tbuckley/cabot-search huggingface dataset:
Phenotypic Heterogeneity and Metastasis of Breast Cancer Cells
Authors: Lauren A. Hapach, Shawn P. Carey, Samantha C. Schwager, Paul V. Taufalele, Wenjun Wang, Jenna A. Mosier, Nerymar Ortiz-Otero, Tanner J. McArdle, Zachary E. Goldblatt, Marsha C. Lampi, Francois Bordeleau, Jocelyn R. Marshall, Isaac M. Richardson, Jiahe Li, Michael R. King, Cynthia A. Reinhart-King
Journal: Cancer Research (2021)

Abstract Although intratumoral genomic heterogeneity can impede cancer research and treatment, less is known about the effects of phenotypic heterogeneities. To investigate the role of cell migration heterogeneities in metastasis, we phenotypically sorted metastatic breast cancer cells into two subpopulations based on migration ability. Although migration is typically considered to be associated with metastasis, when injected orthotopically in vivo, the weakly migratory subpopulation metastasized significantly more than the highly migratory subpopulation. To investigate the mechanism behind this observation, both subpopulations were assessed at each stage of the metastatic cascade, including dissemination from the primary tumor, survival in the circulation, extravasation, and colonization. Although both subpopulations performed each step successfully, weakly migratory cells presented as circulating tumor cell (CTC) clusters in the circulation, suggesting clustering as one potential mechanism behind the increased metastasis of weakly migratory cells. RNA sequencing revealed weakly migratory subpopulations to be more epithelial and highly migratory subpopulations to be more mesenchymal. Depletion of E-cadherin expression from weakly migratory cells abrogated metastasis. Conversely, induction of E-cadherin expression in highly migratory cells increased metastasis. Clinical patient data and blood samples showed that CTC clustering and E-cadherin expression are both associated with worsened patient outcome. This study demonstrates that deconvolving phenotypic heterogeneities can reveal fundamental insights into metastatic progression. More specifically, these results indicate that migratory ability does not necessarily correlate with metastatic potential and that E-cadherin promotes metastasis in phenotypically sorted breast cancer cell subpopulations by enabling CTC clustering. Significance: This study employs phenotypic cell sorting for migration to reveal a weakly migratory, highly metastatic breast cancer cell subpopulation regulated by E-cadherin, highlighting the dichotomy between cancer cell migration and metastasis.
Genetics of atrial fibrillation—practical applications for clinical management: if not now, when and how?
Authors: Shinwan Kany, Bruno Reissmann, Andreas Metzner, Paulus Kirchhof, Dawood Darbar, Renate B Schnabel
Journal: Cardiovascular Research (2021)

Abstract The prevalence and economic burden of atrial fibrillation (AF) are predicted to more than double over the next few decades. In addition to anticoagulation and treatment of concomitant cardiovascular conditions, early and standardized rhythm control therapy reduces cardiovascular outcomes as compared with a rate control approach, favouring the restoration, and maintenance of sinus rhythm safely. Current therapies for rhythm control of AF include antiarrhythmic drugs (AADs) and catheter ablation (CA). However, response in an individual patient is highly variable with some remaining free of AF for long periods on antiarrhythmic therapy, while others require repeat AF ablation within weeks. The limited success of rhythm control therapy for AF is in part related to incomplete understanding of the pathophysiological mechanisms and our inability to predict responses in individual patients. Thus, a major knowledge gap is predicting which patients with AF are likely to respond to rhythm control approach. Over the last decade, tremendous progress has been made in defining the genetic architecture of AF with the identification of rare mutations in cardiac ion channels, signalling molecules, and myocardial structural proteins associated with familial (early-onset) AF. Conversely, genome-wide association studies have identified common variants at over 100 genetic loci and the development of polygenic risk scores has identified high-risk individuals. Although retrospective studies suggest that response to AADs and CA is modulated in part by common genetic variation, the development of a comprehensive clinical and genetic risk score may enable the translation of genetic data to the bedside care of AF patients. Given the economic impact of the AF epidemic, even small changes in therapeutic efficacy may lead to substantial improvements for patients and health care systems.
Abstract P093: Sex-stratified Associations Of Urine Electrolytes With 10th &amp; 90th Percentiles Of Systolic Blood Pressure Distribution
Authors: Abu Mohd Naser, Mahbubur Rahman, Alvaro Alonso, Viola Vaccarino, Matthew Gribble
Journal: Circulation (2021)

Introduction: Electrolytes intake influence systolic blood pressure (SBP). Studies often explore the association of urine electrolytes with the conditional mean difference of SBP, but limited data exist on the sex-specific associations of urine electrolytes’ excretion with low and high end SBP distribution. We examined the sex-stratified association of urine electrolytes with the 10th and 90th percentiles of SBP. Methods: We pooled 9,804 person-visits (n =1467 participants) data of 24-hour urine electrolytes and SBP from three cohorts in coastal Bangladesh. We created sex-stratified restricted cubic spline (RCS) plots from quantile regression for illustrating the associations of urine sodium (Na), potassium (K), calcium (Ca), and magnesium (Mg) excretion with the 10th and 90th percentile of SBP distribution, adjusted for age, body mass index, physical activity, smoking, alcohol consumption, sleep hours, religion, household wealth, cohort ID, and seasonality. Four knots at the 5th, 35th, 65th, and 95th percentiles of each electrolyte distribution were used to create RCS plots. Results: We found linear positive associations for urine Na with 10th and 90th percentiles of SBP for males, but such association for the 10th percentile of SBP for females was less steep. Negative associations were found between urine K and SBP for males for the 90th percentile of SBP; no such association was found for the 10th percentile of SBP. Linear negative associations were found between urine Mg and SBP for males for both the 10th and 90th percentile of SBP distributions, but not for females. There was no association of urine Ca and SBP for both sexes for the 10th percentile of SBP, but negative associations existed for the 90th percentile of SBP for males. Conclusion: Sex-specific associations of urine electrolytes and SBP varied for the low and high end of SBP distribution. Males with higher SBP could benefit from high urine K, Ca, and Mg, representing high intakes of these minerals. However, such benefits may not be present for females.
Abstract 15121: Mortality in Cancer Patients Undergoing Percutaneous Coronary Intervention: Insights From a Hospital-based Cross-sectional Study
Authors: Anusha R Gaddam, Temitope Ajibawo, RIKINKUMAR PATEL
Journal: Circulation (2020)

Introduction: Comorbid risk factors between cancer and coronary artery diseases (CAD) and underlying pathogenesis of inflammation and oxidative stress led to an increase in the number of cancer patients developing CAD. Hypothesis: The prime purpose of our hospital-based study is to evaluate the risk of mortality due to cancer and chronic comorbidities in post-percutaneous coronary intervention (PCI) patients. Methods: We conducted a cross-sectional study using the nationwide inpatient sample (NIS, 2012 to 2014) including 1,131,415 adult patients undergoing PCI with placement of non-drug and/or drug-eluting coronary artery stents. The logistic regression model was used to assess the odds ratio (OR) of the association between comorbid cancer and mortality in post-PCI hospitalized patients. Results: Most of the post-PCI patients with cancer were older adults (mean age 70.6 years), males (71.8%), and Caucasians (80.6%). Females (OR 1.28, 95% CI 1.24-1.34) had higher odds of post-PCI mortality risk compared to males. Among all comorbidities, coagulopathy and deficiency anemia were associated with increased risk of mortality by three times (95% CI 2.837-3.250) and 1.6 times (95% CI 1.534-1.692), respectively in post-PCI hospitalized patients. Comorbid cancer was associated with an increased risk of mortality in post-PCI hospitalized patients (OR 1.88, 95% CI 1.69-2.09) after controlling for potential confounders. Conclusions: Cancer is a significant risk factor increasing the risk of mortality by 88% in post-PCI hospitalized patients. An integrated care model requiring more vigilance and aggressive management for the complex patient population with cancer and other comorbidities are needed.
External Validation and Addition of Prostate-specific Membrane Antigen Positron Emission Tomography to the Most Frequently Used Nomograms for the Prediction of Pelvic Lymph-node Metastases: an International Multicenter Study
Authors: Dennie Meijer, Pim J. van Leeuwen, Matthew J. Roberts, Amila R. Siriwardana, Andrew Morton, John W. Yaxley, Hemamali Samaratunga, Louise Emmett, Peter M. van de Ven, Henk G. van der Poel, Maarten L. Donswijk, Thierry N. Boellaard, Ivo G. Schoots, Daniela E. Oprea-Lager, Geoffrey D. Coughlin, André N. Vis
Journal: European Urology (2021)

Different nomograms exist for the preoperative prediction of pelvic lymph-node metastatic disease in individual patients with prostate cancer (PCa). These nomograms do not incorporate modern imaging techniques such as prostate-specific membrane antigen (PSMA) positron emission tomography (PET).To determine the predictive performance of the Briganti 2017, Memorial Sloan Kettering Cancer Center (MSKCC), and Briganti 2019 nomograms with the addition of PSMA-PET in an international, multicenter, present-day cohort of patients undergoing robot-assisted radical prostatectomy (RARP) and extended pelvic lymph-node dissection (ePLND) for localized PCa.All 757 eligible patients who underwent a PSMA-PET prior to RARP and ePLND in three reference centers for PCa surgery between January 2016 and November 2020 were included.Performance of the three nomograms was assessed using the receiver operating characteristic curve-derived area under the curve (AUC), calibration plots, and decision curve analyses. Subsequently, recalibration and addition of PSMA-PET to the nomograms were performed.Overall, 186/757 patients (25%) had pelvic lymph-node metastatic (pN1) disease on histopathological examination. AUCs of the Briganti 2017, MSKCC, and Briganti 2019 nomograms were 0.70 (95% confidence interval [95% CI]: 0.64-0.77), 0.71 (95% CI: 0.65-0.77), and 0.76 (95% CI: 0.71-0.82), respectively. PSMA-PET findings showed a significant association with pN1 disease when added to the nomograms (p < 0.001). Addition of PSMA-PET substantially improved the discriminative ability of the models yielding cross-validated AUCs of 0.76 (95% CI: 0.70-0.82), 0.77 (95% CI: 0.72-0.83), and 0.82 (95% CI: 0.76-0.87), respectively. In decision curve analyses, the addition of PSMA-PET to the three nomograms resulted in increased net benefits.The addition of PSMA-PET to the previously developed nomograms showed substantially improved predictive performance, which suggests that PSMA-PET is a likely future candidate for a modern predictive nomogram.Different tools have been developed to individualize the prediction of prostate cancer spread to lymph nodes before surgery. We found that the inclusion of modern imaging (prostate-specific membrane antigen positron emission tomography) improved substantially the overall performance of these prediction tools.
Influence of Angiotensin Receptor Blocker (ARB) and Statin on the Prevention of Coronary Atherosclerosis Progression: A 3D Intravascular Ultrasound(IVUS) Study
Authors: Waseda K, Ozaki Y, Yasukawa T, Shinjoh H, Takashima H, Kohno T, Kuroda Y, Wakita Y, Hishida H
Journal: Circulation (2005)
Abstract 16123: <i>In Vitro</i> Valve-on-chip Platform to Assess the Effects of Hemodynamic and Mechanical Stimuli on Early Calcific Disease Progression
Authors: Ishita Tandon, Cody Gish, Nasya Sturdivant, Asya Ozkizilcik, Celeste Dunn, Prashanth Balaji Devisetty Ravishankar, Kartik Balachandran
Journal: Circulation (2020)

Introduction: Calcific aortic valve disease (CAVD) involves mechanical stress, endothelial dysfunction, matrix remodeling, and mineral deposition. Complex mechanical and hemodynamic environment around the valve closely affects its function, biology, and disease. However, the exact role of these forces in regulating cellular dysfunction during disease initiation is yet to be elucidated. Methods and Results: We developed a 3D valve-on-chip (VOC) model that encompasses cell-cell and cell-matrix interactions, flow shear stresses and cyclic strains, better mimicking the native valve. The multilayered VOC construct was built in house using photolithography and soft lithography and a silicon based polymer (Fig.1A). Valve endothelial cells (VECs) are seeded in a monolayer on a porous PDMS membrane (Fig.B) which separates the VECs from the a matrigel-collagen semi interpenetrating hybrid gel housing valve interstitial cells (VICs) (Fig.3C). We simulated either static or 20% (pathological) strain under quiescent or osteogenic conditions. Osteogenic VICs demonstrated nodule formation (Fig.1D) and had reduced redox ratios in 20% stretch conditions suggesting disease progression (Fig.1E,F). Effect of mechanical and hemodynamic forces on structure, function, and phenotypic changes in VECs and VICs particularly during disease initiation will be further assessed. Conclusions: This VOC model for VEC-VIC co-culture better mimics the native valve environment and can be used to study the early disease mechanisms. The VOC platform can be used as a drug testing tool and aid in development of treatment strategies through efficient employment in the laboratory. Further exploring the effect of mechanical and hemodynamic forces may reveal mechanosensitive signaling cascades involved in disease progression, which can be targeted for CAVD therapeutics.
Abstract 13169: US Prevalence Estimates of Individuals With Diabetes and Chronic Kidney Disease Indicated for SGLT-2 Inhibitor Initiation
Authors: Rahul Aggarwal, Kimberly Lu, Nicholas Chiu, George Bakris, Deepak L Bhatt
Journal: Circulation (2020)

Introduction: Since the CREDENCE trial results, the American Diabetes Association (ADA) recommends SGLT-2 inhibitors as first line therapy for patients with stage III Chronic Kidney Disease (CKD) or proteinuric CKD, regardless of baseline A1C. We project the number of US individuals with diabetes and renal disease that meets inclusion into the CREDENCE trial and that are recommended for SGLT-2 inhibitors based on the guidelines. Methods: Our initial cohort consisted of 48,710 individuals from the 2007-2016 National Health and Nutrition Examination Survey with survey weights designed to estimate the US population. CREDENCE eligible patients were patients with diabetes who had an eGFR of 30-90 and urine albumin-to-creatinine ratio (UACR) of &gt;300 mg/g. Guideline eligible patients were stage III CKD individuals and those with a UACR &gt; 30 mg/g. Results: In the US population, 21,411,059 (+/-708,233) individuals are &gt;=18 years and have diabetes. Of these individuals, 578,514 (+/-72,385) are CREDENCE eligible. Based on the ADA recommendations, 7,504,508 (+/- 342,139) adults with CKD and diabetes are recommended for an SGLT-2 inhibitor, representing 35.0% of individuals with diabetes. The mean age of guideline eligible individuals is 64.4 years, with 3,886,904 males (51.8%) and 3,617,604 females (48.2%). Conclusions: In the United States, a large number of individuals--approximately 35% of adults with diabetes--have renal disease characteristics that give them a first-line indication for SGLT-2 inhibitor initiation.
US obstetrician who performed unnecessary surgery is sentenced to 59 years
Authors: Owen Dyer
Journal: BMJ (2021)

A Virginia obstetrician has been sentenced to 59 years in prison for performing unnecessary operations, including removing ovaries and performing hysterectomies without women’s knowledge or consent.

Javaid Perwaiz, 71, was convicted in a federal court of healthcare fraud and making false statements relating to healthcare matters. The false statements concerned dozens of unneeded procedures he performed from 2010 to 2019. He billed insurers for $20m (£14m; €16m) for these procedures, prosecutors said.

The government has seized about $2m in assets, including two properties and a Bentley car. Perwaiz had two offices in the Chesapeake area, …
Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma
Authors: Yueyue Fan, Yuexin Cui, Wenyan Hao, Mengyu Chen, Qianqian Liu, Yuli Wang, Meiyan Yang, Zhiping Li, Wei Gong, Shiyong Song, Yang Yang, Chunsheng Gao
Journal: Bioactive Materials (2021)

Nanosuspensions, as a new drug delivery system for insoluble drugs, are only composed of a drug and a small amount of stabilizer, which is dispersed in an aqueous solution with high drug-loading, small particle size, high dispersion, and large specific surface area. It can significantly improve the dissolution, bioavailability, and efficacy of insoluble drugs. In this study, paclitaxel nanosuspensions ((PTX)NS) were prepared by an ultrasonic precipitation method, with the characteristics of simple preparation and easy repetition. With the help of a homologous targeting mechanism, a kind of glioma C6 cancer cell membrane (CCM)-coated (PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting. The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier (BBB) and selectively target tumor tissues. Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased. Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice. Finally, the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape. This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.
Targeting mesenchymal stromal cells plasticity to reroute acute myeloid leukemia course
Authors: Giulia Borella, Ambra Da Ros, Giulia Borile, Elena Porcù, Claudia Tregnago, Maddalena Benetton, Anna Marchetti, Valeria Bisio, Barbara Montini, Barbara Michielotto, Alice Cani, Anna Leszl, Elisabetta Campodoni, Monica Sandri, Monica Montesi, Silvia Bresolin, Stefano Cairo, Barbara Buldini, Franco Locatelli, Martina Pigazzi
Journal: Blood (2021)
To Perform or Not to Perform Surgery for Frail Patients?—Reply
Authors: Shipra Arya, Elizabeth L. George, Daniel E. Hall
Journal: JAMA Surgery (2021)

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Abstract 16479: A Comparison of Rates of Significant Coronary Artery Disease Found on Invasive Coronary Angiography in Patients Who Underwent Nuclear Stress Testing or CT Coronary Angiography as a Workup for Acute Coronary Syndrome
Authors: Jeanwoo Yoo, Jesse Kane, Jessica Hotelling, Eyal Menashe, William E Lawson
Journal: Circulation (2020)

Introduction: Chest pain syndromes are one of the most common causes of hospital admission. The correct diagnosis as cardiac [acute coronary syndromes (ACS)] with associated morbidity and mortality, or non-cardiac has important medical and legal consequences. Appropriate and timely diagnosis of these conditions is essential, yet limited literature exists comparing two common diagnostic tools, CT coronary angiography (CTCA) and nuclear stress testing (NST) in the acute inpatient setting. Methods: We conducted a retrospective analysis to determine rates of ischemia and intervention needed in patients without ischemic cardiac history, who were evaluated for ACS with NST or CTCA and who subsequently underwent invasive coronary angiography (IA) with iFR and angioplasty as appropriate. Results: We identified 121 CTCA cases and 45 NST cases. There were no significant difference in age, rates of hypertension, diabetes mellitus, renal disease, aspirin or statin use. However, there were more male patients in the CTCA group and higher mean GRACE scores and creatinine on admission in the NST group. Patients who underwent CTCA were found to have higher rates of significant coronary artery disease defined as iFR &lt; 0.9 or ≥70% stenosis on IA (63% vs 44%), and shorter mean length of stay (4.5 vs 6.5 days). Rates of artifact were higher in the NST group (64% vs 24%) and CTCA demonstrated higher specificity (90% vs 28%) and greater positive predictive value (92% vs. 41%) than NST. (Table 1) Conclusions: Our study found that CTCA compared to NST in admitted patients being evaluated for chest pain syndromes was associated with lower rates of reported artifact, shorter length of stay, higher rates of IA confirmed significant coronary disease, and higher specificity and positive predictive value for needed intervention when evaluated with IA. While limited by its single center analysis, our study demonstrates the potential value of CTCA in a real-world population which merits further study.