tbuckley/cabot-search huggingface dataset:
Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease
Authors: Mary M. McDermott, Michael H. Criqui, Kathryn Domanchuk, Luigi Ferrucci, Jack M. Guralnik, Melina R. Kibbe, Kate Kosmac, Christopher M. Kramer, Christiaan Leeuwenburgh, Lingyu Li, Donald Lloyd-Jones, Charlotte A. Peterson, Tamar S. Polonsky, James H. Stein, Robert Sufit, Linda Van Horn, Francisco Villarreal, Dongxue Zhang, Lihui Zhao, Lu Tian
Journal: Circulation Research (2020)

Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD).In a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo.Six-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided P<0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age, 72.3 years [±7.1]; mean ankle brachial index, 0.66 [±0.15]), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved 6-minute walk distance at 6-month follow-up by 42.6 m ([90% CI, +22.2 to +∞] P=0.005) at 2.5 hours after a final study beverage and by 18.0 m ([90% CI, -1.7 to +∞] P=0.12) at 24 hours after a study beverage, compared with placebo. In calf muscle biopsies, cocoa improved mitochondrial COX (cytochrome c oxidase) activity (P=0.013), increased capillary density (P=0.014), improved calf muscle perfusion (P=0.098), and reduced central nuclei (P=0.033), compared with placebo.These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02876887. Visual Overview: An online visual overview is available for this article.
A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies
Authors: Andrea Degasperi, Tauanne Dias Amarante, Jan Czarnecki, Scott Shooter, Xueqing Zou, Dominik Glodzik, Sandro Morganella, Arjun S. Nanda, Cherif Badja, Gene Koh, Sophie E. Momen, Ilias Georgakopoulos-Soares, João M. L. Dias, Jamie Young, Yasin Memari, Helen Davies, Serena Nik-Zainal
Journal: Nature Cancer (2020)
Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment
Authors: Elizabeth Katherine Batchelor, Pinelopi Kapitsinou, Pablo E. Pergola, Csaba P. Kovesdy, Diana I. Jalal
Journal: Journal of the American Society of Nephrology (2020)

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.
T lymphocyte-targeted immune checkpoint modulation in glioma
Authors: William James Kelly, Amber Jin Giles, Mark Gilbert
Journal: Journal for ImmunoTherapy of Cancer (2020)

Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.
Sex-Specific Trends in Acute Myocardial Infarction Within an Integrated Healthcare Network, 2000 Through 2014
Authors: Matthew T. Mefford, Bonnie H. Li, Lei Qian, Stephanie R. Reading, Teresa N. Harrison, Ronald D. Scott, Jeffrey J. Cavendish, Steven J. Jacobsen, Michael H. Kanter, Mark Woodward, Kristi Reynolds
Journal: Circulation (2020)

Background: In recent decades, the rates of incident acute myocardial infarction (AMI) have declined in the United States, yet disparities by sex remain. In an integrated healthcare delivery system, we examined temporal trends in incident AMI among women and men. Methods: We identified hospitalized AMI among members ≥35 years of age in Kaiser Permanente Southern California. The first hospitalization for AMI overall, and for ST-segment–elevation MI and non–ST-segment–elevation MI was identified by International Classification of Diseases, Ninth Revision, Clinical Modification primary discharge diagnosis codes in each calendar year from 2000 through 2014. Age- and sex-standardized incidence rates per 100 000 person-years were calculated by using direct adjustment to the 2010 US Census population. Average annual percent changes (AAPCs) and period percent changes were calculated, and trend tests were conducted using Poisson regression. Results: We identified 45 331 AMI hospitalizations between 2000 and 2014. Age- and sex-standardized incidence rates of AMI declined from 322.4 (95% CI, 311.0–333.9) in 2000 to 174.6 (95% CI, 168.2–181.0) in 2014, representing an AAPC of –4.4% (95% CI, –4.2 to –4.6) and a period percent change of –46.6%. The AAPC for AMI in women was –4.6% (95% CI, –4.1 to –5.2) between 2000 and 2009 and declined to –2.3% (95% CI, –1.2 to –3.4) between 2010 and 2014. The AAPC for AMI in men was stable over the study period (–4.7% [95% CI, –4.4 to –4.9]). The AAPC for ST-segment–elevation MI hospitalization overall was –8.3% (95% CI, –8.0% to –8.6%).The AAPC in ST-segment–elevation MI changed among women in 2009 (2000–2009: –10.2% [95% CI, –9.3 to –11.1] and in 2010–2014: –5.2% [95% CI, –3.1 to –7.3]) while remaining stable among men (–8.0% [95% CI, –7.6 to –8.4]). The AAPC for non–ST-segment–elevation MI hospitalization was smaller than for ST-segment–elevation MI among both women and men (–1.9% [95% CI, –1.5 to –2.3] and –2.8% [95% CI, –2.5 to –3.2], respectively). Conclusions: These results suggest that the incidence of hospitalized AMI declined between 2000 and 2014; however, declines in AMI have slowed among women in comparison with men in recent years. Determining unmet care needs among women may reduce these sex-based AMI disparities.
Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis
Authors: Laura M. Spring, Geoffrey Fell, Andrea Arfe, Chandni Sharma, Rachel Greenup, Kerry L. Reynolds, Barbara L. Smith, Brian Alexander, Beverly Moy, Steven J. Isakoff, Giovanni Parmigiani, Lorenzo Trippa, Aditya Bardia
Journal: Clinical Cancer Research (2020)

While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known.PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24-0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10-0.31) and HER2+ (HR = 0.32; 95% PI, 0.21-0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15-0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19-0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27-0.54), with no significant difference between the two groups (P = 0.60).Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.See related commentary by Esserman, p. 2771.
Build-a-Mouse: Melanoma Modeling Picks up Speed
Authors: Andres Thorkelsson, Glenn Merlino, Helen Michael
Journal: Cancer Research (2020)

The study by Bok and colleagues in this issue introduces a new paradigm for generating new mouse models for melanoma research. Genetically engineered mouse models (GEMM) have been crucial for understanding tumor initiation and modeling potential therapies, but are time consuming to create. Bok and colleagues generated and validated high-contribution chimeric GEMM models using common melanoma GEMMs as a starting point and added additional CRISPR, Cre-inducible, and Dox-inducible alleles. This rapid method for generating new models has the potential to revolutionize mouse modeling for melanoma.See related article by Bok et al., p. 912.
Incidence, Risk Factors, and Mortality Associated With Orofacial Cleft Among Children in Ontario, Canada
Authors: Claudia C. Malic, Melody Lam, Jessy Donelle, Lucie Richard, Simone N. Vigod, Eric I. Benchimol
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Orofacial cleft (OFC) is one of the most common congenital malformations, with a wide variation in incidence worldwide. However, population-based studies on the incidence of OFC in North America are lacking. <h3>Objectives</h3> To examine the incidence of OFC in Ontario, Canada, and to compare risk factors and mortality associated with children with OFC vs children without OFC. <h3>Design, Setting, and Participants</h3> This population-based retrospective cohort study used health administrative data from the province of Ontario, Canada. Children with OFC who were born from April 1, 1994, to March 31, 2017, in Ontario were each matched to 5 children without OFC based on sex, date of birth (±30 days), and mother's age (±5 years). Analyses were conducted from September 2018 to January 2019. <h3>Exposures</h3> Children born with OFC. <h3>Main Outcomes and Measures</h3> Incidence of OFC over time and regional variation. Risk factors for OFC were assessed using 1-way analysis of variance for means, Kruskal-Wallis for medians, and χ<sup>2</sup>tests for categorical variables. Adjusted Cox regression models were used to assess mortality. <h3>Results</h3> From 1994 to 2017, 3262 children were born with OFC in Ontario, Canada, and they were matched to 15 222 children born without OFC. Incidence of OFC in Ontario was 1.12 cases per 1000 live births, with wide geographic variation and a lower incidence from 2004 to 2017 compared with 1994 to 2003 (1.02 vs 1.13 cases per 1000 live births;<i>P</i> = .002), especially for the subgroup with cleft palate (0.52 vs 0.44 cases per 1000 live births;<i>P</i> = .006). Children with OFC, compared with children without OFC, were more likely to be born prematurely (406 children [13.3%] vs 1086 children [7.1%];<i>P</i> &lt; .001; standardized difference, 0.21) and had lower mean (SD) birth weight (3215.3 [687.6] g vs 3382.6 [580.0] g;<i>P</i> &lt; .001; standardized difference, 0.26). The mortality rate among children with OFC was higher than among matched children without OFC (hazard ratio, 10.60; 95% CI, 7.79-14.44;<i>P</i> &lt; .001). When mortality was adjusted for the presence of congenital or chromosomal anomalies, the risk of death was not significantly different between children with OFC and those without OFC (hazard ratio, 1.35; 95% CI, 0.73-2.72). <h3>Conclusions and Relevance</h3> These findings suggest that incidence of OFC In Ontario, Canada, decreased from 1994 to 2017. Mortality in children with OFC was high, especially in the first 2 years of life, and was predominantly associated with the presence of other congenital or chromosomal anomalies. Further research is required to better understand the causes of wide geographical variations of OFC incidence and improve the survival of these patients.
Abstract P1-09-08: Development and characterization of PTEN IHC assay for testing breast cancer patients specimens
Authors: Hua Gong, Emmanuel Pacia, Sharmila Manjeshwar, Beiru Chen, Xun Li, Bashar Dabbas, Jelveh Lameh, Naveen Babbar, Shabnam Tangri
Journal: Cancer Research (2020)

Abstract Background: Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that is a major negative regulator of the Phosphatidylinositol 3-kinase (PI3K) pathway. Loss of PTEN protein expression has been mechanistically linked to tumor progression. Blocking the PI3K pathway might inhibit the growth and proliferation of cells that have deletions in PTEN. Thus characterization of PTEN expression in patient tumor samples may assist prediction of potential response to PI3K inhibitor therapies. Methods: We developed and validated an immunohistochemical assay on Ventana BenchMark XT to detect PTEN in formalin fixed and paraffin-embedded (FFPE) tissue by utilizing a rabbit monoclonal antibody (clone 138G6) from Cell Signaling Technologies that recognizes the carboxy-terminal domain of PTEN. PTEN immunohistochemical staining was performed on 1577 breast tumor specimens to determine PTEN protein loss. A subset of these cases (n=663) was also assessed for PTEN mutation. Results: Cellular localization of PTEN expression was observed in both the cytoplasm and the nucleus. Both cellular compartments were scored and used in the staining intensity determination. We observed that PTEN staining is sensitive to variation in tissue handling, fixation and antigen retrieval. PTEN staining was affected significantly by antigen retrieval method. Optimal staining conditions were determined to be 1:60 antibody dilution using Citrate pH 6.0 as antigen retrieval buffer. In a cohort of 1577 hormone receptor positive HER2-negative locally advanced or metastatic breast cancer patients, loss of PTEN protein was observed in 8.6% (135/1577) of patients. There was a positive correlation between PTEN mutation rate (17 out of 66 PTEN IHC positive cases vs 14 out of 587 negative cases) and loss of PTEN protein expression. PTEN loss was observed to correlate with better clinical response to PI3K inhibitor. Conclusions: Pre-analytical handling of samples is important for PTEN IHC staining. PTEN mutations and insertions/deletions contribute to PTEN protein loss. This study validates a simple method to interrogate PTEN status in clinical specimens and supports the utility of this test in selecting patients who are likely to respond to PI3K inhibitor treatment. Citation Format: Hua Gong, Emmanuel Pacia, Sharmila Manjeshwar, Beiru Chen, Xun Li, Bashar Dabbas, Jelveh Lameh, Naveen Babbar, Shabnam Tangri. Development and characterization of PTEN IHC assay for testing breast cancer patients specimens [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-09-08.
Abstract ES2-1: Guiding decisions to omit radiotherapy after breast-conserving surgery for DCIS. Can genomic biomarkers help?
Authors: E Rakovitch
Journal: Cancer Research (2020)

Abstract Most women diagnosed with ductal carcinoma in situ (DCIS) will be treated with breast-conserving surgery followed by whole breast radiation. We will review the evolving role of genomic biomarkers to personalize radiotherapy treatment recommendations after breast-conserving surgery for DCIS. Citation Format: E Rakovitch. Guiding decisions to omit radiotherapy after breast-conserving surgery for DCIS. Can genomic biomarkers help? [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES2-1.
Light sheet fluorescence microscopy as a new method for unbiased three-dimensional analysis of vascular injury
Authors: Nicholas E Buglak, Jennifer Lucitti, Pablo Ariel, Sophie Maiocchi, Francis J Miller, Edward S M Bahnson
Journal: Cardiovascular Research (2020)

Abstract Aims Assessment of preclinical models of vascular disease is paramount in the successful translation of novel treatments. The results of these models have traditionally relied on two-dimensional (2D) histological methodologies. Light sheet fluorescence microscopy (LSFM) is an imaging platform that allows for three-dimensional (3D) visualization of whole organs and tissues. In this study, we describe an improved methodological approach utilizing LSFM for imaging of preclinical vascular injury models while minimizing analysis bias. Methods and results The rat carotid artery segmental pressure-controlled balloon injury and mouse carotid artery ligation injury were performed. Arteries were harvested and processed for LSFM imaging and 3D analysis, as well as for 2D area histological analysis. Artery processing for LSFM imaging did not induce vessel shrinkage or expansion and was reversible by rehydrating the artery, allowing for subsequent sectioning and histological staining a posteriori. By generating a volumetric visualization along the length of the arteries, LSFM imaging provided different analysis modalities including volumetric, area, and radial parameters. Thus, LSFM-imaged arteries provided more precise measurements compared to classic histological analysis. Furthermore, LSFM provided additional information as compared to 2D analysis in demonstrating remodelling of the arterial media in regions of hyperplasia and periadventitial neovascularization around the ligated mouse artery. Conclusion LSFM provides a novel and robust 3D imaging platform for visualizing and quantifying arterial injury in preclinical models. When compared with classic histology, LSFM outperformed traditional methods in precision and quantitative capabilities. LSFM allows for more comprehensive quantitation as compared to traditional histological methodologies, while minimizing user bias associated with area analysis of alternating, 2D histological artery cross-sections.
Delivering Neonates at High Risk in the Right Place
Authors: Megan Whitham, Donald J. Dudley
Journal: JAMA Pediatrics (2020)

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