bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 73: Targeting B Cells and Tertiary Lymphoid Structures in Lung Cancer Progression
Authors: Bruno Tullia , Liu Dongyan , Kunning Sheryl , Bao Riyue , Stabile Laura , Somasundaram Ashwin
Published: July 2021

Purpose: Immunotherapy has revolutionized treatment options for multiple solid tumors, including non-small cell lung cancer (NSCLC). However, these approaches are only effective in 20-30% of NSCLC patients, thus a more comprehensive picture of the immune response in NSCLC is necessary to develop new therapeutic approaches. Current immunotherapies do not consider or target B cells or tertiary lymphoid structures (TLS) despite their predominance in the tumor microenvironment (TME) and key role in the adaptive immune response. We hypothesize that B cells help generate potent, long-term, immune responses against lung tumor cells by educating T cells within TLS and producing tumor-specific antibodies.

Methods: Toward our hypothesis, we have evaluated B cells and TLS in healthy donor lungs (smoker and nonsmoker), COPD patients, and NSCLC patients via single cell RNA sequencing, spectral cytometry (Cytek Aurora) and multispectral imaging (Vectra Polaris and Nanostring GeoMx DSP). These cellular and spatial analyses have revealed key differences in B cell infiltration and TLS formation as lung cancer develops.

Results: We have observed an increase in mature TLS (with active germinal centers) as patients develop cancer and have identified key genes that govern TLS heterogeneity in the TME. Further, in evaluating the ex vivo function of B cells from patient tumors via antigen presentation and antibody production assays, we have observed differential function of B cells that correlates with B cell activation (increased HLADR, CD40, CD69).

Conclusions: Our studies will provide (a) biomarkers to predict lung cancer progression, (b) targets for early immunotherapeutic intervention in COPD patients that might trigger better anti-tumor immunity as patients develop lung cancer, and (c) immunotherapeutic targets in patients with already established NSCLC.

Citation Format: Tullia Bruno, Dongyan Liu, Sheryl Kunning, Riyue Bao, Laura Stabile, Ashwin Somasundaram. Targeting B Cells and Tertiary Lymphoid Structures in Lung Cancer Progression [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 73.
Abstract 79: Directly Observed Care: Establishing an Enhanced Patient Navigation Program within a New Public Oncology Treatment Program in Belize
Authors: Valtis Yannis , Garrity Philip , Yacab Ramon , Bernard Margaret , Kelly Lorna , Arnold Shanikka , Lattin Jake , Sherry Cirkine , Huang Franklin
Published: July 2021

Purpose: Cancer patients in low-and-middle-income countries face unique economic and structural barriers to accessing and completing cancer treatment. While research has shown the efficacy of patient navigators to improve clinical outcomes for cancer patients, few patient navigation programs for cancer patients exist in resource-limited settings. In 2018, Belize launched its first-ever public oncology treatment program in collaboration with Global Oncology. We hypothesized that it would be feasible to create an enhanced patient navigation program, named “Directly Observed Care (DOC)."

Methods: Two Belizean medical assistants were recruited and trained in patient navigation and education, A training handbook was created collaboratively with Belizean health professionals and utilized materials from U.S.-based patient navigation programs.

Results: Between August and October 2020, 135 cancer patients were seen in the newly formed oncology clinic for a total of 330 patient visits at Karl Heusner Memorial Hospital. Average patient age was 56 and the most common diagnoses were breast cancer (34% of patients), cervical cancer (12%) and prostate cancer (7%). The DOC officers engaged with patients in 70% of all clinical visits (66% of follow-up visits). Patients who were actively in treatment at the time of the visit had the highest rates of DOC officer engagement (84%), while those completing their diagnostic workup and those in palliative care had lower engagement rates (48% and 53% respectively). DOC officers noted 233 follow-up tasks at time of engagement with patients and had completed 70% of them at time of analysis.

Conclusion: Despite limited resources, an enhanced patient navigation program for cancer patients within a country's first public oncology treatment program is feasible. DOC officers, serving as patient navigators and patient educators, were able to engage with the majority of patients. In the future, we aim to evaluate the impact of the program on the patient's ability to complete treatment.

Citation Format: Yannis Valtis, Philip Garrity, Ramon Yacab, Margaret Bernard, Lorna Kelly, Shanikka Arnold, Jake Lattin, Cirkine Sherry, Franklin Huang. Directly Observed Care: Establishing an Enhanced Patient Navigation Program within a New Public Oncology Treatment Program in Belize [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 79.
Abstract 8: Risk Factors and Management of Venous Thromboembolism amongst Patients Undergoing Breast Cancer Treatment at a Referral Hospital in Kenya
Authors: Orangi Gavin , Ndemo  , Menge Tom
Published: July 2021

Purpose Cancer has been associated as a risk factor for hyper-coagulation. The purpose of this study was to establish the predictors of risk factors and management of venous thromboembolism amongst patients undergoing breast cancer treatment at Kenyatta National Hospital -Kenya.

Methods The study adopted a cross-sectional study design. 377 patient's files were sampled by using simple random sampling. Univariate and bivariate analysis was done and the risk of developing a VTE was assessed using the Khorana risk assessment tool. Inferential statistics were used to determine the strength of association between the predictor and outcome variables.

Results 10 (2.65%) of the patients were found to have VTE. Age was found to be a significant risk factor for the development of venous thromboembolism (p= <0.001). (AOR=0.47; CI=0.24-0.94; p=0.032). Surgery done in the last one year was also found to be a predictor of the risk of having a venous thromboembolic event. (AOR= 0.68; CI=0.48-0.98; p=0.04). The duration it took between initiation of chemotherapy from first diagnosis and number of chemotherapy cycles were found to be significant predictors of risk of developing a venous thromboembolic event at (p=0.012) and (p=<0.001) respectively. (AOR= 1.64; CI=1.1-2.44; p= 0.015). Additionally, there was a statistically significant association between the use of radiotherapy and the risk of developing a venous thromboembolism (p=<0.001). (AOR=0.09; CI=0.03-0.24; p=0.001). Warfarin and LMWH were commonly used for the management of VTE.

Conclusion Predictors for the risk of the development of venous thromboembolism were identified in the study All these risk factors need early detection for prompt management. Therefore, use of VTE risk models should be further explored and used to educate high risk patients about the warning signs and symptoms of VTE.

Citation Format: Gavin Orangi, Ndemo, Tom Menge. Risk Factors and Management of Venous Thromboembolism amongst Patients Undergoing Breast Cancer Treatment at a Referral Hospital in Kenya [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 8.
Abstract 80: Outcomes of Acute Lymphoblastic Leukemia among Adolescents and Young Adults in Malawi
Authors: Kimani Stephen , Painschab Matthew , Kasokanji Edwards , Ellis Grace
Published: July 2021

Purpose: There is limited data on treatment and outcomes for acute lymphoblastic leukemia (ALL) among adolescents and young adults (AYA) in sub-Saharan Africa. We describe a prospective observational cohort in Malawi.

Methods: Patients aged 14 - 39 years old with untreated acute lymphoblastic leukemia at Kamuzu Central Hospital, Malawi, underwent comprehensive clinicopathologic evaluation at baseline. ALL diagnosis was confirmed onsite using immunohistochemical (IHC) and telepathology consultations involving pathologists in Malawi and the United States. Patients were treated with a modified regimen for AYA modeled after the CALGB10403 protocol. Key modifications included omission of asparaginase and hematopoietic growth factors due to unavailability, and no dose escalation for methotrexate during interim maintenance. Post-induction remission was confirmed via bone marrow biopsy.

Results: From 2015 to 2019, we enrolled 19 patients. Thirteen (68%) were female, and the median age was 19 years (IQR 17-27). Sixteen (84%) had extramedullary involvement, 10 (53%) had ECOG ≥2, and 11 (58%) had T-cell immunophenotype. None were HIV infected. Four patients died before initiating treatment. Out of 15 patients who initiated treatment, 10 completed induction, of whom 9 achieved remission. The median treatment duration was 8 months (range 0-29). After a median follow-up time of 9 months (range 1-29), no patients were lost to follow-up. Two patients (10%) remain in remission on maintenance therapy after 8 and 29 months, respectively, and 17 (89 %) have died, all from disease progression. OS at 1 year is 31.5% (95% CI 15-64%) and at 2 years is 10.5% (95% CI 3-40%).

Conclusion: Findings were poor but in line with those among pediatric ALL patients from the region. Given no toxicity-related mortality occurred, escalation of therapy is needed and being implemented. Our experience demonstrates that it is possible to achieve modest results using a complex ambulatory chemotherapy regimen modified to resource availability.

Citation Format: Stephen Kimani, Matthew Painschab, Edwards Kasokanji, Grace Ellis. Outcomes of Acute Lymphoblastic Leukemia among Adolescents and Young Adults in Malawi [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 80.
Abstract 85: Solutions for Selective Loss to Follow-Up: Application to HIV-Associated Cancer Cohorts in Malawi
Authors: Kudowa Evaristar , Edwards Jess , Horner Marie Josephe , Chasimpha Steady , Dzamalala  , Chagomerana Maganizo
Published: July 2021

Purpose: Survival estimates among HIV+ cancer patients in sub-Saharan Africa (SSA) are limited and often biased due to high rates of loss to follow-up (LTFU). We explored the application of inverse probability of censoring weights (IPCW) to routinely collected HIV cohort data to correct for survival estimation bias introduced by LTFU, an approach which has been successfully utilized in high-income countries.

Methods: We estimated overall survival (OS) among HIV+ incident cancer cases enrolled between 2000 and 2010 in Malawi. Patients were identified by utilizing probabilistic linkage of two large HIV cohorts to the national cancer registry and has previously been published. LTFU was defined as missed clinic appointment with unsuccessful tracing for ≥180 days. OS was estimated using unweighted and weighted methods. Sensitivity analysis using best- and worst-case scenarios assessed the robustness of estimates from the IPCW approach.

Results: Among 883 cases, median age was 35 years (IQR: 30-41), and the most common cancers were Kaposi sarcoma (89%) and cervical cancer (5%). Median follow-up time was 5 years (IQR: 1-6), and 257 (29%) were LTFU. Males (RR: 1.69, CI: 1.37-2.07) and HIV stage IV patients (RR: 2.24, CI: 1.74-2.89) showed increased risk of LTFU. The 2-year OS were 91.1% and 89.6% for weighted and unweighted methods respectively. Sensitivity analysis estimated best and worst case 2-year OS at 91.5% and 77.4%, respectively.

Conclusion: IPCW method did not appear to significantly correct bias introduced by LTFU, likely yielding continued overestimation of OS. This may be due to limited covariate availability in routinely collected cohort data in SSA to generate appropriate censoring weights or perhaps because of incorrect cancer diagnoses without pathologic confirmation in our setting. In SSA, where comprehensive patient tracing among LTFU groups can be impractical, intensive tracing of representative samples of LTFU patients is likely needed to accurately estimate survival.

Citation Format: Evaristar Kudowa, Jess Edwards, Marie Josephe Horner, Steady Chasimpha, Dzamalala, Maganizo Chagomerana. Solutions for Selective Loss to Follow-Up: Application to HIV-Associated Cancer Cohorts in Malawi [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 85.
Age-Related Alterations of Proteins in Albino Wistar Rat Retina
Authors: Kovács-Valasek Andrea , Pöstyéni Etelka , Dénes Viktória , Mester Adrienn , Sétáló Jr. György , Gábriel Róbert
Published: July 2021

Imbalance of homeostasis causes permanent changes in the body with time. The central nervous system is especially prone to these changes since it possesses limited regenerative capacity. In the retina, neurons are damaged during the aging process, and this eventually leads to deterioration of vision. In our 2-year-long study, we examined genetically closely related rat individuals to disclose the hidden retinal causes of age-associated visual dysfunction. Morphometric analysis showed significant reduction of the retina thickness with aging, particularly that of the inner plexiform layer. To reveal changes between the age groups, we used immunohistochemistry against vesicular glutamate transporter 1 protein for photoreceptor and bipolar cell terminals, Brn3a for ganglion cells, calbindin 28 kDa for horizontal cells, parvalbumin for AII amacrines, protein kinase Cα for rod bipolar cells, tyrosine hydroxylase for dopaminergic cells, glial fibrillary acidic protein for glial cells, and peanut-agglutinin labeling for cones. The most significant decrease was observed in the density of photoreceptor and the ganglion cells in the aging process. By using immunocytochemistry and western blot technique, we observed that calbindin and vesicular glutamate transporter 1 protein staining do not change much with aging; tyrosine hydroxylase, parvalbumin and calretinin showed the highest immunoreactivity during the midlife period. Most interestingly, the level of glial fibrillary acidic protein also changes similarly to the previously named markers. Our results provide further evidence that protein content is modified at least in some cell populations of the rat retina, and the number of retinal cells declined with aging. We conclude that senescence alone may cause structural and functional damage in the retinal tissue.
P190BCR-ABL1 in a Patient with Philadelphia Chromosome Positive T-Cell Acute Lymphoblastic Leukemia: A Rare Case Report and Review of Literature
Authors: Kohla Samah , EL Kourashy Sarah , Nawaz Zafar , Youssef Reda , Al-Sabbagh Ahmad , Ibrahim Feryal A.
Published: July 2021

T-acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) is rare and aggressive leukemia. Philadelphia chromosome positive (Ph+) is the most common cytogenetic abnormality in chronic myeloid leukemia (CML) and B-acute lymphoblastic leukemia (B-ALL). Ph+ T-ALL is exceeding rare and has a therapeutic and prognostic significance. The incidence and outcome of Ph+ T-ALL are unknown. Differentiation between Ph+ T-ALL/LBL and T-cell lymphoblastic crises of CML may be difficult. We report a rare case of adult de novo T-ALL with significant monocytosis, having Ph+ with (P190 BCR-ABL1) as a cytogenetic abnormality. He was treated with ALL induction chemotherapy and imatinib and achieved complete remission, then relapsed twice and expired shortly after the last CNS relapse.
Regional Citrate Anticoagulation during Double-Filtration Plasmapheresis in Kidney Transplant Recipients: A Single-Center Retrospective Cohort Study
Authors: Ho Quan Yao , Teh Swee Ping , Thangaraju Sobhana , Teo Su Hooi , Tan Han Khim , Abdul Rahman Maslinna Binte , Ng Li Choo , Lim Amy Ee Lin , Choong Lina Hui Lin , Kee Terence , Kaushik Manish ,   for the S.I.N:G.A.P.O.R.E Initiative (Science In Nephrology: Growth And Progress Of Research & Education Initiative)
Published: July 2021

Introduction: Double-filtration plasmapheresis (DFPP) may be used for immunomodulation in kidney transplant (KTx). While DFPP reduces plasma product exposure, risk of circuit clotting merits adequate anticoagulation. Regional citrate anticoagulation (RCA) avoids the risks of systemic anticoagulation, but a protocol for RCA-DFPP is not previously widely described. Methods: We conducted a single-center retrospective cohort study involving adult (≥21 years old) KTx recipients who underwent RCA-DFPP from 2018 to 2020 to investigate efficacy and safety for an RCA protocol during DFPP in KTx recipients. Results: Fifty-one (85%) of 60 RCA-DFPP sessions in 17 patients completed without circuit clotting. Circuit clotting was associated with high post-filter ionized calcium (28 vs. 3.7%, odds ratio 10.1, 95% CI 1.1–89.4, p = 0.037). Hypo- and hypercalcemia developed in 5 (8.3%) and 8 (13.3%) sessions, respectively, but no adverse effects were noted despite severe hypocalcemia in one. There was no significant change in pre- and post-RCA-DFPP sodium, bicarbonate, albumin, and platelet levels. With regards DFPP procedure, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) was observed following 38 (64.4%) and 12 (20.3%) sessions, respectively. Severely prolonged (>1.5 × upper limit normal) PT and aPTT were recorded in 2 sessions each. Expectedly, hypofibrinogenemia developed after 31 (51.7%) sessions: including 4 (6.7%) severe hypofibrinogenemia (<0.5 g/L). Two patients developed bleeding requiring blood product transfusion. The median total volume of fluids administered per session was 1.495 (1.373–1.612) L; post-RCA-DFPP significant weight gain of 0.5 (0–1.25) kg was noted. Diuretic was commenced or dose increased following 20 (33.3%) sessions for fluid balance management. Discussion/Conclusion: Protocol-based RCA for DFPP is feasible and safe in KTx recipients. However, DFPP-related coagulopathy can develop consequent to treatment; caution should be exercised for patients with bleeding risk. Close monitoring and management of the patients’ electrolytes, especially hypocalcemia and hypomagnesemia, and fluid status is recommended.
APOA5 Variant rs662799, Role in Cardiovascular Traits and Serum Adipokine Levels in Caucasian Obese Subjects
Authors: de Luis Daniel A. , Izaola Olatz , Primo David , Aller Rocio
Published: July 2021

Background and Aims: This ApoA5-1131C allele of rs662799 variant is related with a higher serum triglyceride levels, and it contributes to increase risk of cardiovascular disease. The aim of the present investigation was to evaluate single nucleotide polymorphism rs662799 in APOA5 gene and its associations with cardiovascular risk factors, MS, and serum adipokine levels. Methods: The study involved a population of 1,002 Caucasian obese subjects. Measurements of body weight, waist circumference, fat mass, arterial blood pressure, blood glucose, C-reactive protein, insulin levels, insulin resistance (HOMA-IR), lipid profile, and adipokines levels were recorded. Genotype of ApoA5 gene polymorphism (rs662799) and prevalence of metabolic syndrome (MS) were evaluated. Results: The distribution of the rs662799 polymorphism in this adult population (n = 1,002) was 88.3% (n = 885) (TT), 11.4% (n = 114) (TC), and 0.3% (n = 3) (CC). No significant differences were found between the 2 genotypes in the anthropometric data, MS, or blood pressure. Triglyceride levels were higher in C-allele carriers (delta total group: 19.7 ± 2.1 mg/dL: p = 0.02) than non C-allele carriers. HDL-cholesterol levels were lower in C-allele carriers (delta total group: −6.7 ± 1.1 mg/dL: p = 0.02) than non C-allele carriers. Adiponectin levels were lower in C-allele carriers (delta total group: −11.6 ± 1.0 mg/dL: p = 0.02) too. In C-allele carriers, logistic regression analysis showed an increased risk of hypertriglyceridemia (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2–3.4, p = 0.001) and percentage of low-HDL-C (OR = 2.2, 95% CI = 1.3–3.7, p = 0.002) after adjusting by body mass index and age. Conclusions: C-allele carriers of rs662799 of APOA5 gene showed high rates of low levels of HDL and hypertriglyceridemia, with differences in triglyceride, HDL cholesterol, and adiponectin levels in Caucasian obese subjects.
Heat Shock Protein 72 Enhances Manganese Superoxide Dismutase Activity During Myocardial Ischemia-Reperfusion Injury, Associated With Mitochondrial Protection and Apoptosis Reduction
Authors: Suzuki Ken , Murtuza Bari , Sammut Ivan A. , Latif Najma , Jayakumar Jay , Smolenski Ryszard T. , Kaneda Yasufumi , Sawa Yoshiki , Matsuda Hikaru , Yacoub Magdi H.
Published: July 2021

Background

Heat shock protein 72 (HSP72) is known to provide myocardial protection against ischemia-reperfusion injury by its chaperoning function. Target molecules of this effect are presumed to include not only structural proteins but also other self-preservation proteins. The details, however, remain unknown. Manganese superoxide dismutase (Mn-SOD) is an enzyme that preserves mitochondria, a key organelle for cellular respiration, from reperfusion injury and limits mitochondria-related apoptosis. We hypothesized that Mn-SOD would play a role in HSP72-mediated cardioprotection.

Methods and Results

Rat hearts were transfected with human HSP72 by intra-coronary infusion of Hemagglutinating Virus of Japan-liposome, resulting in global myocardial overexpression of HSP72. After ischemia-reperfusion injury, cardiac function (left ventricular systolic pressure, maximum dP/dt, minimum dP/dt, and coronary flow) was improved in the HSP72-transfected hearts compared with control-transfected ones, corresponding with less leakage of creatine kinase and mitochondrial aspartate aminotransferase. Postischemic Mn-SOD content and activity in the HSP72-transfected hearts were enhanced in comparison with the controls (content: 96.9±4.1 versus 85.5±2.5% to the preischemic level,
P
=0.038; activity: 93.9±2.2 versus 82.2±3.7%,
P
=0.022), associated with improved mitochondrial respiratory function (postischemic percent respiratory control index; NAD
+
-linked: 81.3±3.8 versus 18.5±4.4%; FAD-linked: 71.8±5.5 versus 20.7±5.3%,
P
<0.001). In addition, incidence of postischemic cardiomyocyte apoptosis was attenuated in the HSP72-transfected hearts (4.0±1.1 versus 10.3±3.3%,
P
=0.036), correlating with an increased Bcl-2 level and reduced up-regulation of caspase-3.

Conclusions

These data suggest that the enhanced Mn-SOD activity during ischemia-reperfusion injury, which is associated with mitochondrial protection and apoptosis reduction, is a possible mechanism of HSP72-induced cardioprotection.
An Alternative Approach Using Long Elephant Trunk for Extensive Aortic Aneurysm: Elephant Trunk Anastomosis at the Base of the Innominate Artery
Authors: Kuki Satoru , Taniguchi Kazuhiro , Masai Takafumi , Yokota Takenori , Yoshida Kiyoshi , Yamamoto Keiji , Matsuda Hikaru
Published: July 2021

Background

Although a staged elephant trunk procedure has been widely used, the early mortality of the first stage operation as well as the interval mortality between operations remains unsatisfactory. We developed an alternative elephant trunk procedure to reduce mortality and morbidity.

Methods
and Results
Ascending aorta and arch vessels were minimally dissected. During systemic cooling, a four-branched arch graft with a sewing “collar” and a long “elephant trunk” was prepared. The ascending aorta was opened under selective brain perfusion with moderate hypothermia (25°C), and the elephant trunk was then pulled down into the descending aorta using the catching catheter introduced
via
a femoral artery. The elephant trunk anastomosis using the collar was made at the base of the innominate artery. The arch vessels were divided and closed at aortic stump, and grafted separately as a consequence of the very proximal site for the elephant trunk anastomosis. Between October 1998 and September 2001, 17 patients, ranging in age from 25 to 79 years (mean 67 years) with extensive aortic aneurysm underwent this operation. Preoperative cardiac complications included coronary artery disease in 5, aortic regurgitation in 3, and 3 of these 8 patients had poor left ventricular function with an ejection fraction less than 40%. Nine patients underwent a second stage operation, in 1 of them the permanent elephant trunk procedure was initially attempted but the second stage procedure was done because of increasing endo-leakage. The mean interval between operations was 8 days (range 1 to 14 days) in the remaining 8 patients. In 5 of 6 patients who underwent the permanent elephant trunk procedure, a decrease in the size of the aneurysm based on thromboexclusion was observed using serial computed tomography scans. A single stage repair was performed in 1 patient. The 30-day survival rate of all operations was 100%, however, there was 1 in-hospital death (6%) after the second operation. There was no stroke, however, paraplegia occurred after the first operation in 1 patient (6%) of the in-hospital death. No new phrenic or recurrent laryngeal nerve palsy occurred as a result of surgery.

Conclusions

The present technique using a modification of the elephant trunk technique for extensive aortic aneurysm provides acceptable mortality and morbidity. The present strategy would be an alternative for the standard elephant trunk procedure in some high-risk patients with advanced age and comorbidities.
Optimal Biomaterial for Creation of Autologous Cardiac Grafts
Authors: Ozawa Tsukasa , Mickle Donald A. G. , Weisel Richard D. , Koyama Nobuya , Ozawa Sumiko , Li Ren-Ke
Published: July 2021

Background

The optimal cardiac graft for the repair of congenital heart defects will be composed of autologous cells and will grow with the child. The biodegradable material should permit rapid cellular growth and delayed degradation with minimal inflammation. We compared a new material, ε-caprolactone-co-
l
-lactide sponge reinforced with knitted poly-
l
-lactide fabric (PCLA), to gelatin (GEL) and polyglycolic acid (PGA), which are previously evaluated materials.

Methods

Syngenic rat aortic smooth muscle cells (SMCs, 2×10
6
) were seeded onto GEL, PGA, and PCLA patches and cultured (n=11 per group). The DNA content in each patch was measured at 1, 2, and 3 weeks after seeding. Histological examination was performed 2 weeks after seeding. Cell-seeded patches were employed to replace a surgically created defect in the right ventricular outflow tract (RVOT) of rats (n=5 per group). Histology was studied at 8 weeks following implantation.

Results

In vitro studies showed that the DNA content increased significantly (
P
<0.05) in all patches between 1 and 3 weeks after seeding. Histology and staining SMCs for anti-α-smooth muscle actin (αSMA) revealed better growth of cells in the interstices of the grafts with GEL and PCLA than the PGA graft. In vivo studies demonstrated that seeded SMCs survived at least 8 weeks after the patch implantation in all groups. PCLA scaffolds were replaced by more cells with larger αSMA-positive areas and by more extracellular matrix with larger elastin-positive areas than with GEL and PGA. The patch did not thin and expanded significantly. The GEL and PGA patches thinned and expanded. All grafts had complete endothelialization on the endocardial surface.

Conclusions

SMC-seeded biodegradable materials can be employed to repair the RVOT. The novel PCLA patches permitted better cellular penetration in vitro and did not thin or dilate in vivo and did not produce an inflammatory response. The cell-seeded PCLA patch may permit the construction of an autologous patch to repair congenital heart defects.
Myocardial Insulin-Like Growth Factor-I Gene Expression During Recovery From Heart Failure After Combined Left Ventricular Assist Device and Clenbuterol Therapy
Authors: Barton Paul J. R. , Felkin Leanne E. , Birks Emma J. , Cullen Martin E. , Banner Nicholas R. , Grindle Suzanne , Hall Jennifer L. , Miller Leslie W. , Yacoub Magdi H.
Published: July 2021

Background—

Patients who undergo mechanical support with a left ventricular assist device (LVAD) exhibit reverse remodeling and in some cases recover from heart failure. We have developed a combination therapy using LVAD support combined with pharmacological therapy to maximize reverse remodeling, followed by the β
2
adrenergic agonist clenbuterol. We recently found that clenbuterol induces insulin-like growth factor I (IGF-I) in cardiac myocytes in vitro. The purpose of this study is to examine IGF-I expression in recovery patients after combination therapy.

Methods and Results—

Myocardial mRNA levels were determined by real-time quantitative polymerase chain reaction in 12 recovery patients (at LVAD implantation, explantation, and 1 year after explantation). IGF-I mRNA was elevated at the time of LVAD explantation relative to donors, with 2 groups distinguishable: Those with low IGF-I mRNA at implantation who showed significant increase during recovery and those with high IGF-I mRNA at implantation who remained high. Levels returned to normal by 1 year after explantation. Microarray analysis of implantation and explantation samples of recovery patients further revealed elevated IGF-II and IGF binding proteins IGFBP4 and IGFBP6. IGF-I levels correlated with stromal cell-derived factor mRNA measured both in LVAD patients and in a wider cohort of heart failure patients.

Conclusions—

The data suggest involvement of elevated myocardial IGF-I mRNA in recovery. IGF-I may act to limit atrophy and apoptosis during reverse remodeling and to promote repair and regeneration in concert with stromal cell derived factor.
Abstract 2: Aorta Intima-Resident Macrophages Contribute to Atherosclerotic Lesion Initiation
Authors: Williams Jesse W , Saunders Brian T , Kim Ki-Wook , Epelman Slava , Lavine Kory , Zinselmeyer Bernd H , Randolph Gwendalyn J
Published: July 2021

Atherosclerosis is an underlying cause of cardiovascular disease and a leading cause of mortality worldwide. Macrophage accumulation in atherosclerotic plaque, their uptake of cholesterol, and subsequent local death drive disease progression. Lipid-laden plaque macrophages are thought to be exclusively derived from blood monocyte progenitors that are recruited following endothelial damage induced by cholesterol exposure. In our current study, we focused on characterization of resident vascular macrophages that reside in the aortic intima in plaque-prone areas, previously identified as ‘vascular dendritic cells’. Using en face whole-mount confocal microscopy of aortas, we confirm a uniform resident CD64
+
CD11c
+
CX3CR1
+
MHCII
+
macrophage population, which is present in C57/BL6 mice resistant to atherosclerosis. Importantly, they do not express dendritic cell restricted genes zBTB46 or L-myc. We find aortic macrophages require M-CSF and Flt3 signaling for survival, but are independent of CCR2, CCR7, and GM-CSF receptor signaling, making them a distinct myeloid population. Lineage-tracing and parabiosis approaches suggest these cells derive from definitive hematopoiesis and are then self-maintained independent of blood-progenitors. Using these characterization data, we developed a labeling strategy to identify resident from recruited macrophages during kinetic studies of lesion progression. We find that resident aortic macrophages are the first cells to take up lipid following high fat diet exposure and expand within the arterial wall to form the initial lesion bed. In the absence of resident macrophages early lipid deposition in the aortic arch is ablated. Finally, utilizing an intravital carotid artery imaging approach, we identify resident aortic macrophages to be potential mediators of monocyte recruitment through direct interactions with rolling monocytes on the endothelial surface under diseased and steady-states. Overall, these results shift our understanding of the cellular mechanisms responsible for plaque construction and maintenance.
Endothelial-Mesenchymal Transition in Cardiovascular Disease
Authors: Alvandi Zahra , Bischoff Joyce
Published: July 2021

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) β influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.
Abstract 002: Circulating Levels of Natural Killer Cells and Monocyte Subsets Are Associated With Higher Systolic Blood Pressure: The Multi-Ethnic Study of Atherosclerosis
Authors: Doyle Margaret F , Sitlani Colleen M , Olson Nels C , Huber Sally A , Landay Alan L , Tracy Russell P , Psaty Bruce M , Delaney Joseph A
Published: July 2021

Introduction:
Hypertension is a multifactorial process. Activation of the innate immune system and subsequent upregulation of adaptive immunity have been shown to promote hypertension in various mouse models Large scale human population studies examining the composition of the innate and adaptive immune system as it pertains to hypertension are lacking.

Hypothesis:
The composition of innate and adaptive immune cells are risk factors for increased systolic blood pressure (SBP).

Methods:
Using cells cryopreserved from the baseline exam, we measured 34 immune cell subsets from participants of the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age 64 years, 53% male), sampled from a case-cohort study of myocardial infarction (n=1,200). SBP was assessed at baseline and at four follow-up exams over the succeeding ten years. Our approach to anti-hypertensive medication use was to add 10mmHG to SBP for treated participants. Associations between immune cell subpopulations and SBP were conducted using linear mixed models, with sampling weights to account for the sampling strategy and robust confidence intervals; immune cells were modeled per standard (SD) deviation higher value. We adjusted for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and log- transformed cytomegalovirus levels.

Results:
After adjustment for potential confounders, 5 of 34 immune cells subsets were significantly associated with mean levels of SBP. For each standard deviation increment higher immune cell proportion, natural killer (NK) cells, defined as CD3-CD56+CD16+, (1.9 mmHG; 95% CI: 0.8-2.9), classic monocytes, defined as CD14++CD16-, (-1.3 mmHG; 95% CI: -2.5 to -0.1) and non-classic monocytes, defined as CD14+CD16++, (1.4 mmHG; 95% CI: 0.3 to 2.6) had the strongest associations with SBP changes over 10-years of follow-up. Sensitivity analyses with principal components analysis were supportive of these findings. After using a Bonferroni corrected threshold to account for for multiple testing only NK remained significant.

Conclusions:
NK cells, classic monocytes and non-classic monocytes, all components of the innate immune system, were associated with higher levels of SBP over follow-up. The strongest association was with natural killer cells; in agreement with previous studies that showed circulating levels of interferon gamma and tumor necrosis factor alpha, the two main cytokines produced by NK cells, correlate with systolic blood pressure.
Abstract MP42: Dietary Linoleic Acid Intake Is Inversely Associated With Type 2 Diabetes Risk In Three Large Prospective Cohort Studies Of U.s. Men And Women.
Authors: Zong Geng , Liu Gang , Wanders Anne J , Alssema Marjan , Zock Peter L , Willett Walter , Hu Frank B , Sun Qi
Published: July 2021

Introduction:
Recent studies reported inverse associations between circulating levels of n-6 polyunsaturated fatty acids (PUFAs) and type 2 diabetes (T2D) risk, although whether intake of these fatty acids is associated T2D risk remains to be elucidated.

Hypothesis:
We examined the hypothesis that long-term intake of n-6 PUFAs, especially linoleic acid (LA), is associated with lower T2D risk.

Methods:
Diet was assessed using validated food-frequency questionnaires every 4 years in women participating in Nurses' Health Study (NHS, n=83,648) and NHSII (n=88,610), and men participating in the Health Professionals Follow-Up Study (n=41,771). Incident T2D was identified by self-report and confirmed by a supplemental questionnaire.

Results:
N-6 PUFAs accounted for 4.7-6.8% total energy on average, and 98% of n-6 PUFA intake was from LA. We identified 18,442 T2D cases during 4.93 million person-years of follow-up. In multivariate-adjusted models, HRs (95%CIs) of T2D comparing extreme quintiles (high vs low) were 0.92 (0.88, 0.97; P
trend
=0.01) for LA intake, and 1.14 (1.08, 1.20; P
trend
<0.001) for arachidonic acid (AA) intake. It was further estimated that T2D risk were 6% lower when SFAs (2% of total energy) were iso-calorically replaced by LA intake (
table
below). For each 2% energy from LA intake, T2D risk was 17% lower for iso-calorically replacing
trans
fats, and 4% lower for iso-calorically replacing total carbohydrates, and refined carbohydrates (All P values <0.05). These findings remained after adjusting for baseline BMI instead updated BMI, further adjusting for incident hypertension and hypercholesterolemia, or placing a 4-year lag between dietary assessments and disease incidence.

Conclusion:
Higher LA consumption is associated with a lower T2D risk, especially when substituting for SFAs,
trans
fats, or refined carbohydrates. AA mainly comes from poultry and meats, and is associated with higher T2D risk.
Abstract MP60: Depressive Symptoms and Risk of Incident Atrial Fibrillation: The Multi-Ethnic Study of Atherosclerosis
Authors: Garg Parveen K , O'Neal Wesley T , Diez Roux Ana V , Alonso Alvaro , Soliman Elsayed , Heckbert Susan
Published: July 2021

Background:
Depression has been suggested as a potential risk factor for atrial fibrillation (AF) through effects on the autonomic nervous system and hypothalamus-pituitary-adrenal axis. Current literature examining the prospective relationship between depression and AF is inconsistent and limited to studies performed in predominantly white populations. We determined the relationship of both depressive symptoms and anti-depressant use with incident AF in a multi-ethnic cohort.

Methods:
The Multi-Ethnic Study of Atherosclerosis is a prospective study of 6,814 individuals without clinical cardiovascular disease. Depressive symptoms were assessed at baseline by the 20-item Center for Epidemiologic Studies Depression Scale (CES-D) and use of anti-depressant medications. Five CES-D groups were created based on the score distribution in approximate quartiles, and the top quartile split in 2 such that the top group represented persons with a score ≥16, a value commonly used to identify clinically relevant symptoms. Incident AF was identified from study ECGs verified for AF, ICD-9 hospital discharge diagnoses consistent with AF, and, for participants enrolled in fee-for-service Medicare, inpatient and outpatient AF claims data.

Results:
6,644 participants (mean age=62; 53% women; 38% white; 28% black; 22% Hispanic; 12% Chinese-American) were included and followed for a median of 13 years. In separate adjusted Cox proportional hazards analyses, a CES-D≥16 (referent=CES-D<2) and anti-depressant use were each associated with higher incidence of AF (Table). Associations did not differ by race or gender (interaction p-values of 0.18 and 0.17 respectively). Similar results were obtained using time-updated measures of depression.

Conclusions:
Depressive symptoms are associated with an increased risk of incident AF. Further study into whether improving depressive symptoms reduces AF incidence is important.
Abstract MP65: Metabolomics Associated With Augmentation Index and Pulse Wave Velocity: Findings From the Bogalusa Heart Study
Authors: Li Changwei , He Jiang , Li Shengxu , Chen Wei , Bazzano Lydia , Sun Xiao , Shen Luqi , Gu Xiaoying , Kelly Tanika
Published: July 2021

Background:
Large scale untargeted metabolomics studies are needed to understand the mechanisms of arterial stiffness.

Methods:
We performed untargeted metabolomics profiling among 1,239 participants of the biracial Bogalusa Heart Study. After quality control, 1,202 metabolites were evaluated for associations with augmentation index (AI) and pulse-wave velocity (PWV) overall and by race, adjusting for age, sex, education, smoking, drinking, body mass index, and physical activity. Weighted correlation network analysis (WGCNA) was applied to build metabolites modules among all participants. Bonferroni correction was used to determine significant metabolites. Significant metabolites should also have
P
<0.05 and consistent effect directions in both races.

Results:
We identified 4 and 17 novel metabolites associated with AI and PWV, respectively (
Table
). We also replicated associations of 12 previously reported metabolites with PWV in the overall sample, including 1,5-anhydroglucitol (
P
=5.55E-9), glucose (
P
=8.19E-14), glutamic acid (
P
=1.56E-8), glycine (
P
=9.87E-6), serine (
P
=0.003), urea (
P
=0.03), uridine (
P
=0.002), glutamine (
P
=0.001), 3-phenylpropionate (
P
=0.004), trans-4-hydroxyproline (
P
=0.001), pyruvate (
P
=0.002), and lysine (
P
=0.007). WGCNA identified two modules in significant associations with both AI (
P
=3E-4 and 8E-4, respectively) and PWV (
P
=2E-6 and 7E-5, respectively). One module was composed of metabolites of glycerolipids recycling pathway. The other module consisted of amino acids involved in glutamate, leucine, isoleucine, valine, methionione, systein, taurine, and alanine metabolisms. WGCNA also identified a network of sphingolipid metabolism for PWV (
P
=0.002). Investigation to hub metabolites of these modules identified 3 novel metabolites for AI and 4 novel metabolites for PWV (
Table
).

Conclusions:
The current study identified important metabolites and metabolites networks associated with AI and PWV.
Abstract MP67: Pregnancy Outcomes in Women With Congenital Heart Defects in Colorado: Results From the Colorado CHD Surveillance System in Adolescents and Adults (COCHD)
Authors: Crume Tessa , Duca Lindsey , Rausch Christopher , Khanna Amber
Published: July 2021

Introduction:
The normal hemodynamic changes of pregnancy can trigger cardiac dysfunction in women with congenital heart defects (CHD), leading to an increased risk of cardiac events. Further, utero-placental flow is impaired in women with CHD which can result in higher risk of adverse offspring outcomes.

Hypothesis:
Severity of maternal CHD is associated with adverse maternal cardiovascular events and offspring events by severity of CHD in 1074 pregnancies that resulted in a live birth in Colorado between 2011-13.

Methods:
Using data from the Colorado CHD Surveillance System in Adolescents and Adults, 926 pregnant women with CHD were identified that resulted in 1074 live births between 2011-2013. Maternal CHD type was dichotomized as severe (n=149) and moderate (total n=882). The risk of adverse maternal cardiac and offspring events were calculated out of the total number of pregnancies in each severity category.

Results:
Primary maternal cardiac events including cardiovascular mortality, arrhythmia, heart failure, thromboembolic events (pulmonary embolism, valve thrombosis or deep venous thrombosis), vascular events (stroke, myocardial infarction or dissection) and endocarditis occurred in 15% and 7% of women with severe and moderate CHD, respectively. Premature birth (delivery <37 weeks) and/or low birth weight (<2,500 grams) occurred in >18% of the women with severe CHD and 17% of women with moderate CHD. The risk of offspring congenital anomalies among women with severe CHD was extremely high for circulatory/respiratory, musculoskeletal/integumentary, cyanotic congenital heart disease and Down syndrome. The risk of infant congenital anomalies was lower for women with moderate CHD, with the most common being circulatory/respiratory, urogenital, Down syndrome and cyanotic congenital heart disease.

Conclusions:
Population-level surveillance system of CHD in Colorado provides novel assessment of the substantial risk of maternal and neonatal cardiac events associated with pregnancy in women with CHD.