tbuckley/cabot-search huggingface dataset:
Which Holds the Key to BRCAness: Inability to Repair the Break, Protect the Fork, or Prevent the Gap?
Authors: Christine E. Canman
Journal: Cancer Research (2021)

Abstract Defects in genes crucial for the process of DNA repair by homology-directed DNA repair (HDR), such as BRCA1 and BRCA2, are well-known contributors to cancer pathogenesis as well as an Achilles' heel that can be exploited therapeutically. BRCA1/2-deficient cells are exquisitely sensitive to agents that stall replication forks, such as PARP inhibitors and platinating drugs, presumably due to the inability to repair double-stranded breaks that form as a consequence of replication fork collapse. BRCA1/2 also promote tolerance to DNA replication stress by protecting replication forks from nucleolytic degradation. Both biological endpoints involve the deposition of RAD51 onto single-stranded DNA (ssDNA) for homology searching and strand exchange during HDR repair, as well as protection of newly synthesized DNA from nucleolytic degradation (i.e., replication fork protection). In this issue of Cancer Research, Panzarino and colleagues performed multiple separation-of-function studies and identify the lesion most associated with intolerance to replication stress in BRCA1/2-deficient cells is persistent ssDNA gaps in newly synthesized DNA, resulting from a failure to restrain DNA replication. Mechanisms that suppress gap formation are closely associated with chemoresistance, and the authors’ findings challenge the paradigm that lack of HR repair or fork protection underlie the phenotype known as BRCAness. See related article by Panzarino et al., p. 1388
Abstract IA-11: Combining multiplexed assays of variant effect and modeling to drive variant interpretation
Authors: Douglas Fowler
Journal: Clinical Cancer Research (2021)

Abstract Germline genetic variation can strongly influence lifetime cancer risk and somatic variation can influence prognosis and treatment. However, variants are difficult to interpret, even when they occur in cancer-associated genes. Multiplexed assays of variant effect leverage deep sequencing to enable the experimental assessment of thousands of genetic variants simultaneously. The resulting large-scale variant functional data can be used to drive variant interpretation, empowering the use of genetic information in cancer prevention and treatment. We are developing multiplexed assays of variant effect that can be deployed widely, with the ultimate goal of measuring the effect of most variants at most disease-related genes in the human genome. Citation Format: Douglas Fowler. Combining multiplexed assays of variant effect and modeling to drive variant interpretation [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-11.
Effector and stem-like memory cell fates are imprinted in distinct lymph node niches directed by CXCR3 ligands
Authors: Brigette C. Duckworth, Fanny Lafouresse, Verena C. Wimmer, Benjamin J. Broomfield, Lennard Dalit, Yannick O. Alexandre, Amania A. Sheikh, Raymond Z. Qin, Carolina Alvarado, Lisa A. Mielke, Marc Pellegrini, Scott N. Mueller, Thomas Boudier, Kelly L. Rogers, Joanna R. Groom
Journal: Nature Immunology (2021)
Electrocardiographic features of immune checkpoint inhibitor associated myocarditis
Authors: Daniel A Zlotoff, Malek Z O Hassan, Amna Zafar, Raza M Alvi, Magid Awadalla, Syed S Mahmood, Lili Zhang, Carol L Chen, Stephane Ederhy, Ana Barac, Dahlia Banerji, Maeve Jones-O'Connor, Sean P Murphy, Merna Armanious, Brian J Forrestal, Michael C Kirchberger, Otavio R Coelho-Filho, Muhammad A Rizvi, Gagan Sahni, Anant Mandawat, Carlo G Tocchetti, Sarah Hartmann, Hannah K Gilman, Eduardo Zatarain-Nicolás, Michael Mahmoudi, Dipti Gupta, Ryan Sullivan, Sarju Ganatra, Eric H Yang, Lucie M Heinzerling, Franck Thuny, Leyre Zubiri, Kerry L Reynolds, Justine V Cohen, Alexander R Lyon, John Groarke, Paaladinesh Thavendiranathan, Anju Nohria, Michael G Fradley, Tomas G Neilan
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. Methods From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. Results Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p&lt;0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p&lt;0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). Conclusions The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
Lack of Guideline-Directed Medical Therapy in Patients Undergoing Endovascular Procedures for Critical Limb Ischemia
Authors: Fiorella Llanos-Chea, Qurat-Ul-Ain Jelani, Camila Trejo-Paredes, Jeptha P. Curtis, Craig S. Parzynski, Jiaming Huang, Kamil F. Faridi, Jeffrey Turner, Kim G. Smolderen, Carlos Mena-Hurtado
Journal: Journal of the American College of Cardiology (2021)
Prevalence of oligoprogression in metastatic hormone-resistant prostate cancer patients on androgen targeted therapies: Could targeted radiotherapy improve patient outcomes?
Authors: Priyanka Patel, Nina Tunariu, Alison Tree
Journal: Journal of Clinical Oncology (2021)

110 Background: Androgen receptor-targeted therapies (ART) such as Abiraterone and Enzalutamide have shifted the management paradigm of metastatic castrate-resistant prostate cancer (mCRPC). These treatments are well-tolerated with less toxicities compared to chemotherapy, therefore methods to delay chemotherapy are beneficial to patients. Patients eventually become resistant to ARTs, and some patients will progress in a limited number of sites. This study investigated the prevalence of oligoprogressive disease (OPD) amenable to Stereotactic-body radiotherapy (SBRT). OPD is defined as ≤3 metastatic lesions which are progressing or new whilst all other sites of disease are well-controlled by ART. Methods: Retrospective analysis of electronic patient records and imaging studies of 95 patients treated with ART for mCRPC between April 2015 – 2017 from a single centre was undertaken. Data was analysed at the time of first tumour progression on ART. Results: The median (IQR) age of patients was 78.8 (74.4-83.6) years. OPD was found in 27 (28%) patients, 18 (19%) had lesions suitable for SBRT (Table). Seventeen (63%) patients were treated with abiraterone, 10 (27%) patients with enzalutamide. Median (IQR) time from starting ART to OPD was 16.4 (8.6-19.9) months. Five (19%) patients had 3 sites of OPD, 8 (29%) patients had 2 sites of OPD and 14 (52%) patients had 1 site of OPD. Nineteen patients continued ART beyond OPD for ≥3months. OPD was diagnosed using CT scan (56%), whole body diffusion-weighted MRI (22%), choline PET/CT (19%) and bone scan (3%). Six (22%) patients were treated with radiotherapy for OPD, 3 as participants of the TRAP trial (NCT03644303). Median time to subsequent progression after OPD for the 3 patients treated off trial with radiotherapy was 20.5 months. The OPD lesions treated with radiotherapy included the prostate (2 patients, 30 Gy in 5 and 24 Gy in 4 fractions) and para-aortic lymph node (1 patient, 30 Gy in 5 fractions). Median time to subsequent progression after OPD for those who did not receive radiotherapy was 6.4 months. There was no significant difference between median overall survival between patients with OPD and those who progressed with &gt; 3 lesions (7 vs 9.2 years, P= 0.54). Ten (66%) patients who progressed after initial OPD on continuation of ART progressed with further OPD (≤3 lesions including original OPD lesion). Conclusions: OPD is prevalent in patients on ART for mCRPC. The most frequent site of OPD was in bone and majority of patients had only 1 site of OPD at presentation. These results identify a cohort of patients who may benefit from SBRT to maximise ART treatment. Fourteen (14%) patients met entry criteria for TRAP trial which is currently testing the role of SBRT to sites of OPD in mCRPC. [Table: see text]
Differential levels of serum PSA related to volume of benign, Gleason pattern 3 and pattern 4 prostate tissue.
Authors: Ciro Andolfi, Andrew Vickers, Matthew R. Cooperberg, Peter Carroll, Janet E. Cowan, Gladell P Paner, Scott E. Eggener
Journal: Journal of Clinical Oncology (2021)

164 Background: PSA is an essential component of prostate cancer screening, management, and oncologic risk. We evaluated how serum levels of PSA vary by volume of benign tissue, Gleason pattern 3 (GP3), and Gleason pattern 4 (GP4). Methods: Consecutive men undergoing radical prostatectomy at two academic institutions for pT2N0, Gleason grade group 1-4, and undetectable postoperative PSA were reviewed. For each man, estimated volume (cc) of benign, GP3, and GP4 were extracted from the prostatectomy specimen. The primary analysis evaluated the association between pre-operative PSA and volume of each type of prostate tissue using multivariable linear regression with adjustment for age. An assessment of predictiveness (R 2 ) for PSA level was performed with each predictor and associated non-linear terms were removed from the model. Results: Estimated contribution to serum PSA for institutions A and B was 0.04-0.05 ng/ml/cc for benign, 0.08-0.11 ng/ml/cc for GP3, and 0.62-0.83 ng/ml/cc for GP4 (Table). We did not see a difference between PSA levels per cc of GP3 vs. benign tissue (p=0.4). R 2 decreased only slightly when removing age (0.006-0.010), benign tissue (0.049-0.051) or GP3 (0.011-0.023) from the model. When GP4 was removed, R 2 decreased 0.063-0.310. R 2 was far higher for GP4 than for Grade Group alone and was equal or superior to Grade Group plus total prostate volume. Conclusions: In early stage Grade Group 1-4 prostate cancer, one cc of Gleason pattern 4 was associated with 6 to 20-fold more serum PSA than one cc of Gleason pattern 3 or benign tissue. No difference in PSA per cc was observed between Gleason pattern 3 and benign tissue which has clinical implications for screening and active surveillance. [Table: see text]
Abstract 14708: Waist Circumference is the Most Powerful Predictor of Maladaptive Left Ventricular Remodeling in Otherwise Healthy Adolescents
Authors: Gurpreet S Johal, Kristen Brown, Maribeth Johnson, Mathew Humphries, Bernard Gutin, Gaston Kapuku, Vincent J Robinson
Journal: Circulation (2019)

Introduction: In healthy adolescents, it is unclear which risk factors are associated with cardiac remodeling. This study aims to identify variables associated with abnormal left ventricular (LV) m...
AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Dana E. Rathkopf, Kim N. Chi, David Olmos, Heather H. Cheng, Neeraj Agarwal, Julie N Graff, Shahneen Kaur Sandhu, Vinny Hayreh, Angela Lopez-Gitlitz, Peter St. John Francis, Gerhardt Attard
Journal: Journal of Clinical Oncology (2021)

TPS176 Background: Clinical benefit has been observed with poly(ADP-ribose) polymerase (PARP) inhibition in patients with metastatic castration-resistant prostate cancer tumors that carry HRR gene defects. Niraparib is a highly selective and potent PARP inhibitor, with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. The objective of AMPLITUDE is to assess the efficacy and safety of niraparib/placebo added to AAP with androgen deprivation therapy (ADT) in a biomarker-selected population with mCSPC. Methods: AMPLITUDE (NCT04497844) is a phase 3, randomized, double-blind, placebo-controlled study with an expected enrollment of 788 patients at ~350 sites in ~30 countries. Clinical trial information: NCT04497844. [Table: see text]
Abstract 30: In vitro Fabrication of Human Cardiac Tissues With Porcine Perfusable Blood Vessels
Authors: Akitoshi Inui, Hidekazu Sekine, Kazunori Sano, Izumi Dobashi, Azumi Yoshida, Katsuhisa Matsuura, Eiji Kobayashi, Minoru Ono, Tatsuya Shimizu
Journal: Circulation Research (2016)

The definitive treatment of severe heart failure is heart transplantation; however the number of heart transplantation procedures performed in Japan per year ranges from 30-40 due to donor shortage. Therefore, recently other treatments such as ventricular assist device or regenerative therapy by human cardiac tissue engineering have been developed and are considered as appropriate alternatives. We have developed an original technology, which was named cell-sheet based tissue engineering to fabricate functional three-dimensional tissue by layering cell sheets. The utilization of this technique allowed us to successfully engineer thick rat cardiac tissue with perfusable blood vessels in vitro. Here, we demonstrate a technique to engineer human cardiac tissue with perfusable blood vessels using cardiac cell sheets derived from human induced pluripotent stem cells, and porcine small intestine as a vascular bed for perfusion culture. The small intestine was harvested from with a branch of the superior mesenteric artery and vein and underwent mucosal resection after harvested tissue was cut open. To engineer cardiac tissue with perfusable blood vessels, cardiac cell sheets co-cultured with endothelial cells, were triple-layered and then was overlaid on the vascular bed in the bioreactor system. One day after perfusion culture, overlaid cardiac tissues pulsated spontaneously and were synchronized. The cardiac tissue construct was viable tissue without any observable necrosis. Furthermore we examined the possibility of transplantation of the in vitro engineered human cardiac tissue with the connectable host artery and vein. Engineered cardiac tissue was removed from the bioreactor system after 4-day perfusion, and transplanted to another pig heart. The branch of the superior mesenteric artery and vein of the graft were then reconnected to the host internal thoracic artery and vein. When the cardiac tissue reperfused, it began to beat spontaneously after a few minutes. We believe that this method is useful to fabricate functional cardiac tissue and may become an appropriate treatment for severe heart failure.
Age-specific effects of vaccine egg adaptation and immune priming on A(H3N2) antibody responses following influenza vaccination
Authors: Feng Liu, F. Liaini Gross, Stacie N. Jefferson, Crystal Holiday, Yaohui Bai, Li Wang, Bin Zhou, Min Z. Levine
Journal: Journal of Clinical Investigation (2021)

A(H3N2) influenza vaccine effectiveness (VE) was low during the 2016-19 seasons and varied by age. We analyzed neutralizing antibody responses to egg- and cell-propagated A(H3N2) vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all vaccine-eligible age groups in 3 influenza seasons. Antibody responses to cell- versus egg-propagated vaccine viruses were significantly reduced due to the egg-adapted changes T160K, D225G, and L194P in the vaccine hemagglutinins. Vaccine egg adaptation had a differential impact on antibody responses across the different age groups. Immunologically naive children immunized with egg-adapted vaccines mostly mounted antibodies targeting egg-adapted epitopes, whereas those previously primed with infection produced broader responses even when vaccinated with egg-based vaccines. In the elderly, repeated boosts of vaccine egg-adapted epitopes significantly reduced antibody responses to the WT cell-grown viruses. Analysis with reverse genetic viruses suggested that the response to each egg-adapted substitution varied by age. No differences in antibody responses were observed between male and female vaccinees. Here, the combination of age-specific responses to vaccine egg-adapted substitutions, diverse host immune priming histories, and virus antigenic drift affected antibody responses following vaccination and may have led to the low and variable VE against A(H3N2) viruses across different age groups.
Abstract 21262: Multi-Morbidity, Cardiac Disease and Cognition
Authors: Lisa C Bratzke, Beverly Carlson
Journal: Circulation (2017)

Introduction: Several chronic illnesses have demonstrated relationships to cognitive decline and risk of Alzheimer’s disease (AD); however, researchers have largely ignored the effects of multi-morbidity (two or more chronic illnesses) on cognition and risk of AD. Multi-morbidity may mimic the early symptomology of AD and represent a modifiable risk factor for cognitive decline. Therefore, the purpose of this study is to examine the relationship between multi-morbidity and cognition in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a longitudinal observational cohort with multiple waves of cognitive assessment. Hypothesis: We hypothesized that cognition would differ between the multi-morbidity subgroups. Methods: Latent class analysis (LCA) was completed to identify different subgroups of the 1,285 WRAP participants who were recognized based on their self-reported chronic illnesses. The final model was validated using several variables of interest ( i.e., biomarkers and depressive symptom scores). Chi-square tests were used to examine the association between multi-morbidity and cognitive status. Results: The LCA revealed a four-class model best fit solution, see Figure 1. Cholesterol was present across all four classes. Chi-square statistic revealed a significant difference in the proportion of participants with cognitive impairment between the classes (χ2 = 8.46, p = 0.03), with the largest differences observed between classes II (sleep) (19%) and III (cardiovascular) (9%) (p&lt;0.01) and classes II (19%) and IV (healthy) (12%) (p&lt;0.01). Conclusions: Findings offer initial evidence of an association between multi-morbidity clusters and the development of cognitive decline. Sleep and hypercholesterolemia may present a larger burden to cognitive health than previously reported. Disease management programs targeting optimal control of multiple cardiac illnesses may aid supporting optimal cognitive function and decreasing AD risk.
Very High Coronary Artery Calcium (≥1000) and Association With Cardiovascular Disease Events, Non–Cardiovascular Disease Outcomes, and Mortality
Authors: Allison W. Peng, Zeina A. Dardari, Roger S. Blumenthal, Omar Dzaye, Olufunmilayo H. Obisesan, S.M. Iftekhar Uddin, Khurram Nasir, Ron Blankstein, Matthew J. Budoff, Martin Bødtker Mortensen, Parag H. Joshi, John Page, Michael J. Blaha
Journal: Circulation (2021)

There are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations. Our study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Compared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm2), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63-6.11), 7.57- (5.50-10.42), 4.86-(3.32-7.11), and 1.94-fold (1.57-2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25-2.16), 1.66- (1.22-2.25), 1.51- (1.03-2.23), and 1.34-fold (1.05-1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57-2.41) and 1.43-fold (1.12-1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups. Individuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.
The Counteracting Effects of Demography on Functional Genomic Variation: The Roma Paradigm
Authors: Neus Font-Porterias, Rocio Caro-Consuegra, Marcel Lucas-Sánchez, Marie Lopez, Aaron Giménez, Annabel Carballo-Mesa, Elena Bosch, Francesc Calafell, Lluís Quintana-Murci, David Comas
Journal: Molecular Biology and Evolution (2021)

Demographic history plays a major role in shaping the distribution of genomic variation. Yet the interaction between different demographic forces and their effects in the genomes is not fully resolved in human populations. Here, we focus on the Roma population, the largest transnational ethnic minority in Europe. They have a South Asian origin and their demographic history is characterized by recent dispersals, multiple founder events, and extensive gene flow from non-Roma groups. Through the analyses of new high-coverage whole exome sequences and genome-wide array data for 89 Iberian Roma individuals together with forward simulations, we show that founder effects have reduced their genetic diversity and proportion of rare variants, gene flow has counteracted the increase in mutational load, runs of homozygosity show ancestry-specific patterns of accumulation of deleterious homozygotes, and selection signals primarily derive from preadmixture adaptation in the Roma population sources. The present study shows how two demographic forces, bottlenecks and admixture, act in opposite directions and have long-term balancing effects on the Roma genomes. Understanding how demography and gene flow shape the genome of an admixed population provides an opportunity to elucidate how genomic variation is modeled in human populations.