tbuckley/cabot-search huggingface dataset:
Steroid Hormone Receptor and Infiltrating Immune Cell Status Reveals Therapeutic Vulnerabilities of <i>ESR1</i>-Mutant Breast Cancer
Authors: Michelle M. Williams, Nicole S. Spoelstra, Spencer Arnesen, Kathleen I. O'Neill, Jessica L. Christenson, Jordan Reese, Kathleen C. Torkko, Andrew Goodspeed, Emmanuel Rosas, Toru Hanamura, Sharon B. Sams, Zheqi Li, Steffi Oesterreich, Rebecca B. Riggins, Britta M. Jacobsen, Anthony Elias, Jason Gertz, Jennifer K. Richer
Journal: Cancer Research (2020)

Mutations in ESR1 that confer constitutive estrogen receptor alpha (ER) activity in the absence of ligand are acquired by ≥40% of metastatic breast cancers (MBC) resistant to adjuvant aromatase inhibitor (AI) therapy. To identify targetable vulnerabilities in MBC, we examined steroid hormone receptors and tumor-infiltrating immune cells in metastatic lesions with or without ER mutations. ER and progesterone receptor (PR) were significantly lower in metastases with wild-type (WT) ER compared with those with mutant ER, suggesting that metastases that evade AI therapy by mechanism(s) other than acquiring ER mutations lose dependency on ER and PR. Metastases with mutant ER had significantly higher T regulatory and Th cells, total macrophages, and programmed death ligand-1 (PD-L1)-positive immune-suppressive macrophages than those with WT ER. Breast cancer cells with CRISPR-Cas9-edited ER (D538G, Y537S, or WT) and patient-derived xenografts harboring mutant or WT ER revealed genes and proteins elevated in mutant ER cells, including androgen receptor (AR), chitinase-3-like protein 1 (CHI3L1), and IFN-stimulated genes (ISG). Targeting these proteins blunted the selective advantage of ER-mutant tumor cells to survive estrogen deprivation, anchorage independence, and invasion. Thus, patients with mutant ER MBC might respond to standard-of-care fulvestrant or other selective ER degraders when combined with AR or CHI3L1 inhibition, perhaps with the addition of immunotherapy. SIGNIFICANCE: Targetable alterations in MBC, including AR, CHI3L1, and ISG, arise following estrogen-deprivation, and ER-mutant metastases may respond to immunotherapies due to elevated PD-L1+ macrophages.See related article by Arnesen et al., p. 539.
Abstract 14952: Hemodynamic Comparison of Left Ventricular Function in Pressure Overload- versus Volume Overload-Induced Heart Failure Models by Invasive Pressure-Volume Analysis
Authors: Mihály Ruppert, Christian Karime, Alex A Sayour, Attila Oláh, Dávid Nagy, Tímea Bálint, Béla Merkely, Tamás Radovits
Journal: Circulation (2020)

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p&lt;0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p&lt;0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p&gt;0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p&lt;0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.
Associations Between Carotid Artery Plaque Burden, Plaque Characteristics, and Cardiovascular Events
Authors: Gerd Brunner, Salim S. Virani, Wensheng Sun, Li Liu, Rhiannon C. Dodge, Vijay Nambi, Josef Coresh, Thomas H. Mosley, A. Richey Sharrett, Eric Boerwinkle, Christie M. Ballantyne, Bruce A. Wasserman
Journal: JAMA Cardiology (2020)

It remains unknown whether in an asymptomatic community-based cohort magnetic resonance imaging (MRI) measures of plaque characteristics are independently associated with incident cardiovascular disease (CVD) events when adjusted for carotid artery (CA) wall thickness, a measure of plaque burden.To assess associations of CA MRI plaque characteristics with incident CVD events.The Atherosclerosis Risk in Communities (ARIC) study is a prospective epidemiologic study of the incidence of CVD in 15 792 adults of which 2066 women and men were enrolled in the ARIC Carotid MRI substudy. ARIC participants were enrolled from 1987 to 1989, and the substudy was conducted between January 2004 and December 2005. Analysis began January 2017 and ended August 2020.Incident CVD events during a median (interquartile range [IQR]) follow-up time of 10.5 (8.1-10.9) years were assessed.Proportional hazards Cox analyses were performed to ascertain associations between MRI variables of CA plaque burden and plaque characteristics.Of 15 792 ARIC participants, 2066 were enrolled in the substudy, of whom 1256 (701 women [55.8%]) had complete data and were eligible for incident CVD analyses. Carotid artery plaques in participants with incident CVD events (172 [13.7%]) compared with those without (1084 [86.3%]) had a higher normalized wall index (median [IQR], 0.48 [0.36-0.62] vs 0.43 [0.34-0.55]; P = .001), maximum CA wall thickness (median [IQR], 2.22 [1.37-3.52] mm vs 1.96 [1.29-2.85] mm; P = .01), maximum CA stenosis (median [IQR], 5% [0%-22%] vs 0% [0%-13%]; P < .001), and when present, a larger lipid core volume (median [IQR], 0.05 [0.02-0.11] mL vs 0.03 [0.01-0.07] mL; P = .03), respectively. The presence of a lipid core was independently associated with incident CVD events when adjusted for traditional CVD risk factors and maximum CA wall thickness (hazard ratio, 2.48 [95% CI, 1.36-4.51]; P = .003), whereas the presence of calcification was not. The frequency of intraplaque hemorrhage presence in this population of individuals free of CVD at baseline who were not recruited for carotid stenosis was too small to draw any meaningful conclusions (intraplaque hemorrhage presence: 68 of 1256 participants [5.4%]). Carotid artery lumen area and maximum stenosis, which were overall low, were independently associated with incident CVD events when adjusted for traditional CVD risk factors, as anticipated.The presence of a CA lipid core on MRI is associated with incident CVD events independent of maximum CA wall thickness in asymptomatic participants.
FDA Approval Summary: Pertuzumab, Trastuzumab, and Hyaluronidase–zzxf Injection for Subcutaneous Use in Patients with HER2-positive Breast Cancer
Authors: Jennifer J. Gao, Christy L. Osgood, Yutao Gong, Hui Zhang, Erik W. Bloomquist, Xiling Jiang, Junshan Qiu, Jingyu Yu, Pengfei Song, Nam Atiqur Rahman, Haw-Jyh Chiu, Tiffany K. Ricks, Fatima Rizvi, Sherry Hou, Willie Wilson, Abde M. Abukhdeir, Jeffrey Seidman, Soma Ghosh, Reena Philip, William F. Pierce, Vishal Bhatnagar, Paul G. Kluetz, Richard Pazdur, Julia A. Beaver, Laleh Amiri-Kordestani
Journal: Clinical Cancer Research (2020)

On June 29, 2020, the FDA approved pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection (Phesgo) for the treatment of patients with HER2-positive early-stage and metastatic breast cancer. Patients should be selected for therapy based on an FDA-approved companion diagnostic test. Approval was primarily based on the FeDeriCa trial, a randomized, open-label, multicenter comparability study of pertuzumab, trastuzumab, and hyaluronidase-zzxf subcutaneous injection compared with intravenous pertuzumab and intravenous trastuzumab administered in the neoadjuvant and adjuvant settings with chemotherapy for the treatment of patients with early breast cancer. The pharmacokinetic endpoints were, first, to demonstrate that the exposure of subcutaneous pertuzumab was not inferior to that of intravenous pertuzumab, and then to demonstrate that the exposure of subcutaneous trastuzumab was not inferior to that of intravenous trastuzumab. The primary endpoints were met with the observed lower limit of the two-sided 90% confidence intervals above the prespecified noninferiority margins. The most common adverse reactions were alopecia, nausea, diarrhea, anemia, and asthenia. The totality of the evidence demonstrated comparability of the subcutaneous product to intravenous, allowing for extrapolation and approval of all breast cancer indications for which intravenous trastuzumab and pertuzumab are approved.
Abstract 14108: Does Primary Graft Dysfunction Increase First Year Intimal Thickness After Heart Transplantation?
Authors: Keith Nishihara, Babak Azarbal, Evan P Kransdorf, Lillian Benck, Jignesh K Patel, Jon A Kobashigawa
Journal: Circulation (2020)

Introduction: Primary graft dysfunction (PGD) has been reported in between 7-30% of heart transplant recipients with severe PGD known to have poor outcome. Due to graft dysfunction and potential for endothelial cell injury, it is not known whether all grades of PGD can increase first year intimal thickening, which may be a harbinger for clinical cardiac allograft vasculopathy (CAV). Methods: Between 2010 and 2017, we assessed 769 heart transplant patients and divided them into those patients with mild PGD (n=12), moderate PGD (n=35), severe PGD (n=36) and no PGD (n=686). Endpoints included 3-year survival and freedom from angiographic CAV (stenosis ≥30%) and non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, percutaneous coronary intervention, new congestive heart failure, pacemaker/implantable cardioverter-defibrillator placement, stroke); and 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR), antibody mediated rejection (AMR). First year intravascular ultrasound (IVUS) was performed at baseline 4-8 weeks and at 1 year after transplant. IVUS parameters included first-year average change in MIT and change in MIT ≥0.5mm. Results: First year change in average MIT and MIT ≥0.5mm and 3-year freedom from CAV were not significantly different in all groups. The severe PGD group compared to all groups had significantly lower 3-year survival and freedom from NF-MACE. There was lower freedom from various types of rejection in the PGD groups compared to the no PGD group. Specifically, 1-year freedom from ACR was significantly lower in the mild PGD group compared to the moderate PGD group and the no PGD group (see table). Conclusions: PGD grades do not appear to lead to increased first year intimal thickening or angiographic CAV at 3 years. Lower freedom from ACR in the mild PGD group and ATR in the severe PGD group will need further study. Larger numbers of patients are needed to confirm these findings.
Lightweight 3D bioprinting with point by point photocuring
Authors: Peng Zhang, Haoxuan Wang, Peng Wang, Yating Zheng, Linxiang Liu, Jun Hu, Yande Liu, Qing Gao, Yong He
Journal: Bioactive Materials (2020)

As photocrosslinkable materials, methacryloyl-modified hydrogels are widely used as bioinks in tissue engineering. Existing printing methods to use these hydrogels, including changing the viscosity of the material or mixing them with other printing components, have been explored, but their application has been limited due to low printing quality or high cost. In addition, the complex operation of bulky equipment restricts the application of these existing printing methods. This study presents a lightweight stereolithography-based three-dimensional (3D) bioprinting system with a smart mechanical and structural design. The developed bioprinter dimensions were 300 mm × 300 mm × 200 mm and it can be placed on a benchtop. The equipment has a mini bioink chamber to store a small amount of bioink for each printing. We systematically investigated the point-by-point curing process in the 3D bioprinting method, which can print mixed cells accurately and have good biocompatibility. Here, we provide a compact, low-cost stereolithography bioprinting system with excellent biocompatibility for 3D bioprinting with methacryloyl-modified hydrogels. It can be potentially used for drug screening, studying pathological mechanisms, and constructing biological disease models.
Abstract 14198: Anatomic Repair of Congenitally Corrected Transposition of the Great Arteries is Associated With Significant Mid- and Long-term Electrophysiologic Morbidity
Authors: Rebecca R Hartog, Kimberly J Watkins, Megan Wilde, Tiffany R Lim, Andrew Rodenbarger, Sunkyung Yu, Ray Lowery, Katherine Afton, Caren S Goldberg, Richard G Ohye, Martin J LaPage
Journal: Circulation (2020)

Introduction: Limited data exist on the electrophysiologic outcomes of patients undergoing anatomic repair (AR) for congenitally corrected transposition of the great arteries (ccTGA). AR was defined as an atrial switch procedure plus either arterial switch (ASO) or Rastelli operation. Aims: To report mid and late electrophysiologic outcomes after AR and identify risk factors for those outcomes. Methods: Single center retrospective cohort study of patients undergoing AR between 1993-2017. Data were collected from available records. Transplant-free survival to 1 year post repair was required for inclusion. Standard descriptive statistical analysis and Cox proportional hazards were used. Results: Of 85 patients included, 95% had lesions in addition to ccTGA: most commonly VSD (84%) and pulmonary stenosis or atresia (58%). Median age at AR was 1.5y (IQR 0.9-2.8) with Senning/ASO in 56%, Senning/Rastelli in 38%, and hemi-Senning/Glenn/Rastelli in 6%. During a median follow-up of 10.6y, 45 (53%) patients developed an arrhythmia requiring intervention. Atrial tachycardia (AT) in 27 (32%) or ventricular tachycardia (VT) in 11 (13%) patients required intervention at a median of 7.4y (IQR 1.6-15.3y) and 15.9y (IQR 4.5-17.9) post-AR, respectively. Treatments included chronic medications in 29 (64%), cardioversion in 15 (33%) and catheter ablation in 10 (22%). Median freedom from AT and VT was 17.3y and 25y post-AR, respectively. D-looped ventricles (p=0.03) and multiple operations prior to AR (p=0.02) were associated with increased AT risk; and native pulmonary stenosis with increased VT risk (p=0.01). Those needing heart failure/transplant referral had increased risk of both AT and VT (both p=0.04). Pacemaker was implanted for heart block and/or SND prior to or during AR in 14 (16%), immediately post-op in 9 (11%), and late (median 6y post-AR) in 24 (28%). ICDs were implanted in 5 (6% of cohort), 4 for primary prevention. No patient had an appropriate shock. Conclusions: Anatomic ccTGA repair is associated with significant electrophysiologic morbidity. AT, VT, and SND develop at a similar incidence to that reported for d-TGA patients after atrial switch. The incidence of AV block follows a similar trajectory to that of physiologically palliated ccTGA.
Updates in the quantitative assessment of liver fibrosis for nonalcoholic fatty liver disease: Histological perspective
Authors: Gwyneth Soon, Aileen Wee
Journal: Clinical and Molecular Hepatology (2020)

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) is a major cause of liver fibrosis and cirrhosis. Accurate assessment of liver fibrosis is important for predicting disease outcomes and assessing therapeutic response in clinical practice and clinical trials. Although noninvasive tests such as transient elastography and magnetic resonance elastography are preferred where possible, histological assessment of liver fibrosis via semiquantitative scoring systems remains the current gold standard. Collagen proportionate area provides more granularity by measuring the percentage of fibrosis on a continuous scale, but is limited by the absence of architectural input. Although not yet used in routine clinical practice, advances in second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy imaging show great promise in characterising architectural features of fibrosis at the individual collagen fiber level. Quantification and calculation of different detailed variables of collagen fibers can be used to establish algorithm-based quantitative fibrosis scores (e.g., qFibrosis, q-FPs), which have been validated against fibrosis stage in NAFLD. Artificial intelligence is being explored to further refine and develop quantitative fibrosis scoring methods. SHG-microscopy shows promise as the new gold standard for the quantitative measurement of liver fibrosis. This has reaffirmed the pivotal role of the liver biopsy in fibrosis assessment in NAFLD, at least for the near-future. The ability of SHG-derived algorithms to intuitively detect subtle nuances in liver fibrosis changes over a continuous scale should be employed to redress the efficacy endpoint for fibrosis in NASH clinical trials; this approach may improve the outcomes of the trials evaluating therapeutic response to antifibrotic drugs.
Evaluation of STEMI Regionalization on Access, Treatment, and Outcomes Among Adults Living in Nonminority and Minority Communities
Authors: Renee Y. Hsia, Harlan Krumholz, Yu-Chu Shen
Journal: JAMA Network Open (2020)

Cardiac care regionalization, specifically for patients with ST-segment elevation myocardial infarction (STEMI), has been touted as a potential mechanism to reduce systematic disparities by protocolizing the treatment of these conditions. However, it is unknown whether such regionalization arrangements have widened or narrowed disparities in access, treatment, and outcomes for minority communities.To determine the extent to which disparities in access, treatment, and outcomes have changed for patients with STEMI living in zip codes that are in the top tertile of the Black or Hispanic population compared with patients in nonminority zip codes in regionalized vs nonregionalized counties.This cohort study used a quasi-experimental approach exploiting the different timing of regionalization across California. Nonpublic inpatient data for all patients with STEMI from January 1, 2006, to October 31, 2015, were analyzed using a difference-in-difference-in-differences estimation approach.Exposure to the intervention was defined as on and after the year a patient's county was exposed to regionalization.Access to percutaneous coronary intervention (PCI)-capable hospital, receipt of PCI on the same day and at any time during the hospitalization, and time-specific all-cause mortality.This study included 139 494 patients with STEMI; 61.9% of patients were non-Hispanic White, 5.6% Black, 17.8% Hispanic, and 9.0% Asian; 32.8% were women. Access to PCI-capable hospitals improved by 6.3 percentage points (95% CI, 5.5 to 7.1 percentage points; P < .001) when patients in nonminority communities were exposed to regionalization. Patients in minority communities experienced a 1.8-percentage point smaller improvement in access (95% CI, -2.8 to -0.8 percentage points; P < .001), or 28.9% smaller, compared with those in nonminority communities when both were exposed to regionalization. Regionalization was associated with an improvement to same-day PCI and in-hospital PCI by 5.1 percentage points (95% CI, 4.2 to 6.1 percentage points; P < .001) and 5.0 percentage points (95% CI, 4.2 to 5.9 percentage points; P < .001), respectively, for patients in nonminority communities. Patients in minority communities experienced only 33.3% and 15.1% of that benefit. Only White patients in nonminority communities experienced mortality improvement from regionalization.Although regionalization was associated with improved access to PCI hospitals and receipt of PCI treatment, patients in minority communities derived significantly smaller improvement relative to those in nonminority communities.
Progression of Paroxysmal to Persistent Atrial Fibrillation: Factors Promoting the HATCH Score**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Arshad Jahangir, Shishir Murarka
Journal: Journal of the American College of Cardiology (2010)
UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes
Authors: Yasuyuki Sera, Yuichiro Nakata, Takeshi Ueda, Norimasa Yamasaki, Shuhei Koide, Hiroshi Kobayashi, Ken-ichiro Ikeda, Kohei Kobatake, Masayuki Iwasaki, Hideaki Oda, Linda Wolff, Akinori Kanai, Akiko Nagamachi, Toshiya Inaba, Yusuke Sotomaru, Tatsuo Ichinohe, Miho Koizumi, Yoshihiko Miyakawa, Zen-ichiro Honda, Atsushi Iwama, Toshio Suda, Keiyo Takubo, Hiroaki Honda
Journal: Blood (2020)
Abstract 16534: Pulmonary Artery Tapering Pattern on Chest CT-Angiogram Predicts Phenotype of Pulmonary Hypertension
Authors: Ali Ahsan A Azeem, Scott A Laurenzo, Ravi Dhingra, James R Runo, Roderick C Deano, Christopher J Francois, Farhan Raza
Journal: Circulation (2020)

Introduction: Non-invasive methods to identify phenotype of pulmonary hypertension (PH) are essential to improve the diagnostic algorithm of PH. Hypothesis: Delayed tapering of pulmonary artery (PA) is a signature of pre-capillary PH, while in post-capillary PH, the PA tapers rapidly. This differential tapering pattern of PA can be detected on a chest CT-angiogram (CTA), and quantified as a ratio of main PA diameter to PA branch diameter (right or left) at 5.0 cm length after the PA bifurcation. Methods: We identified 30 subjects with chest CTA and PH confirmed with invasive right heart catheterization (RHC). We identified 3 PH phenotypes: 1. “PVD” (pulmonary vascular disease) = Pre-capillary PH (n=10, PVR&gt;3.0 WU, PAWP &lt;15mmHg), 2. “Mixed” = pre- and post-capillary PH (n=10, PVR&gt;3.0 WU, PAWP &gt;15mmHg), and 3. “PVH” (pulmonary venous hypertension) = post-capillary PH (n=10, PVR&lt;3.0 Woods units [WU], PAWP &gt;15mmHg). Results: The results are summarized in Table. Additional results are expressed as comparison among the three groups in order: PVD vs Mixed vs PVH (mean±SD, % or n, as appropriate). CTA-chest findings: RV basal diameter (mm)= 51.1±8.4 vs 51.0±5.4 vs 38.1±13.9, left ventricular (LV) basal diameter (mm)= 32.1±7.2 vs 31.6±13.3 vs 56.6±15.2*, PA:Ao ratio= 1.1±0.1 vs 1.1±0.2 vs 1.0±0.1. Echo findings: tricuspid annular plane systolic excursion (TAPSE, mm)= 16±3 vs 19±4 vs 22±10*. We performed ROC to identify predictive ability of PA:RPA-5 and PA:LPA-5 to predict PVR&gt;3 WU. The AUC for PA:RPA-5 = 0.859 (p=0.03) and for PA:LPA-5 = 0.812 (p=0.01); with optimal cut-off for both parameters (PA:RPA-5 and PA:LPA-5) was 1.85. Among the overall cohort, the patients with PA:RPA&lt;1.85, 15/16 had PVR&gt;3 and 11/16 were on PH meds. Conclusion: Pattern of PA tapering quantified with PA:RPA-5 or PA:LPA-5 can reliably identify elevated PVR (&gt;3.0 WU). Pre-capillary PH imprints a signature morphological mark on the pattern of PA dilation that can be identified with a CTA-thorax.