve the quick response to the actuator faults and the update of the MANN weights. As a result, the MANN-based intelligent adaptive fault tolerant control structure has been constructed for the launch vehicles. It has been proven that all the signals in the closed-loop system are bounded. Simulation results demonstrate the desired performance and the advantages of the proposed control algorithm.
TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
Authors: Maifrede Silvia , Le Bac Viet , Nieborowska-Skorska Margaret , Golovine Konstantin , Sullivan-Reed Katherine , Dunuwille Wangisa M.B. , Nacson Joseph , Hulse Michael , Keith Kelsey , Madzo Jozef , Caruso Lisa Beatrice , Gazze Zachary , Lian Zhaorui , Padella Antonella , Chitrala Kumaraswamy N. , Bartholdy Boris A. , Matlawska-Wasowska Ksenia , Di Marcantonio Daniela , Simonetti Giorgia , Greiner Georg , Sykes Stephen M. , Valent Peter , Paietta Elisabeth M. , Tallman Martin S. , Fernandez Hugo F. , Litzow Mark R. , Minden Mark D. , Huang Jian , Martinelli Giovanni , Vassiliou George S. , Tempera Italo , Piwocka Katarzyna , Johnson Neil , Challen Grant A. , Skorski Tomasz
Published: July 2021

Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.

Significance:

TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors.
Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations
Authors: Cheruiyot Abigael , Li Shan , Nonavinkere Srivatsan Sridhar , Ahmed Tanzir , Chen Yuhao , Lemacon Delphine S. , Li Ying , Yang Zheng , Wadugu Brian A. , Warner Wayne A. , Pruett-Miller Shondra M. , Obeng Esther A. , Link Daniel C. , He Dalin , Xiao Fei , Wang Xiaowei , Bailis Julie M. , Walter Matthew J. , You Zhongsheng
Published: July 2021

Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation, however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1, which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared with wild-type (WT) cells, SF3B1- and U2AF1-mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations.

Significance:

This study has developed a novel NMD reporter system and identified a potential therapeutic approach of targeting the NMD pathway to treat cancer with spliceosome gene mutations.
Development of a Novel Mouse Model of Spontaneous High-Risk HPVE6/E7–Expressing Carcinoma in the Cervicovaginal Tract
Authors: Henkle Talia R. , Lam Brandon , Kung Yu Jui , Lin John , Tseng Ssu-Hsueh , Ferrall Louise , Xing Deyin , Hung Chien-Fu , Wu T.-C.
Published: July 2021

Current preclinical models for cervical cancer lack important clinical and pathologic features. To improve upon these models, we aimed to develop a novel, spontaneous HPV16-expressing carcinoma model that captures major aspects of HPV-associated cancer in the female genital tract. This novel preclinical model features (i) expression of HPV oncogenes E6 and E7 in the tumors in female reproductive tract of mice, (ii) spontaneous progression through high-grade squamous intraepithelial lesion (HSIL) to carcinoma, and (iii) flexibility to model cancers from different high-risk HPV genotypes. This was accomplished by injecting plasmids expressing HPV16 E6/E7-luciferase, AKT, c-myc, and Sleeping Beauty transposase into the cervicovaginal tract of C57BL/6 mice followed by electroporation. Cell lines derived from these tumors expressed HPV16 E6/E7 oncogenes, formed tumors in immunocompetent mice, and displayed carcinoma morphology. In all, this novel HPV-associated cervicogenital carcinoma model and HPV16E6/E7–expressing tumor cell line improves upon current HPV16-E6/E7–expressing tumor models. These tumor models may serve as important preclinical models for the development of therapeutic HPV vaccines or novel therapeutic interventions against HPV E6/E7–expressing tumors.

Significance:

This study describes the development of a clinically relevant mouse model of cervicovaginal carcinoma that progresses from high-grade lesions and recapitulates key features of human HPV+ cervical cancer.
Insulin-Like Growth Factor 1 in the Preterm Rabbit Pup: Characterization of Cerebrovascular Maturation following Administration of Recombinant Human Insulin-Like Growth Factor 1/Insulin-Like Growth Factor 1-Binding Protein 3
Authors: Gram Magnus , Ekström Claes , Holmqvist Bo , Carey Galen , Wang Xiaoyang , Vallius Suvi , Hellström William , Ortenlöf Niklas , Agyemang Alex Adusei , Smith Lois E.H. , Hellström Ann , Mangili Alexandra , Barton Norman , Ley David
Published: July 2021

Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.
Intrauterine Low-Protein Diet Exacerbates Abnormal Development of the Urinary System in Gen1-Mutant Mice
Authors: Yu Minghui , Li Yaxin , Tan Lihong , Chen Jing , Zhai Yihui , Rao Jia , Fang Xiaoyan , Liu Jialu , Liu Jiaojia , Wu Xiaohui , Xu Hong , Shen Qian
Published: July 2021

Background: Gen1 mutation can cause various phenotypes of congenital anomaly of the kidney and urinary tract (CAKUT). An intrauterine low-protein isocaloric diet can also cause CAKUT phenotypes in offspring. However, single factors such as gene mutation or abnormal environmental factor during pregnancy can only explain part of the pathogenesis of CAKUT. Objectives: A low-protein isocaloric diet was fed to Gen1-mutant mice throughout pregnancy to establish a Gen1-mutant mouse model exposed to a low-protein isocaloric intrauterine environment. The mice were divided into 4 groups: normal (22%) protein diet (ND) + wild-type mice (CON group), ND + Gen1PB/+ mice (Gen1PB/+ group), low (6%)-protein isocaloric diet (LD) + wild-type mice (LD group), and the LD + Gen1PB/+ groups. Methods: The experimental design included observing proportion and distribution of CAKUT phenotypes of neonatal mice; evaluating the number of ureteric buds (UBs) on embryonic day (E) 11.5, the location of UBs on E11.5, and length of the common nephric duct (CND); isolating embryonic kidneys on E11.5 from the Gen1PB/+ group and culturing embryonic kidneys in medium containing 10% serum or serum-free medium to observe the branching of UBs; and detecting the p-PLCγ, p-Akt, and p-ERK1/2 in UBs and CND on E11.5, as well as the apoptosis and proliferation of tissues by immunofluorescence staining. Results: We found that the incidence of CAKUT in offspring of Gen1PB/+ mice under an intrauterine low-protein isocaloric diet environment was significantly increased, and a duplicated collecting system was the dominant phenotype of CAKUT. During the early stage of metanephric development, ectopic protrusion of UBs may appear and lower locations of UBs in Gen1PB/+ mice under an intrauterine low-protein isocaloric diet environment and the number of UB branches in the serum-free culture condition significantly decreased. Further examination revealed that p-PLCγ signaling and tissue apoptosis were abnormal in UBs and the CND at the early stage of kidney development. Conclusions: The aforementioned findings suggest that an intrauterine low-protein isocaloric diet can aggravate the occurrence of CAKUT in Gen1-mutant mice, which might affect key steps in the metanephric development, such as the protrusion of UBs, which might be related to mediate UBs and CND apoptosis through p-PLCγ signaling.
Does Profound Hypothermic Circulatory Arrest Improve Survival in Patients With Acute Type A Aortic Dissection?
Authors: Lai David T. , Robbins Robert C. , Mitchell R. Scott , Moore Kathleen A. , Oyer Philip E. , Shumway Norman E. , Reitz Bruce A. , Miller D. Craig
Published: July 2021

Objective

No evidence exists that profound hypothermic circulatory arrest (PHCA) improves survival or reduces the likelihood of distal aortic reoperation in patients with acute type A aortic dissection.

Methods

Records of 307 patients with acute type A aortic dissection from 1967 to 1999 were retrospectively reviewed. The influence of repair using PHCA (n=121) versus without PHCA (n=186) on death and freedom from distal aortic reoperation was analyzed using multivariable Cox regression models. Propensity score analysis identified a subset of 152 comparable patients in 3 quintiles (QIII–V) in which the effects of PHCA (n=113) versus no PHCA (n=39) were further compared.

Results

For all patients, 30-day, 1-year, and 5-year survival estimates were 81±2%, 74±3%, and 63±3% (±1 SE). Survival rates and actual freedom from distal aortic reoperation was not significantly different between treatment methods in the entire patient cohort nor in the matched patients in quintiles III–V. Treatment method was not associated with differences in early major complications, late survival, or distal aortic reoperation rates in the entire patient sample or in quintiles III–V.

Conclusions

Aortic repair with or without circulatory arrest was associated with comparable early complications, survival, and distal aortic reoperation rates in patients with acute type A aortic dissection. Despite the lack of concrete evidence favoring the use of PHCA, it does no harm, and most of our group uses PHCA regularly because of its practical technical advantages and theoretical potential merit.
Abstract 1319: Plasma Levels of Fatty Acid Binding Proteins 4 and 5 are Markers of Adiposity and the Metabolic Syndrome but are not Independent Predictors of Subclinical Atherosclerosis in Type 2 Diabetes
Authors: Bagheri Roshanak , Lehrke Michael , Kapoor Shiv , Wolfe Megan , Terembula Karen , Barou Daniella , Iqbal Nayyar , Rader Daniel , Reilly Muredach P
Published: July 2021

Objectives:
Adipocyte-fatty acid binding protein (aP2) or FABP4 is expressed predominantly in adipose and macrophages. Its less abundant family member, FABP5 (Mal1), is more diffusely expressed but also found in adipocytes and macrophages. Gene deletion studies in rodents suggest that FABP4, to a greater extent than FABP5, modulates obesity and atherosclerosis. Preliminary clinical studies support a relationship of circulating FABP4 with obesity and the metabolic syndrome (MetSyn). However, there are no studies of circulating FABPs and atherosclerosis in humans.

Methods:
We evaluated the association of FABP4 and 5 (ELISA, Biovender) with cardiovascular risk factors, NCEP-defined MetSyn and Coronary Artery Calcification (CAC) in 846 asymptomatic, type 2 DM subjects (62.5% Caucasian, 32.5% African-American; 60% male; aged 58.6±9.2) recruited to the Penn Diabetes Heart Study.

Findings
: Levels [(median (IQ range)] of FABP4 [37.1 (23.0–55.2) vs 20.9 (14.0–31.0) ng/mL; p<0.001] and FABP5 [1.5 (1.2–1.9) vs 1.4 (1.1–1.8) ng/mL; p<0.01] were higher in women than men. FABP4 was significantly correlated with waist circumference (r=0.4, p<0.001), levels of leptin (r=0.5, p<0.001), insulin (r=0.21, p<0.001), hsCRP (r=0.23, p<0.001), triglycerides (r=0.25, p<0.001) and inversely with HDL cholesterol (women r=−0.23, p<0.001; men r=−0.11, p<0.05). Plasma FABP5 had similar, but weaker biomarker correlations. Both were strongly associated with MetSyn (FABP4 χ
2
=29.8, p<0.0001; FABP5 χ
2
=36.2, p<0.0001). Notably, FABP4 [22.7 (15.0–35.9) vs 34.4 (22.9–55.0), p<0.001], but not FABP5 (p<0.89), levels were lower in subjects on thiazolidinedione therapy. In tobit regression, FABP4, but not FABP5, levels above the median were associated with CAC scores after adjustment for age, gender and ethnicity [1.68 (1.05–2.66), Ratio (CI), p<0.03] but this was attenuated after further adjusting for BMI and established risk factors [1.52 (0.49–2.48), Ratio (CI), p<0.09].

Conclusion:
Both FABP 4 and 5 are biomarkers of adiposity and MetSyn. In the first study of its kind, plasma FABP4, but not FABP5, was associated with CAC in type 2 DM, but neither were independent predictors of this subclinical atherosclerosis measure.
Abstract 3493: Epidemiology and Genetic Cause of Sudden Unexplained Nocturnal Death Syndrome in Southern China
Authors: Cheng Jian-Ding , Shi Nian-Qing , Makielski Jonathan , Ye Bin
Published: July 2021

Sudden unexplained nocturnal death syndrome (SUNDS) is a sleep disorder that leads to sudden cardiac death in Southeast Asian ethnic groups such as Thai, Japanese, Philippine and Cambodian. SUNDS mainly occurs during sleep in young healthy males without sign of cardiac dysfunction. The lack of epidemiologic data is always being a formidable bottleneck for studying SUNDS around the world. Although the annual occurrence rate of SUNDs is high (over 2/100,000) for the aged 20 to 40 years males in Southern China, the disease epidemiology in regions of China may be underestimated in the absence of systemic monitoring. Autopsy data collected in Guangdong Province (a Southern China province) from 2001–2006 reported 975 cases of SUNDS. Among the victims, 93.2% were males while 6.8% were females. In 772 cases with complete medical records, 86.3% deaths occurred between ages 16 to 40. The peak months for SUNDS occurrence were April (111 cases), May (112 cases) and June (80 cases), which corresponded to highest numbers of fever patients in this period indicating that fever may play a role in SUNDS. In 75.4% cases where witnesses were present, victims died in sleep between 11 PM to 4 AM and showed signs that matched reported cases in other Southeast Asian populations. Other collected data included birthplace and profession and details of events at death. The genetic cause of Chinese SUNDS is being investigated more recently. Mutations in the voltage-gated sodium channel (
SCN5A
) have been linked to SUNDS. We traced four generations in two families with SUNDS history and in each case, diseased male victims in the second and third generations at the age of 17–38 were found. Surviving relatives did not show any significant cardiac structural defects but their ECGs displayed an abnormal Q wave or sinus bradycardia in male siblings who approached age 30. Mutation screening in the
SCN5A
gene using specimen obtained from diseased victims and survived relatives was undertaken to identify SUNDS-related mutations in these two families. This is the first report of SUNDS epidemiology and its impact in the Han population of Southern China.
Abstract 1680: Notch Signaling Directly Targets Msx2: Possible Role of Notch Signaling in Osteogenic Conversion of Vascular Smooth Muscle Cells and Vascular Calcification
Authors: Shimizu Takehisa , Tanaka Toru , Iso Tatsuya , Kurabayashi Masahiko
Published: July 2021

Vascular calcification is a prominent feature of atherosclerosis and closely correlated with cardiovascular morbidity and mortality. In this study, we hypothesize that Notch signaling plays an important role in osteogenic conversion of smooth muscle cells (SMCs) and vascular calcification.

 Either Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) induced expression of Msx2, a key regulator of osteogenic conversion, in human aortic SMCs (HASMCs). In addition, overexpression of Notch1 intracellular domain (N1-ICD) markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2, but not Runx2/Cbfa1, another key osteogenic transcription factor, is responsible for Notch1-induced osteogenic conversion of HASMCs. Furthermore, this Notch1-Msx2 pathway was independent of bone morphogenetic protein-2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by Notch ligands stimulation, whereas it was abrogated by a specific Notch signaling inhibitor. The RBP-Jk binding element within the Msx2 promoter was critical to Notch1-induced Msx2 gene expression, and correspondingly, neither N1-ICD overexpression nor Notch ligands stimulation increase the Msx2 expression or transcriptional activity of the Msx2 promoter, respectively, in RBP-Jk-deficient fibroblasts. Immunohistochemistry of human artery specimens revealed colocalization of Notch1 and Msx2 within atherosclerotic plaques, indicating a role of Notch1-Msx2 pathway in vascular calcification in vivo. These results suggest that Notch signaling directly targets Msx2, thus accelerating osteogenic conversion of HASMCs and, as a result, a formation of vascular calcification.
Abstract 4855: Influence of Left Ventricular End Diastolic Diameter Index on Clinical Outcomes with Cardiac Resynchronization: Insights from the COMPANION Study
Authors: De Marco Teresa , Lee Byron , Lindenfeld JoAnn , Saxon Leslie A , Boehmer John , Turakhia Mintu , Leigh Jill , Yong Patrick , Curran Colleen , Feldman Arthur M , Bristow Michael R
Published: July 2021

Background:
Although cardiac resynchronization therapy (CRT) has been shown to slow the progression of heart failure (HF), it has not been well described whether the baseline severity of ventricular remodeling influences clinical outcomes.

Methods:
The COMPANION study database was analyzed retrospectively. This study randomized patients (pts) with NYHA Class III/IV HF, wide QRS, and systolic dysfunction to optimal pharmacologic therapy (OPT) alone or to OPT plus CRT either with (CRT-D) or without a defibrillator (CRT-P). For this analysis both CRT arms were combined. Ventricular remodeling was measured as left ventricular end diastolic dimension indexed by body surface area (LVEDDI). Data were stratified around the median value: LVEDDI≥ 35 mm/m
2
and < 35 mm/m
2
. CRT was compared to OPT for each cohort using functional outcomes at six months [exercise capacity, quality of life, functional status, and the Clinical Composite Endpoint] as well as event-driven outcomes [all-cause mortality alone and in combination with cause-specific hospitalization].

Results:
Baseline LVEDDI data were available for 1260 pts. Pts in the larger LVEDDI cohort were characterized at baseline with wider QRS, lower EF, and a greater proportion of non-ischemic, female, and NYHA Class IV. Clinical outcomes are summarized below:

Conclusion:
In the COMPANION study, both cohorts demonstrated significant benefit in functional outcomes with CRT when compared to OPT. However, significant improvement in event-driven outcomes were seen only in the population with larger baseline LVEDDI. A prospective study is needed to confirm that LVEDDI can predict potential for improvement with CRT.
Abstract 15182: Calibration and Feedback of Speckle Strain Measurement Improves Segmental Strain Concordance
Authors: Negishi Tomoko , Negishi Kazuaki , Hristova Krassimira , Kurosawa Koji , Yuda Satoshi , Popescu Bogdan A , Vinereanu Dragos , Thavendiranathan Paaladinesh , Penicka Martin , Bansal Manish , Fukuda Nobuaki , Cho Goo-Yeong , Seldrum Stéphanie , Marwick Thomas H ,   Strain sUrveillance during Chemotherapy for improving Cardiovascular Outcomes (SUCCOUR study)
Published: July 2021

Purpose:
Inter-institutional agreement of imaging measurements is important in shared clinical management and in trials. 2D strain is sensitive to changes in LV function, automated and may be less variable than ejection fraction (EF), which is used widely but has inherent variability. We sought whether strain would have better concordance between different centers and that feedback from a calibration exercise would reduce the variability among institutions.

Methods:
108 global longitudinal strain (GLS) measurements, calculated from 1944 segmental strains, were performed blindly by 21 experienced readers from 12 different institutes (5 Europe, 5 Asia, 1 North America and 1 Australia) in 6 cases. Intraclass correlation coefficients (ICCs) were used to determine concordance. All individual measurements were reviewed and some key points were identified to optimize strain measurement. After feedback, strain was remeasured and improvement of agreement sought using coefficient variance (CV) and mean difference (MD) from the reference standard.

Results:
GLS was -17.9±3.3%, while EF was 60±7%. The ICC in GLS (0.994 [95%CI 0.983, 0.999]) was better than that of 2DEF (0.928 [0.809, 0.988], p<0.001) at baseline. Two main sources of discordance in GLS measurements were the width and location of regions of interest, especially at mitral annulus and apex. After feedback, re-measurement showed the CV (p=0.02) and MD (p=0.03) of segmental strain improved, but comparison of 2nd vs 1st GLS showed no changes of ICC (p=0.85), CV (p=0.80) or MD (p=0.92).

Conclusions:
Feedback significantly decreased segmental strain variability, but did not improve the concordance in GLS, which had better precision than EF at baseline.
Abstract 001: Effects of Intensive Blood Pressure Control in Adults With and Without Albuminuria: Results From the SPRINT Trial
Authors: Chang Alex
Published: July 2021

Background:
Albuminuria is strongly associated with elevated risk of cardiovascular disease (CVD). While the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure (BP) lowering reduces CVD in high-risk non-diabetic adults, it is unclear whether this effect varies by albuminuria status.

Methods:
SPRINT randomized non-diabetic adults with elevated blood pressure and increased CVD risk to a systolic BP (SBP) goal of <120 or <140 mmHg. Albuminuria (>=30 mg/g) was measured by albumin/creatinine ratio (ACR) at baseline. Outcomes examined included the primary composite CVD outcome (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from CVD) and all-cause death.

Results:
A total of 8913/9361 (95.2%) participants had baseline ACR data; 51.9%, 28.7%, and 19.4% had baseline ACR < 10, 10-29.9, and >=30 mg/g, respectively. The primary composite outcome occurred in 4.0%, 6.7%, and 11.2% of individuals with baseline ACR <10, 10-29.9, and >=30 mg/g, respectively. The effect of intensive BP lowering on the primary outcome was similar in patients with albuminuria (HR 0.74, 95% CI: 0.55-0.99) and without albuminuria (HR 0.73, 95% CI: 0.59-0.91; p for interaction = 0.77). Intensive BP lowering reduced risk of stroke in patients with albuminuria (HR 0.45, 95% CI: 0.24-0.85) but not patients without albuminuria (1.13, 95% CI: 0.73-1.74; p for interaction = 0.03). Absolute risk reduction was particularly high in those with albuminuria, with a number needed to treat (NNT) of 32 to prevent 1 primary outcome and a NNT of 37 to prevent 1 death from any cause at 3 years of follow-up. By comparison, the NNT to prevent 1 primary outcome was 72 for ACR < 30 mg/g at 3 years of follow-up.

Conclusions:
The effect of Intensive BP lowering reduces CVD risk similarly in non-diabetic adults with and without albuminuria. Given the high CVD risk in patients with albuminuria, this high-risk population may particularly benefit from efforts to intensify BP control.
Abstract 019: Cost-effectiveness of the FDA Sodium Reduction Targets for the Processed Food Industry: Are There Internal Incentives to Reformulate?
Authors: Collins Brendan , Kypridemos Chris , Pearson-Stuttard Jonathan , Huang Yue , Bandosz Piotr , Wilde Parke , Kersh Rogan , Capewell Simon , Mozzafarian Dariush , Whitsel Laurie , Micha Renata , O'Flaherty Martin
Published: July 2021

Introduction:
In 2016, the US Food & Drug Administration (FDA) proposed voluntary industry reductions in sodium, a major modifiable risk factor for CVD, for processed foods. Yet, reformulation could cost the food industry up to $16bn over 10 years, perhaps partly explaining why in 2017 Congress blocked the FDA from implementing these long-term voluntary targets.

Aim:
To estimate the potential health gains and health-related cost savings for food industry employees from the FDA sodium targets. We defined the industry perspective as including all costs to the food industry and all health-related costs and health benefits to people working in the industry.

Methods:
Utilizing the validated US IMPACT Food Policy dynamic microsimulation model, we estimated QALYs gained, costs, and incremental cost effectiveness ratios (incremental cumulative cost per QALY gained, with costs and QALYs discounted at 3%) from 2017-2036 in individuals working in the wider food system (food services and drinking places; food and beverage stores; food manufacturing) and the subset of food manufacturing. Data sources included NHANES, matched to demographic data for workers from the American Community Survey, and meta-analyses of sodium effects on blood pressure and blood pressure on CVD. Costs included industry reformulation costs, government costs, and health-related costs (healthcare, productivity, informal care) for individuals working in the industry. We modelled the FDA sodium targets under 2 scenarios: a) Short-term, 100% compliance of 2-year reformulation targets with no further progress. b) Long-term, 100% compliance of 10-year reformulation targets We tested our assumptions with probabilistic sensitivity analysis.

Results:
Achieving the short-term, 2-year reformulation targets would generate net discounted industry costs of ~$7bn, health-related cost savings of ~$1.7bn (95% UI: $1.0bn, $2.9bn) and health gains of ~60,000 QALYs (50,000, 77,000) over 20 years, with an ICER of ~$85,000 ($12,000, $243,000) per QALY gained. Achieving the long-term sodium reduction targets could result in industry costs of ~$16bn, health-related cost savings of approximately $5.1bn ($3.4bn, $8.3bn), and industry health gain of ~180,000 (149,000, 209,000) QALYs, with an ICER of ~$60,000 ($2,000, $168,000). For the subset of food manufacturing, the long-term sodium reduction targets would lead to health-related savings of ~$1bn ($0.6bn, $1.6bn) and ~32,000 (27,000, 37,000) QALYs gained with an ICER of $489,000 ($160,000, $1,052,000).

Conclusions:
Sustained sodium reduction is estimated to benefit the overall food industry with a healthier workforce and partly offset the reformulation costs for the subset of the processed food industry.
Abstract 030: Natural History of Obesity Subphenotypes: Dynamic Changes Over Two Decades and Prognosis in the Framingham Heart Study
Authors: Echouffo Tcheugui Justin B , Short Meghan I , Sponholtz Todd R , Field Patrick , Xanthakis Vanessa , Larson Martin G , Vasan Ramachandran S
Published: July 2021

Introduction:
The natural history of obesity (body mass index [BMI]≥30 kg/m
2
) sub-phenotypes is not fully understood. We investigated longitudinal changes in obesity sub-phenotypes, and their associations with health outcomes.

Hypothesis:
We hypothesized that metabolically heathy obesity (MHO) is associated with elevated risk of cardiovascular disease [CVD], metabolic disease and cancer, compared to healthy non-obesity.

Methods:
We evaluated 4,291 Framingham Offspring Study participants attending at least two examinations between cycles 2 [1979-1983] through 7 [1998-2001] (26,508 participant-observations). Obesity subphenotypes were defined using metabolic health (<2 of Adult Treatment Panel-III criteria) and BMI (metabolically healthy non-obese [MHNO], MHO, metabolically unhealthy non-obese [MUNO], metabolically unhealthy obese [MUO]). We assessed changes in subphenotypes over time, and their relations to coronary artery calcification (CAC), subclinical CVD (presence of one or more of the following: left ventricular [LV] systolic dysfunction, LV hypertrophy, increased carotid intima-media thickness, reduced ankle-brachial index or microalbuminuria) and incident diabetes, hypertension, chronic kidney disease, CVD and mortality.

Results:
At baseline, 4% and 31% of participants exhibited the MHO and MUNO subphenotypes, respectively. Between two consecutive exams, >40% of MHO participants became MUO. Transition probabilities were highest for MHO to MUO changes (43-46%). Compared to MHNO, MHO participants had 1.28-fold and 1.9-fold higher odds of subclinical CVD and CAC, respectively; corresponding values for MUNO were 1.95 and 1.92 (
P
<0.05). Compared to MHNO, MHO increased the risks of diabetes and hypertension (
Table
); while MUNO increased the risks of diabetes, hypertension, CVD and death.

Conclusion:
Over two decades, most MHO participants developed metabolic abnormalities, subclinical and clinical disease, suggesting that this subphenotype is a harbinger of future disease risk.
Abstract MP05: N Terminal Pro B Type Natriuretic Peptide as a Stroke Risk Factor in the European Population: Results From the Biomarcare Consortium
Authors: Di Castelnuovo Augusto Filippo , Veronesi Giovanni , Costanzo Simona , Bonaccio Marialaura , Zeller Tanja , Schnabel Renate , Joergensen Torben , Salomaa Veikko , Yarnell John , Ferrario Marco , Giampaoli Simona , Meisinger Christa , Kee Frank , Koenig Wolfgang , Landmesser Ulf , de Gaetano Giovanni , Kuulasmaa Kari , Blankenberg Stefan , Iacoviello Licia ,   BiomarCaRE Investigators
Published: July 2021

Introduction:
N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a risk factor for atrial fibrillation and a marker of cardiac function used in detection of heart failure. Few studies evaluated the role of NT-proBNP as risk factor for stroke.

Hypothesis:
Given the link between cardiac dysfunction and stroke, NT-proBNP is a candidate marker of stroke risk. Our aim was to evaluate the association of NT-proBNP with stroke outcomes and to determine the predictive value beyond a panel of established risk factors for stroke.

Methods:
Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project we analysed data of 43,815 participants (48.3% men; mean age 52 yr) free of cardiovascular disease from 6 prospective population-based cohorts across Europe with a maximum follow-up of 22 years. All NT-proBNP measurements were performed on frozen samples in the central BiomarCaRE laboratory. The endpoints considered were validated fatal and non-fatal stroke.

Results:
We observed 565 stroke events (78 fatal) in men and 290 (54) in women. Growing quartiles of NT-proBNP were associated with increasing risk of stroke (Table; multivariable cox regression analysis adjusted for the base model: age, centre, smoking, BMI, diabetes, hypertension medication, systolic and diastolic blood pressure, total and HDL cholesterol), both in men (p for trend <0.0001) and in women (P<0.0001). Examining C-statistics for prediction of stroke we could observe only very small changes after the addition of NT-proBNP to the base model (delta AUC=0.0053 and 0.0048 in men and women, respectively).

Conclusions:
In European individuals free of cardiovascular disease, levels of NT-proBNP in the top quartile (>87.7 pg/mL) are associated with a doubled risk of stroke. However, the addition of NT-proBNP to variables of established risk score poorly improves prediction of stroke disease.
Abstract MP18: The Risk of Venous Thromboembolism is Lower in Multiple Asian Ethnic Groups
Authors: Tran H. Nicole , Udaltsova Natalia , Siu Stanton , Darbinian Jeanne , Klatsky Arthur L
Published: July 2021

Background:
Several studies suggest a lower risk of venous thromboembolism (VTE) in Asians compared to other racial groups, and genetic mechanisms have been suspected. Despite their biological and cultural diversity, data have been sparse comparing risk of VTE among specific Asian ethnicities. Our previous report from 2000 on hospitalizations for VTEs in Asian Americans had included 337 subjects (all races) and numbers were insufficient to study specific Asian groups. We present here data from a new study with 4,674 VTE subjects.

Hypothesis:
Similar low VTE risk is present in multiple Asian ethnic groups.

Methods:
We studied composite VTE risk in 61,459 members of a comprehensive health plan, who had supplied self-classified ethnicity data on prior health examinations between 1978 and 1985 and had remained plan members in 1996, when outpatient diagnoses were added to computerized files. The subjects were 58% (n = 35,573) female and 42% (n= 25,886) male. From 1996 through 2015, at least one diagnosis of VTE was made during an outpatient visit or hospitalization for 4,675 persons. With Whites as the referent group, we performed logistic regressions controlled for age, sex, education, BMI, and smoking, yielding hazard ratios (HR) and 95% confidence intervals (CI).

Results:
The table shows HRs (CI) versus Whites (n=32,557) with 2,576 VTE.

These lower HRs for VTE in Asians were generally similar in men and women. In the Asian stratum, a model with Chinese as referent showed an increased HR = 1.87 (1.09-3-21; p=0.02) for South Asians. Among covariates sex, education, and smoking were unrelated to VTE risk and BMI was positively associated; these results were similar in Whites, Blacks, and Asians.

Conclusions:
In conclusion, Chinese, Japanese, Filipinos and Other Asian Americans but not South Asians had substantially lower VTE risk compared to Whites. These data indirectly support a genetic explanation.