tbuckley/cabot-search huggingface dataset:
Abstract 12112: Near Infrared Spectroscopic Characterization of Cardiac and Renal Fibrosis
Authors: John Adeola Adegoke, Callum Gassner, Isaac O Afara, Varun Sharma, Sheila K Patel, Kamila Kochan, Louise M Burrell, Jaishankar RAMAN, Bayden R Wood
Journal: Circulation (2021)

Introduction: Fibrosis is significantly associated with nearly all forms of heart and kidney disease. Clinical diagnosis of fibrosis is currently reliant on conventional methods that do not have the sensitivity and specificity required for effective diagnosis. Hypothesis: An handheld portable near-infrared (NIR) spectrometer, usable intraoperatively coupled to machine learning algorithms can discriminate between fibrotic and healthy cardiac and renal tissue. We sought to validate this in an animal model. Methods: 10 Male Sprague Dawley rats (SDR) with either induced cardiac (SDR-H) and renal (SDR-K) fibrosis (n=5) compare to normal controls (n=5). Hearts from all rats were used as tissue screening in model validation as they contain a high amount of collagen. Multiple tissue samples were harvested from SDR-K ( n fibrosis = 12, n control = 4) and SDR-H ( n fibrosis = 12, n control = 4) groups. NIR spectra (1350 - 2500 nm) were acquired from all tissue sections. Results: Stained sections showed insignificant differences between the fibrotic SDR-H and their corresponding controls as collagen fibrils dominated both groups. SDR-K showed distinguishable features between examined groups. NIR absorption at 1509, 1725, 2055, and 2306 nm were found to be highly indicative of fibrosis (Figure1). PCA (57% explained variance) and PLS-DA (sensitivity: 96%) showed excellent discrimination for SDR-K groups while the heart shows no meaningful discrimination for SDR-H groups. SVM and LR analysis corroborated these results by achieving a 98% classification accuracy for SDR-K and no discrimination for SDR-H. All machine learning models were cross-validated with outcomes of histological staining to establish a robust interpretation and underpin their pathological meanings. Conclusions: NIR accurately diagnoses cardiac and renal fibrosis in rats model. There is potential for this technology to be translated into an intraoperative instrument for tissue diagnosis
TMOD-11. A PREDICTIVE MICROFLUIDIC MODEL OF VASCULARIZED GLIOMA TUMORS TO ASSESS TRAFFICKING OF THERAPEUTICS ACROSS THE BLOOD-BRAIN BARRIER
Authors: Cynthia Hajal, Joelle Straehla, Giovanni Offeddu, Hannah Safford, Paula Hammond, Roger Kamm
Journal: Neuro-Oncology (2021)

Abstract Although important distinctions exist between subtypes of HGGs, all patients fare poorly with a 5-year survival of &amp;lt; 5%. The infiltrative growth of HGGs imposes significant challenges to treatment, with the presence of residual microscopic tumors post-surgery and hampered chemotherapeutic penetration due to the blood-brain barrier (BBB), a highly selective endothelium regulating transport between blood and brain. Moreover, current preclinical models are costly, low throughput, and often fail to predict drug performance in the clinic. There is thus an increasing need for in vitro models of HGG tumors, surrounded by a realistic BBB vasculature, to recapitulate therapeutic trafficking. To this end, we engineered a high-throughput microfluidic model composed entirely of human cells where HGG spheroids are embedded in a BBB microvascular network of endothelial cells, pericytes, and astrocytes. Tumors co-opt the vasculature as observed in patients and BBB permeability measurements with perfused dextran demonstrate unaltered paracellular transport near and far from the tumors. Lipoprotein receptor protein 1 (LRP1) expression, however, is increased near HGG spheroids. These results were leveraged to synthesize layer-by-layer nanoparticles with angiopep-2 ligands exhibiting high affinity to LRP1 for targeted delivery. Angiopep-2 nanoparticles displayed the largest permeability across the BBB near tumors compared to bare nanoparticles. Knock-down of LRP1 in the BBB-HGG model decreased angiopep-2 nanoparticle permeability confirming LRP1-mediated transport. We next assessed the therapeutic implications of our findings by encapsulating cisplatin in the particles. Administration of cisplatin-loaded angiopep-2 nanoparticles resulted in significant tumor shrinkage with targeted apoptosis in the tumor area compared to bare cisplatin nanoparticles or free cisplatin which damaged the surrounding healthy BBB vessels. Validations in orthotopic tumor-bearing mice are ongoing. In summary, we propose a novel preclinical model with a functional human BBB vasculature surrounding HGG tumors for high-throughput investigations and validate that this platform predicts the transport of targeted drug-loaded carriers.
Abstract 11145: Waist Circumference is a Predicter of All-Cause Death in General Population in Wanshou Lu
Authors: Man Li, Ping Zhu
Journal: Circulation (2021)

Introduction: The accumulation of abdominal fat increases risk of metabolic disorders and premature death. Whether waist circumference (WC), a surrogate marker for abdominal adiposity can predict all-cause death in general population is still inconclusive. Hypothesis: We assessed the hypothesis that higher level of WC is significantly associated with long-term all-cause death in general population. Methods: In this prospective cohort study, a total of 1521 consecutive subjects were included. The subjects. The end point was all-cause death. The association between Waist circumference and outcomes was investigated using multivariable COX regression. Results: During a median follow up of 9.1 years, there were 265 patients died. Kaplan-Meier survival estimates indicated that the patients with higher levels of waist circumference (WC&gt; 94cm) had a significantly increased risk of all-cause death (log-rank p&lt;0.001). After adjustment for potential confounders, multiple COX regression models showed that higher level of WC was an independent predictor in developing all-cause death (HR 3.02; 95% CI: 1.88-4.83; p&lt;0.001). We saw a significant increase of AUC in ROC curve after addition of WC to a clinical model, the increase of AUC is (0.586 vs 0.619) for long-term all-cause death (p&lt;0.001). Furthermore, WC significantly improved the net reclassification index (0.629; P=0.001), and integrated discrimination index (0.035; P=0.002). Conclusion: In conclusion, higher level of WC is significantly associated with long-term all-cause death. WC may provide incremental prognostic value beyond traditional risks factors. Key words: Waist circumference, obesity, all-cause death
Paralysis of the cytotoxic granule machinery is a new cancer immune evasion mechanism mediated by chitinase 3-like-1
Authors: Abbass Darwich, Alessandra Silvestri, Mohamed-Reda Benmebarek, Juliette Mouriès, Bruno Cadilha, Alessia Melacarne, Lapo Morelli, Domenico Supino, Alexandre Taleb, Hannah Obeck, Claudio Sustmann, Agnese Losurdo, Giovanna Masci, Giuseppe Curigliano, Sebastian Kobold, Giuseppe Penna, Maria Rescigno
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Natural killer (NK) cells require a functional lytic granule machinery to mediate effective antitumor responses. Evading the lytic cargo deployed at the immune synapse (IS) could be a critical step for cancer progression through yet unidentified mechanisms. Methods NK cell antibody-dependent cellular cytotoxicity (ADCC) is a major determinant of the clinical efficacy of some therapeutic antibodies including the anti-HER2 Trastuzumab. Thus, we screened sera of Trastuzumab-resistant HER2 +patients with breast cancer for molecules that could inhibit NK cell ADCC. We validated our findings in vitro using cytotoxicity assays and confocal imaging of the lytic granule machinery and in vivo using syngeneic and xenograft murine models. Results We found that sera from Trastuzumab-refractory patients could inhibit healthy NK cell ADCC in vitro. These sera contained high levels of the inflammatory protein chitinase 3-like 1 (CHI3L1) compared with sera from responders and healthy controls. We demonstrate that recombinant CHI3L1 inhibits both ADCC and innate NK cell cytotoxicity. Mechanistically, CHI3L1 prevents the correct polarization of the microtubule-organizing center along with the lytic granules to the IS by hindering the receptor of advanced glycation end-products and its downstream JNK signaling. In vivo, CHI3L1 administration drastically impairs the control of NK cell-sensitive tumors, while CHI3L1 blockade synergizes with ADCC to cure mice with HER2 +xenografts. Conclusion Our work highlights a new paradigm of tumor immune escape mediated by CHI3L1 which acts on the cytotoxic machinery and prevents granule polarization. Targeting CHI3L1 could mitigate immune escape and potentiate antibody and cell-based immunotherapies.
Racial, Ethnic, and Gender Disparities in Awareness of Preexposure Prophylaxis Among HIV-Negative Heterosexually Active Adults at Increased Risk for HIV Infection — 23 Urban Areas, United States, 2019
Authors: Amy R. Baugher, Lindsay Trujillo, Dafna Kanny, Jincong Q. Freeman, Terence Hickey, Catlainn Sionean, Ebony Respress, Johanna Chapin Bardales, Ruthanne Marcus, Teresa Finlayson, Cyprian Wejnert, Yingbo Ma, Hugo Santacruz, Ekow Kwa Sey, Adam Bente, Anna Flynn, Sheryl Williams, Willi McFarland, Desmond Miller, Danielle Veloso, Alia Al-Tayyib, Daniel Shodell, Irene Kuo, Jenevieve Opoku, Monica Faraldo, David Forrest, Emma Spencer, David Melton, Jeff Todd, Pascale Wortley, Antonio D. Jimenez, David Kern, Irina Tabidze, Narquis Barak, Jacob Chavez, William T. Robinson, Colin Flynn, Danielle German, Monina Klevins, Conall O’Cleirigh, Shauna Onofrey, Vivian Griffin, Emily Higgins, Corrine Sanger, Abdel R. Ibrahim, Corey Rosmarin-DeStafano, Afework Wogayehu, Meaghan Abrego, Bridget J. Anderson, Ashley Tate, Sarah Braunstein, Sidney Carrillo, Alexis Rivera, Lauren Lipira, Timothy W. Menza, E. Roberto Orellana, Tanner Nassau, Jennifer Shinefeld, Kathleen A. Brady, Sandra Miranda De León, María Pabón Martínez, Yadira Rolón-Colón, Meredith Brantley, Monica Kent, Jack Marr, Jie Deng, Margaret Vaaler, Salma Khuwaja, Zaida Lopez, Paige Padgett, Jennifer Kienzle, Toyah Reid, Brandie Smith, Sara Glick, Tom Jaenicke, Jennifer Reuer
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In 2019, heterosexual sex accounted for 23% of new HIV diagnoses in the United States and six dependent areas (1). Although preexposure prophylaxis (PrEP) can safely reduce the risk for HIV infection among heterosexual persons, this group is underrepresented in PrEP research (2). CDC analyzed National HIV Behavioral Surveillance (NHBS) data to describe PrEP awareness among heterosexually active adults in cities with high HIV prevalence. Overall, although 32.3% of heterosexually active adults who were eligible were aware of PrEP, <1% used PrEP. Racial, ethnic, and gender disparities were identified, with the lowest awareness of PrEP among residents of Puerto Rico (5.8%) and Hispanic or Latino (Hispanic) men (19.5%) and women (17.6%). Previous studies have found that heterosexual adults are interested in taking PrEP when they are aware of it (3); tailoring PrEP messaging, including Spanish-language messaging, to heterosexual adults, might increase PrEP awareness and mitigate disparities in use.
C-reactive protein rise in response to macronutrient deficit early in critical illness: sign of inflammation or mediator of infection prevention and recovery
Authors: Catherine Ingels, Lies Langouche, Jasperina Dubois, Inge Derese, Sarah Vander Perre, Pieter J. Wouters, Jan Gunst, Michaël Casaer, Fabian Güiza, Ilse Vanhorebeek, Greet Van den Berghe
Journal: Intensive Care Medicine (2021)
Abstract 12591: Mitochondrial Dysfunction and Reticulocytes Maturation: Contribution to the Pathogenesis of Pulmonary Hypertension
Authors: Maki Niihori, Joel James, Mathews Valuparampil Varghes, Ruslan Rafikov, Olga Rafikova
Journal: Circulation (2021)

Introduction: Sugen/Hypoxia treated rats and idiopathic pulmonary arterial hypertension (PAH) patients have increased circulating levels of cell-free heme (CFH). However, the mechanisms responsible for the elevated CFH and its pathogenic role are not fully identified. Hypothesis: Mitochondrial energy plays a critical role in the maturation of the red blood cell precursors, reticulocytes (RTC). We propose that incomplete RTC maturation due to mitochondrial dysfunction (MD) could increase RTC fragility and rupture, elevate the plasma CFH and promote PAH. Methods: The rat model of severe MD induced by NFU1 G206C mutation is associated with spontaneous PAH phenotype. This model was used to study erythropoiesis activation, total/immature RTC count, and plasma CFH levels. FITC-dextran extravasation was analyzed in fresh transversely cut pulmonary slices 24h after FITC-dextran injection (60 mg/kg. i.v.) by ChemiDoc MP Imaging System. The effects of free heme in vitro were evaluated using pulmonary arterial smooth muscle cells (PASMCs) isolated from NFU1 G206C and WT rats. Results: NFU1 G206C rats had increased erythropoietin levels and significantly higher total and immature RTC counts compared to WTs. In contrast, NFU1 G206C rats with a restored mitochondrial function, achieved by a chronic supplementation with lipoic acid (LA,1.7 mM orally), had normalized total/immature RTC counts (WT/NFU1 G206C /NFU1 G206C +LA for total and immature RTC: 2.5±0.2%/4.4±0.3%/3.4±0.3%, p&lt;0.002 and 2.2±0.4%/9.8±1.9%/0.8±0.2%, p&lt;0.001, N=8-12). These changes corresponded to the significantly elevated plasma CFH levels and elevated extravasation of FITC-dextral in the lungs in untreated NFU1 G206C rats, suggesting the disruptive effect of CFH on the pulmonary endothelial barrier. Finally, the exposure of PASMC isolated from NFU1 G206C rats to heme (50μM) significantly increased the proliferation rate ~1.5 and ~2.9 folds compared to untreated NFU1 G206C or WT PASMC. Conclusions: We conclude that MD mediates activation of erythropoiesis coupled with an impaired RTC maturation. These effects promote an increase in circulating CFH, disruption of endothelial barrier, and elevated rate of PASMC proliferation, contributing to the PAH pathobiology.
QOLP-02. HEALTH-RELATED QUALITY OF LIFE (HRQOL) AMONG PEDIATRIC PATIENTS WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMA (PN) IN THE UNITED STATES: PERSPECTIVES OF THE PATIENTS AND CAREGIVERS
Authors: Xiaoqin Yang, Hyun Kyoo Yoo, Suvina Amin, Wendy Cheng, Heather Sipsma, Sanjana Sundaresan, Lujia Zhang, Mei Sheng Duh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND PNs occur in 30-50% of pediatric patients with NF1, often resulting in debilitating pain, mobility limitations, significant disfigurement, and may be life-threatening. Real-world evidence on the HRQoL of pediatric NF1 PN patients is limited. METHODS Patients ages 8-18 years with NF1 PN (treatment-naïve/new on selumetinib [≤ 1 month of use]) and their caregivers were recruited through Children’s Tumor Foundation to participate in an online cross-sectional survey (12/2020-1/2021). HRQoL measures included Pediatric Quality of Life Inventory (PedsQL; Acute version), Pain Interference Index (PII), and Patient-Reported Outcomes Measurement Information System (PROMIS) mobility and upper extremity functioning subscales. Patients provided self-reported responses; caregivers provided proxy responses and patient characteristics. Agreement between patient-reports and caregiver proxies was assessed using intra-class correlation coefficients (ICCs). RESULTS 61 patient-caregiver dyads participated in the survey. Patients were mostly white/Caucasian (90.2%), 50.8% female, with a median (range) age of 13.0 (11-16) years. Most were treatment-naïve (96.7%), with NF1 and PN diagnosis for &amp;gt; 5 years (91.8%, 82.0%). On the PedsQL (range: 0-100; higher=better; healthy patient mean scores typically &amp;gt; 80), patient-reported mean scores were 50.3, 56.1, 60.7, and 63.7 for school, emotional, social, and physical functioning; mean total score= 58.5. Caregiver-proxy mean scores ranged from 49.9-61.5 across subscales; mean total score= 55.4. Among patients reporting pain in the last 7 days, PII mean scores (range: 0-6; higher=more interference) were 3.0 (patient-reports) and 2.9 (caregiver proxies). Among patients with movement difficulty in the past 7 days, mean PROMIS scales t-scores (distribution mean= 50; higher=better) were 40.2 and 39.5 (patient-reports), and 35.6 and 30.1 (caregiver proxies), for mobility and upper extremity functioning. ICCs were very good, ranging from 0.85-0.93 across HRQoL measures. CONCLUSION NF1 PN can have substantial negative impact on pediatric patients, as demonstrated across various HRQoL domains, highlighting the importance of collecting patient-centered outcomes to guide treatment decisions.
Outcomes with Venetoclax in Relapsed Acute Myeloid Leukemia after Allogenic Hematopoietic Stem Cell Transplantation: A Systemic Review and Meta-Analysis
Authors: Pranali Santhoshini Pachika, Moazzam Shahzad, Razwana Khanam, Adeel Masood, Zahoor Ahmed, S Fatima Ali, Asmi Chattaraj, Muhammad Tahir, Faiz Anwer, Ramesh Balusu, Sibgha Gull Chaudhary, Sunil Abhyankar, Nausheen Ahmed, Joseph P. McGuirk, Muhammad Umair Mushtaq
Journal: Blood (2021)
Abstract 10687: Structural Remodeling of Na <sub>V</sub> 16 Channel Clusters Contributes to Arrhythmogenic Late Sodium Current in the Presence of D96V Mutant Calmodulin
Authors: Heather Struckman, Mikhail Tarasov, yusuf olgar, Alec Miller, Jonathan P Davis, Sandor Gyorke, Rengasayee Veeraraghavan, Przemyslaw Radwanski
Journal: Circulation (2021)

Calmodulin facilitates normal sodium channel (Na V ) inactivation, necessary to prevent proarrhythmic late sodium current (I Na ). Previous studies have implicated Na V 1.6 dysfunction in late I Na -mediated arrhythmias. Therefore we investigated Na V dysregulation by arrhythmogenic CaM mutant D96V. Chinese hamster ovary cells expressing Na V 1.6 were transfected with either WT- or D96V-CaM. STED microscopy revealed enlarged Na V 1.6 clusters in cells receiving D96V-CaM relative to WT. Therefore we explored Na V 1.6 remodeling in transgenic mice with cardiac-specific expression of D96V-CaM (cD96V). Confocal microscopy confirmed expression of Na V 1.6 and FLAG-tagged D96V-CaM in a striated pattern along with RyR2 in cD96V hearts, consistent with T-tubular localization. STORM microscopy enabled the quantitative assessment of Na V 1.6 clustering. In both WT and cD96V hearts, ~50% of Na V 1.6 clusters localized &lt;100 nm from RyR2. However, Na V 1.6 density within these regions increased 67% in cD96V relative to WT. We probed the functional impact of this surprising remodeling using SICM-guided “smart” patch clamp recording of NaV activity from T-tubule openings. The number of NaVs as well as frequency of late Na V 1.6 burst openings were significantly increased in cD96V myocytes relative to WT (Fig 1). Previous work implicates aberrant late Na V 1.6 activity in proarrhythmic Ca2+ mishandling. Indeed, STORM revealed significant enrichment of NCX near Na V 1.6 in both WT and cD96V. Consistent with these data cD96V myocytes displayed larger, more frequent Ca2+ sparks relative to WT. This effect was reversed by cardiac-specific Na V 1.6 knockout. To our knowledge, this is the first report of proarrhythmic cardiac structural remodeling secondary to a defect in calmodulin, which may shed mechanistic insight into calmodulinopathy.
Scalable and modular wireless-network infrastructure for large-scale behavioural neuroscience
Authors: Raza Qazi, Kyle E. Parker, Choong Yeon Kim, Ruediger Rill, Makenzie R. Norris, Jaeyoon Chung, John Bilbily, Jenny R. Kim, Marie C. Walicki, Graydon B. Gereau, Hyoyoung Lim, Yanyu Xiong, Jenna R. Lee, Melissa A. Tapia, Alexxai V. Kravitz, Matthew J. Will, Sangtae Ha, Jordan G. McCall, Jae-Woong Jeong
Journal: Nature Biomedical Engineering (2021)
Abstract 12460: The Effect of Alirocumab on the Plasma Metabolome and Lipidome in End-Stage-Renal Disease
Authors: Teodoro Bottiglieri, Ankit Mehta, Cara East
Journal: Circulation (2021)

Introduction: Atherosclerotic disease is the major cause of morbidity and mortality among patients maintained on dialysis for end-stage renal disease (ESRD). Cardiovascular disease specifically accounts for almost 50% of deaths of these patients. In a pilot study to determine the safety of Alirocumab we investigated the plasma metabolome and lipidome in patients on dialysis and after treatment with a PCSK9 inhibitor. Methods: We recruited 14 subjects (10 male/4 female) from outpatient nephrology practices on hemodialysis (n=12) or peritoneal dialysis (n=2) for 3 months without complications. Subjects received Alirocumab (150 mg, i.m.) every 2 weeks. Blood was drawn from 13 subjects at baseline and after 12 weeks (6 injections) at completion of the trial. In addition, blood was drawn from 21 healthy controls. Plasma obtained was stored at -80 o C for biomarker analysis. Targeted metabolomic analysis allowed quantitative detection of 542 metabolites including 480 lipid species in 13 lipid classes. This analysis was performed by liquid chromatography mass spectrometry using the Quant 500 metabolomic kit. Results: Metabolomic analysis identified 152 metabolites significantly different (FDR p&amp;lt0.05) between control and ESRD subjects. Notably, various elevated metabolites as well as lower triglyceride and phosphatidylcholine lipid species. Twenty-three metabolites were significantly decreased after Alirocumab treatment (FDR paired t-test, p&amp;lt0.05), all of which were lipid species from the following classes: cholesterol esters, ceramides, hexosylceramides and sphingomyelins (Figure 1). Conclusions: Subjects with ESRD have dysregulation of lipid metabolism that may contribute to atherosclerosis. The effect of Alirocumab on plasma ceramides and sphingomyelins is of particular interest since increased levels in these lipid species have been shown to be associated with vascular disease and increased mortality.