tbuckley/cabot-search huggingface dataset:
Abiraterone decanoate (AD): Potent and long-acting activity of a novel intramuscular (IM) abiraterone prodrug depot in a castrate monkey model.
Authors: William R. Moore, Matthew Sharp, Caroline Bell, Stuart Freeman, Alan Parr, Joel Robert Eisner, Robert Schotzinger
Journal: Journal of Clinical Oncology (2021)

78 Background: Oral abiraterone acetate (AA) is a standard of care for castration-resistant (CRPC) and castration-sensitive prostate cancer (CSPC). Due to poor oral bioavailability, the recommended AA dose is 1,000 mg (4 x 250mg) once-daily on an empty stomach. The daily oral regimen produces high peak plasma concentrations that may be associated with safety issues (e.g., hepatotoxicity) and low trough concentrations that may be associated with inadequate CYP17 inhibition. AD is one of a series of novel abiraterone prodrugs that were designed to provide a controlled release of abiraterone and long-acting CYP17 inhibition with IM delivery. Following successful preclinical pilot studies, AD was further developed into a clinically acceptable formulation (PRL-02) and its PK/PD characteristics were evaluated and compared to oral AA in a castrate monkey pharmacology model in support of future clinical development. Methods: Sexually mature male cynomolgus monkeys underwent chemical castration using Lupron depot. Plasma samples were analyzed for prodrug, abiraterone and steroid concentrations following a single oral AA dose (5, 15 or 45 mg/kg) and a single IM AD injection (10, 30 or 100 mg/kg) (n=3/dose group). The combined activity of IM AD plus glucocorticoid replacement (single 0.5 mg/kg IM dexamethasone (DEX) dose or weekly doses of 1.29 mg/kg IM methylprednisolone acetate (MPA)) was also evaluated. AD, abiraterone and adrenal steroid levels were evaluated by LC-MS/MS. Results: Chemical castration resulted in a plasma testosterone (T) decrease of 72% from intact. T was further reduced to sub-castrate levels by both AA and AD (98.6% and 99.7% maximum decrease from castrate baseline, respectively). All dose levels of AD were highly effective in reducing plasma T yet led to abiraterone plasma concentrations (Cmax, AUC, Cmin) that were much less than those associated with steady-state clinical levels from oral AA. Sustained T suppression was observed following all single AD IM doses for 14 weeks, the last timepoint tested.The addition of a glucocorticoid replacement (DEX or MPA) starting at week 9 further reduced T in all AD groups. Conclusions: Single-dose IM AD suppressed T to the same or greater extent than single-dose oral AA in castrate monkeys, while providing much lower abiraterone exposures than the oral acetate prodrug. As such, IM AD may offer an improved risk-benefit profile due to the consistently lower abiraterone levels. The durable, profound T reductions provided by all AD doses are consistent with a 3-month clinical regimen that can be given in conjunction with Lupron. IM AD may thus offer patients with CSPC and CRPC a more convenient, safe and effective alternative than daily oral AA.
Abstract 3371: Recurrence of Atrial fibrillation Following RF Ablation Correlates with the Extent of Post-procedural Left Atrial Scarring on Delayed-Enhancement CMR
Authors: Dana C Peters, John V Wylie, Thomas H Hauser, Reza Nezafat, Kraig V Kissinger, Beth Goddu, Mark E Josephson, Warren J Manning
Journal: Circulation (2007)

The reasons for success or failure of radiofrequency (RF) ablation therapy in atrial fibrillation (AF) patients remain to be defined. Cardiovascular magnetic resonance (CMR) can visualize RF ablati...
Understanding racial disparities in survival among U.S. veterans with localized high-risk prostate cancer, 2004-2019.
Authors: Ravi Bharat Parikh, Sumedha Chhatre, Ruchika Talwar, Elina Medvedeva, John Cashy, S. Bruce Malkowicz, Vivek Narayan, Ronac Mamtani, Kyle William Robinson, Ravishankar Jayadevappa
Journal: Journal of Clinical Oncology (2021)

202 Background: Known racial disparities in prostate cancer outcomes between African-American (AA) and non-Hispanic White (W) men may be ameliorated in the Veterans Health Administration (VA), a large national equal-access health system. We examined factors contributing to racial disparities in mortality among men with high-risk localized prostate cancer diagnosed in the VA. Methods: In this retrospective cohort study, we used linked administrative, survey, and electronic health record data from the Veterans Health Administration (VA) Corporate Data Warehouse to identify AA and W Veterans who were diagnosed with high-risk localized PC, as defined by D’Amico criteria, between January 1, 2004 and December 31, 2013. Patients were followed through December 31, 2019. The primary outcome was all-cause mortality. We used hierarchical Cox regression models, sequentially adjusting for covariates related to social determinants of health (e.g. travel time, marital status), clinical factors at diagnosis (e.g. PSA, Gleason, comorbidity), diagnosing facility, and prostate cancer treatment and adherence to American Cancer Society survivorship care guidelines. Results: Among 21,338 Veterans receiving continuous VA-based care (median age at diagnosis 66 years [interquartile range [IQR] 61-74]), 7,472 (28.7%) were AA, 9,404 (44.1%) died, and median follow-up was 8.4 years (IQR 6.1-11.1). After adjusting for all covariates, AA Veterans (adjusted hazard ratio [aHR] 0.84, 95% confidence interval [CI] 0.83-0.91) had improved overall survival compared to W Veterans. This association persisted in all hierarchical regressions (see Table), was present in all pre-specified subgroups, and was strongest among Veterans living in rural domiciles (aHR 0.70, 95% CI 0.64-0.77). Conclusions: AA Veterans with high-risk localized prostate cancer had improved long-term survival compared to W Veterans, which stands in contrast to prior studies among non-Veterans. Equal access to care may improve racial disparities in prostate cancer, although future studies should clarify mechanisms of improved survival for AA Veterans with prostate cancer in order to provide insights for ameliorating outcome disparities in non-Veterans with prostate cancer. [Table: see text]
Anthony Denys Bostock
Authors: Richard Keal, Pamela Keal
Journal: BMJ (2021)

Anthony Denys Bostock (“Tony,” as he was always known) was born in Stockport. His father, of the Manchester bakery family Birkett and Bostock, died when Tony was only 1 year old. He was bought up by his mother, a hospital dispenser, and educated at Stockport Grammar School. His childhood holidays were spent at Dovercourt in Essex with his Uncle Jack, who was a Trinity House Pilot at Harwich. It was here that his lifelong love of the sea began, and he decided to join the Thames Nautical Training College, HMS Worcester , in 1937.

After the outbreak of the second world war, Tony left HMS Worcester in early November 1939, joining the shipping company Shaw, Savill and Albion …
Bridging the Gap Between Intensivists and Primary Care Clinicians in Extracorporeal Membrane Oxygenation for Respiratory Failure in Children
Authors: Ryan P. Barbaro, Daniel Brodie, Graeme MacLaren
Journal: JAMA Pediatrics (2021)

Extracorporeal membrane oxygenation (ECMO) is a form of advanced life support that may be used in children with refractory respiratory or cardiac failure. While it is required infrequently, in the US, ECMO is used to support childhood respiratory failure as often as children receive kidney or heart transplants. ECMO is complex, resource intensive, and potentially lifesaving, but it is also associated with risks of short-term complications and long-term adverse effects, most importantly with neurodevelopmental outcomes that are relevant to all pediatric clinicians, even those remote from the child's critical illness.The 2009 influenza A(H1N1) pandemic, along with randomized clinical trials of adult respiratory ECMO support and conventional management, have catalyzed sustained growth in the use of ECMO. The adult trials built on earlier neonatal ECMO randomized clinical trials that demonstrated improved survival in severe perinatal lung disease. For children outside of the neonatal period, there appear to have been no respiratory ECMO clinical trials. Applying evidence from adult respiratory failure or perinatal lung disease to children outside the neonatal period has important potential pitfalls. For these children, the underlying diseases and risks of ECMO are different. Despite these differences, both neonates and older children are at risk of neurologic complications, such as intracranial hemorrhage, ischemic stroke, and seizures, and those complications may contribute to adverse neurodevelopmental outcomes. Without specific screening, subtle neurodevelopmental impairments may be missed, but when they are identified, children have the opportunity to receive therapy to optimize long-term development.All pediatric clinicians should be aware not only of the potential benefits and complications of ECMO but also that survivors need effective screening, support, and follow-up.
Abstract 15628: HeartCare: Improving Clinical Practice Through Comprehensive Cardiovascular Genetic Testing
Authors: David Murdock, Trevor Hadley, Eric Venner, Donna Muzny, Ginger Metcalf, Mullai Murugan, Varuna Chander, Xiaoming Jia, Aliza Hussain, Jianhong Hu, Michelle Cohen, Christie Kovar, Marie-Claude Gingras, Viktoriya Korchina, Chad Howard, Daniel Riconda, Stacey Pereira, Hadley Smith, Paul DeVries, Zohra Huda, Alexandria Buentello, Patricia Marino, Andrew Civitello, Mihail Chelu, Lee Leiber, Amy McGuire, Ashok Balasubramanyam, Chris Amos, Eric Boerwinkle, Christie M Ballantyne, Xander Wehrens, Richard Gibbs
Journal: Circulation (2020)

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality in the United States, leading to one in four deaths. The role of inherited susceptibility to CVD is well established, from rare monogenic disorders to polygenic traits. For many of these conditions, guidelines exist for medical interventions and other preventative care that can improve outcomes and quality of life. Methods: We developed a comprehensive genetic screen, "HeartCare", consisting of a 158 gene panel evaluating 1) Mendelian conditions including cardiomyopathies, aortopathies, arrhythmias, and dyslipidemias, 2) a coronary artery disease polygenic risk score (PRS), 3) variants in the LPA gene encoding Lipoprotein(a) that are an independent risk factor for atherosclerotic CVD events, and 4) pharmacogenetic (PGx) variants contributing to simvastatin-induced myopathy and warfarin metabolism. After sequencing in a CAP/CLIA certified laboratory, results were returned to the ordering physician after a multi-disciplinary sign-out conference and uploaded to the EMR. Results: As of June 2020, 678 individuals had completed testing with a 31% overall positive rate for Mendelian genes, elevated polygenic risk, and LPA risk alleles (excluding PGx). Of these, 8.1% had a positive finding for a Mendelian condition, the majority (60%) being dyslipidemias (e.g., FH), followed by 25% cardiomyopathies (e.g., HCM, DCM, ARVC) and 6% aortopathies (e.g., Marfan, Loeys-Dietz). Approximately 20% of individuals carried an LPA risk allele, and 9.3% belonged to the high-risk group according to their PRS. Approximately half had a PGx finding related to simvastatin and/or warfarin metabolism. Nearly one in five individuals had a finding with direct clinical care impact, including referral to specialists, imaging, laboratory studies, therapies/procedures (e.g., PCSK9i, ICD). Conclusions: To our knowledge, this is the first test of its kind assaying four distinct categories of genetic variation related to cardiovascular health. Our results demonstrate that comprehensive testing can be routinely used to identify individuals who may benefit from interventions to improve survival, reduce morbidity, and enhance quality of life.
Abstract PO043: TERT expression increases with tumor grade in a cohort of IDH mutant gliomas
Authors: John L. Caniglia, Anvesh Jalasutram, Kiran K. Velpula, Maheedhara R. Guda, Sarah E. Bach, Andrew J. Tsung
Journal: Cancer Research (2021)

Abstract Glioblastoma multiforme is the most deadly primary brain tumor, exhibiting a median survival of just 13 months despite aggressive treatments including surgery, radiation, and chemotherapy. There are two main subtypes of glioblastoma, denoted primary and secondary glioblastoma, respectively. While the former begins as a grade IV tumor, secondary glioblastomas evolve from a lineage that may include grade II astrocytomas and grade III anaplastic astrocytomas, a class of tumors which are molecularly defined by mutations in isocitrate dehydrogenase (IDH). The molecular mechanisms underlying progression of these tumors are poorly understood. Telomerase reverse transcriptase (TERT), a gene encoding for the catalytic subunit of telomerase, is upregulated in a plethora of cancers and represents a probable mechanism by which malignant cells delay senescence and evade cell death. TERT activity is the primary mechanism by which malignant cells replenish telomeres with the other being the alternative lengthening of telomeres (ALT) system, known to become active in tumors harboring loss of function mutations in ATRX. In data obtained from The Cancer Genome Atlas, significantly lower rates of survival were observed in low grade glioma patients with tumors highly expressing TERT as compared to tumors with low/medium expression. However, studies comparing the expression of TERT across different grades of glioma have not been performed to date. Using immunohistochemical staining we show that, controlling for ATRX and IDH mutational status, TERT expression increases as a function of tumor grade in a cohort of patient-derived astrocytoma, anaplastic astrocytoma, and secondary glioblastoma samples. These findings indicate that as astrocytomas progress to more aggressive tumors, TERT expression likely increases to provide enhanced genomic stability. Citation Format: John L. Caniglia, Anvesh Jalasutram, Kiran K. Velpula, Maheedhara R. Guda, Sarah E. Bach, Andrew J. Tsung. TERT expression increases with tumor grade in a cohort of IDH mutant gliomas [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO043.
Audio Interview: A New SARS-CoV-2 Vaccine and a New Look at Treatment
Authors: Eric J. Rubin, Lindsey R. Baden, Stephen Morrissey
Journal: New England Journal of Medicine (2021)

A New SARS-CoV-2 Vaccine and a New Look at Treatment In this audio interview conducted on March 2, 2021, the editors discuss the recently approved Ad26.Cov2.S vaccine, as well as two new studies of...
Tea eggs-inspired high-strength natural polymer hydrogels
Authors: Tengling Wu, Chunyan Cui, Chuanchuan Fan, Ziyang Xu, Yang Liu, Wenguang Liu
Journal: Bioactive Materials (2021)

Natural polymer (NP) hydrogels are an irreplaceable class of biomaterials owing to their identified biosafety; however, the intrinsic poor mechanical strengths severely limit their applications as structural tissue engineering scaffolds. Inspired by the stiffening albumen gel of tea eggs, a traditional Chinese snack, high-strength NP hydrogels are constructed by simply soaking in aqueous solution of tea polyphenols (TP), an active ingredient extracted from tea. The TP-treated representative NP hydrogels exhibit considerably enhanced multifaceted mechanical properties with maximum 19-/30-, 8.4-, 6.1-, 72-fold increases in tensile/compressive strengths, Young's modulus, elongation at break and facture toughness, respectively, compared with pristine hydrogels, primarily due to the hydrogen bonding interactions between TP and NP chains. The TP-treated NP hydrogels can resist different large deformations, which cannot be achieved by their original species at all. In aqueous solution, the TP-treated NP hydrogels can still maintain robust mechanical performances, in spite of somewhat decline in strengths with release of TP, which just favorably affords increased water contents, antibacterial and antioxidant activities. GelMA-TP hydrogel is shown to facilitate wound healing in a full-thickness skin defect model. Importantly, the weak 3D printed GelMA scaffolds are significantly strengthened by TP treatment, broadening the possibility for customizing individualized bioscaffolds.
CONTACT-03: Randomized, open-label phase III study of atezolizumab plus cabozantinib versus cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ICI) treatment in patients with advanced/metastatic renal cell carcinoma.
Authors: Sumanta K. Pal, Laurence Albiges, Cristina Suarez Rodriguez, Bo Liu, Jennifer Doss, Sudha Khurana, Christian Scheffold, Martin H Voss, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

TPS370 Background: Combining anti-angiogenic drugs with immune checkpoint inhibitors (ICI) after progression on ICIs presents a promising therapeutic approach in renal cell carcinoma (RCC). Atezolizumab (anti-PD-L1 mAb) has shown activity in combination with anti-angiogenic therapy after prior progression with ICI. Cabozantinib (VEGFR-TAM-TKI), a standard of care therapy in RCC, promotes an immune-permissive environment and may enhance atezolizumab activity. In phase Ib COSMIC-021, cabozantinib + atezolizumab safety and efficacy was favorable in clear-cell(cc) RCC and non(n)-ccRCC (Pal et al [702O] and McGregor et al [709P], ESMO 2020). The phase III CONTACT-03 study is further evaluating cabozantinib + atezolizumab vs cabozantinib in second-line/third-line RCC after prior ICC therapy. Methods: CONTACT-03 (NCT04338269) is a phase III, open-label, randomized, multicenter study that will enroll ≈500 patients across more than 150 sites globally. The trial opened in July 2020 and is actively recruiting adult patients with RCC. Key inclusion criteria include histologically confirmed locally advanced or metastatic ccRCC or nccRCC (papillary or unclassified); radiographic disease progression during or following first-line/second-line ICI treatment; measurable disease (RECIST 1.1); KPS score ≥70%; and availability of an archival tumor specimen and fresh biopsy (if clinically feasible). Patients must have adequate hematological and end organ function. Prior ICI therapy must be a PD-1/PD-L1 inhibitor (mono- or combination therapy) and must be in the immediate preceding line of therapy. Key exclusion criteria include prior treatment with cabozantinib or a mTOR inhibitor. Patients with symptomatic, untreated, or actively progressing CNS metastases or significant other intercurrent illness are not eligible. Stratification factors are IMDC risk group (0 vs 1-2 vs ≥3); line of most recent prior ICI therapy (first vs second); and histology (dominant cc without sarcomatoid vs dominant non-cc [papillary or unclassified] without sarcomatoid vs any sarcomatoid component [cc or ncc]). Patients will be randomized 1:1 to receive atezolizumab (1200 mg/IV/q3w) plus cabozantinib (60 mg/oral/qd) or cabozantinib alone (60 mg/oral/qd) until unacceptable toxicity or loss of clinical benefit. Patients will not be allowed to crossover from the control arm to the experimental arm. Multiple primary endpoints are independent review facility (IRF)-assessed PFS and OS. Additional endpoints include investigator-assessed PFS, IRF- and investigator-assessed ORR and DOR; HRQOL, biomarkers and safety. Radiographic efficacy will be assessed per RECIST 1.1. Clinical trial information: NCT04338269 .
Association Between Alopecia Areata and Natural Hair Color Among White Individuals
Authors: Ahmed Yousaf, Justin Lee, Wei Fang, Michael S. Kolodney
Journal: JAMA Dermatology (2021)

<h3>Importance</h3> Alopecia areata (AA) is a complex immune-mediated disorder that causes nonscarring hair loss. Previous reports have documented preferential targeting of pigmented hair follicles with sparing of gray, nonpigmented hair follicles in alopecia lesions. Thus, immune targeting of melanogenesis-associated proteins in melanocytes and keratinocytes represents a potential mechanism for the inflammation that targets anagen hairs in alopecia areata. <h3>Objective</h3> To investigate the association of alopecia areata with hair color among White residents of the UK. <h3>Design, Setting, and Participants</h3> This matched, case-control study conducted in October 2020 used a large prospectively acquired cohort and included data that were collected from the UK Biobank, a large-scale prospective resource designed to study phenotypic and genotypic determinants in adults. A total of 502 510 UK Biobank participants were reviewed for inclusion. Among these individuals, 1673 cases of alopecia areata with reported hair color were captured and matched by age and sex to 6692 controls without alopecia areata using 1:4 matching. <h3>Main Outcomes and Measures</h3> Conditional logistic regression analysis was performed, in which the outcome variable was alopecia areata and the main predictor was natural hair color before graying. The variables considered included diabetes, hypothyroidism, hyperthyroidism, and vitiligo. <h3>Results</h3> Of 464 353 participants, 254 505 (54.8%) were women, and the mean (SD) age for those with alopecia areata was 46.9 (16.5) years. Alopecia areata was significantly more common in individuals with black (adjusted odds ratio [aOR], 2.97; 95% CI, 2.38-3.71) and dark brown hair (aOR, 1.26; 95% CI, 1.11-1.42) compared with light brown hair. In contrast, blond individuals exhibited significantly decreased alopecia areata compared with those with light brown hair (aOR, 0.69; 95% CI, 0.56-0.85). Red hair color was not significantly different from light brown hair. <h3>Conclusions and Relevance</h3> The findings of this matched case-control study seem to indicate that alopecia areata is modulated by natural hair color, preferentially targeting darker hair. Our results support a previously proposed model of alopecia areata in which immunity is directed against melanogenesis-associated proteins in the anagen hair follicles. However, further study is needed to more precisely understand the immunopathogenic association between alopecia areata and hair color.
Abstract 17723: Low-flow Low-gradient Aortic Stenosis With Low Ejection Fraction: Does Myocardial Fibrosis Predict Recovery of Postoperative Ventricular Function?
Authors: Vitor E Rosa, Roney O Sampaio, Antonio S de Santis, Joao Ricardo C Fernandes, Tarso A Accorsi, Marcela E Rosa, Marcelo L Vieira, Thamara C Morais, Juliana H Bello, Wilson Mathias, Carlos E Rochitte, Pablo M Pomerantzeff, Flavio Tarasoutchi
Journal: Circulation (2016)

Introduction: There is a lack of studies related to predictors of ventricular function improvement after surgical intervention in patients with low-flow low-gradient aortic stenosis with low ejecti...