bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toll-like receptor 7/8 agonist R848 alters the immune tumor microenvironment and enhances SBRT-induced antitumor efficacy in murine models of pancreatic cancer
Authors: Ye Jian , Mills Bradley N , Qin Shuyang S , Garrett-Larsen Jesse , Murphy Joseph D , Uccello Taylor P , Han Booyeon J , Vrooman Tara G , Johnston Carl J , Lord Edith M , Belt Brian A , Linehan David C , Gerber Scott A 
Published: July 2022

BackgroundStereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and damage-associated molecular patterns. However, this induction often fails to generate sufficient response to overcome pre-existing tumor microenvironment (TME) immunosuppression. Toll-like receptor (TLR) 7/8 ligands, such as R848, can amplify the effect of tumor vaccines, with recent evidence showing its antitumor effect in pancreatic cancer by modulating the immunosuppressive TME. Therefore, we hypothesized that the combination of R848 and SBRT would improve local and systemic antitumor immune responses by potentiating the antitumor effects of SBRT and reversing the immunosuppressive nature of the PDAC TME.MethodsUsing murine models of orthotopic PDAC, we assessed the combination of intravenous TLR7/8 agonist R848 and local SBRT on tumor growth and immune response in primary pancreatic tumors. Additionally, we employed a hepatic metastatic model to investigate if the combination of SBRT targeting only the primary pancreatic tumor and systemic R848 is effective in controlling established liver metastases.ResultsWe demonstrated that intravenous administration of the TLR7/8 agonist R848, in combination with local SBRT, leads to superior tumor control compared with either treatment alone. The combination of R848 and SBRT results in significant immune activation of the pancreatic TME, including increased tumor antigen-specific CD8+T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10. Importantly, the combination of SBRT and systemic R848 also resulted in similar immunostimulatory changes in liver metastases, leading to improved metastatic control. CD8+T cell depletion studies highlighted the necessity of these effector cells at both the local and hepatic metastatic sites. T cell receptor (TCR) clonotype analysis indicated that systemic R848 not only diversified the TCR repertoire but also conditioned the metastatic foci to facilitate entry of CD8+T cells generated by SBRT therapy.ConclusionsThese findings suggest that systemic administration of TLR7/8 agonists in combination with SBRT may be a promising avenue for metastatic PDAC treatment.
Recommendations for the execution and reporting of skin ultrasound in systemic sclerosis: an international collaboration under the WSF skin ultrasound group
Authors: Santiago Tânia , Santos Eduardo José Ferreira , Ruaro Barbara , Lepri Gemma , Green Lorraine , Wildt Marie , Watanabe Shinji , Lescoat Alain , Hesselstrand Roger , del Galdo Francesco , Pauling John D , Reeve Lucy Jean , D'Agostino Maria Antonieta , Matucci-Cerinic Marco , Iagnocco Annamaria , da Silva Jose Antonio Pereira 
Published: July 2022

ObjectiveUltrasound is a promising tool to foster much-needed improvement of skin assessment in systemic sclerosis (SSc). Our aim was to develop evidence and expert opinion-based recommendations to promote the standardisation and harmonisation of technical execution and reporting of skin ultrasound studies in SSc.MethodsA multidisciplinary task force of 16 members from five European countries and Japan was convened under the auspices of World Scleroderma Foundation. First, a systematic literature review (SLR) was performed. Then, each member proposed and formulated items to the overarching principles, recommendations and research agenda. Two rounds of mails exchange for consensus as well as an on-line meeting were performed to debate and refine the proposals. Two Delphi rounds of voting resulted in the final recommendations. Levels of evidence and strengths of recommendations were assigned, and task force members voted anonymously on the level of agreement with each of the items.ResultsFive overarching principles and seven recommendations were developed, based on an SLR and expert opinion, through consensus procedures. The overarching principles highlight the promising role of skin ultrasound in SSc assessment, the need for standardisation of technical aspects, sufficient training and adequate equipment. The recommendations provide standards for the execution and reporting of skin ultrasound in SSc. The research agenda includes the need for more research into unmet needs according to Outcome Measures in Rheumatology Algorithm requirements.ConclusionThese are the first recommendations providing guidance on the execution and reporting of skin ultrasound in SSc patients, aiming at improving the interpretability, reliability and generalisability of skin ultrasound, thus consolidating its role in research and practice.
Near-memory Computing on FPGAs with 3D-stacked Memories: Applications, Architectures, and Optimizations
Authors: Iskandar Veronia , Ghany Mohamed A. Abd El , Göhringer Diana 
Published: July 2022

The near-memory computing (NMC) paradigm has transpired as a promising method for overcoming the memory wall challenges of future computing architectures. Modern systems integrating 3D-stacked DRAM memory can be leveraged to prevent unnecessary data movement between the main memory and the CPU. FPGA vendors have started introducing 3D memories to their products in an effort to remain competitive on bandwidth requirements of modern memory-intensive applications. Recent NMC proposals target various types of data processing workloads such as graph processing, MapReduce, sorting, machine learning, and database analytics.
In this article, we conduct a literature survey on previous proposals of NMC systems on FPGAs integrated with 3D memories. By leveraging the high bandwidth offered from such memories together with specifically designed hardware, FPGA architectures have become a competitor to GPU solutions in terms of speed and energy efficiency. Various FPGA-based NMC designs have been proposed with software and hardware optimization methods to achieve high performance and energy efficiency. Our review investigates various aspects of NMC designs such as platforms, architectures, workloads, and tools. We identify the key challenges and open issues with future research directions.
Preinvasive to Invasive: PD-1–Expressing Macrophages Shift Lung Cancer into High Gear
Authors: Lee Juyeun , Bayik Defne , Lathia Justin D. 
Published: July 2022

AbstractLung adenocarcinoma is the most common subtype of lung cancer, which has the second highest incidence among cancers. Immunotherapy has revolutionized lung cancer treatment, yet the checkpoint blockade response rate is less than 20% in patients with lung adenocarcinoma. As lung adenocarcinoma consists of heterogeneous histologic subsets with diverse tumor invasion phenotypes and clinical outcomes, understanding the mechanisms of resistance based on the histology subset is essential. In the current issue, Jang and colleagues demonstrated that PD-1–expressing macrophages are the dominant immune cell population in the tumor-immune microenvironment (TiME) of invasive lung adenocarcinoma and are responsible for driving tumor progression from preinvasive to invasive subtypes. PD-1–expressing macrophages are protumorigenic and highly plastic, potentially promoting invasive solid tumor development. Ablation of macrophages remodels the TiME and leads to a favorable anti-PD-1 blockade response, suggesting a potential combination therapy in patients with lung adenocarcinoma resistant to monotherapy. This current work highlights the spatiotemporal dynamics of the TiME during lung adenocarcinoma progression and the critical role of PD-1–expressing macrophages in driving tumorigenesis as well as resistance to immunotherapy.See related article by Jang et al., p. 2593
Highly Sensitive EGFRvIII Detection in Circulating Extracellular Vesicle RNA of Glioma Patients
Authors: Batool Syeda Maheen , Muralidharan Koushik , Hsia Tiffany , Falotico Sarah , Gamblin Austin S. , Rosenfeld Yulia B. , Khanna Sirena K. , Balaj Leonora , Carter Bob S. 
Published: July 2022

Abstract

Purpose:
Liquid biopsy offers an attractive platform for noninvasive tumor diagnosis, prognostication, and prediction of glioblastoma clinical outcomes. Prior studies report that 30% to 50% of GBM lesions characterized by EGFR amplification also harbor the EGFRvIII mutation.

Experimental Design:
A novel digital droplet PCR (ddPCR) assay for high GC content amplicons was developed and optimized for sensitive detection of EGFRvIII in tumor tissue and circulating extracellular vesicle RNA (EV RNA) isolated from the plasma of patients with glioma.

Results:
Our optimized qPCR assay detected EGFRvIII mRNA in 81% [95% confidence interval (CI), 68%–94%] of EGFR-amplified glioma tumor tissue, indicating a higher than previously reported prevalence of EGFRvIII in glioma. Using the optimized ddPCR assay in discovery and blinded validation cohorts, we detected EGFRvIII mutation in 73% (95% CI, 64%–82%) of patients with a specificity of 98% (95% CI, 87%–100%), compared with qPCR tumor tissue analysis. In addition, upon longitudinal monitoring in 4 patients, we report detection of EGFRvIII in the plasma of patients with different clinical outcomes, rising with tumor progression, and decreasing in response to treatment.

Conclusions:
This study demonstrates the feasibility of detecting EGFRvIII mutation in plasma using a highly sensitive and specific ddPCR assay. We also show a higher than previously reported EGFRvIII prevalence in glioma tumor tissue. Several features of the assay are favorable for clinical implementation for detection and monitoring of EGFRvIII-positive tumors.
Plasma Metabolomics Analysis of Aspirin Treatment and Risk of Colorectal Adenomas
Authors: Barry Elizabeth L. , Fedirko Veronika , Jin Yutong , Liu Ken , Mott Leila A. , Peacock Janet L. , Passarelli Michael N. , Baron John A. , Jones Dean P. 
Published: July 2022

AbstractDespite substantial observational and experimental evidence that aspirin use can provide protection against the development of colorectal neoplasia, our understanding of the molecular mechanisms involved is inadequate and limits our ability to use this drug effectively and safely for chemoprevention. We employed an untargeted plasma metabolomics approach using liquid chromatography with high-resolution mass spectroscopy to explore novel metabolites that may contribute to the chemopreventive effects of aspirin. Associations between levels of metabolic features in plasma and aspirin treatment were investigated among 523 participants in a randomized placebo-controlled clinical trial of two doses of aspirin (81 or 325 mg/day) and were linked to risk of colorectal adenoma occurrence over 3 years of follow-up. Metabolic pathways that were altered with aspirin treatment included linoleate and glycerophospholipid metabolism for the 81-mg dose and carnitine shuttle for both doses. Metabolites whose levels increased with 81 mg/day aspirin treatment and were also associated with decreased risk of adenomas during follow-up included certain forms of lysophosphatidylcholine and lysophosphatidylethanolamine as well as trihydroxyoctadecenoic acid, which is a derivative of linoleic acid and is upstream of cyclooxygenase inhibition by aspirin in the linoleate and arachidonic acid metabolism pathways. In conclusion, our findings regarding lysophospholipids and metabolites in the linoleate metabolism pathway may provide novel insights into the chemopreventive effects of aspirin in the colorectum, although they should be considered hypothesis-generating at this time.Prevention Relevance:This research used metabolomics, an innovative discovery-based approach, to identify molecular changes in human blood that may help to explain how aspirin use reduces the risk of colorectal neoplasia in some individuals. Ultimately, this work could have important implications for optimizing aspirin use in the prevention of colorectal cancer.
County-Level Social Vulnerability is Associated With In-Hospital Death and Major Adverse Cardiovascular Events in Patients Hospitalized With COVID-19: An Analysis of the American Heart Association COVID-19 Cardiovascular Disease Registry
Authors: Islam Shabatun J. , Malla Gargya , Yeh Robert W. , Quyyumi Arshed A. , Kazi Dhruv S. , Tian Wei , Song Yang , Nayak Aditi , Mehta Anurag , Ko Yi-An , de Lemos James A. , Rodriguez Fatima , Goyal Abhinav , Wadhera Rishi K. 
Published: July 2022

Background:
The COVID-19 pandemic has disproportionately affected low-income and racial/ethnic minority populations in the United States. However, it is unknown whether hospitalized patients with COVID-19 from socially vulnerable communities experience higher rates of death and/or major adverse cardiovascular events (MACEs). Thus, we evaluated the association between county-level social vulnerability and in-hospital mortality and MACE in a national cohort of hospitalized COVID-19 patients.

Methods:
Our study population included patients with COVID-19 in the American Heart Association COVID-19 Cardiovascular Disease Registry across 107 US hospitals between January 14, 2020 to November 30, 2020. The Social Vulnerability Index (SVI), a composite measure of community vulnerability developed by Centers for Disease Control and Prevention, was used to classify the county-level social vulnerability of patients’ place of residence. We fit a hierarchical logistic regression model with hospital-level random intercepts to evaluate the association of SVI with in-hospital mortality and MACE.

Results:

Among 16 939 hospitalized COVID-19 patients in the registry, 5065 (29.9%) resided in the most vulnerable communities (highest national quartile of SVI). Compared with those in the lowest quartile of SVI, patients in the highest quartile were younger (age 60.2 versus 62.3 years) and more likely to be Black adults (36.7% versus 12.2%) and Medicaid-insured (31.1% versus 23.0%). After adjustment for demographics (age, sex, race/ethnicity) and insurance status, the highest quartile of SVI (compared with the lowest) was associated with higher likelihood of in-hospital mortality (OR, 1.25 [1.03–1.53];
P
=0.03) and MACE (OR, 1.26 [95% CI, 1.05–1.50];
P
=0.01). These findings were not attenuated after accounting for clinical comorbidities and acuity of illness on admission.

Conclusions:
Patients hospitalized with COVID-19 residing in more socially vulnerable communities experienced higher rates of in-hospital mortality and MACE, independent of race, ethnicity, and several clinical factors. Clinical and health system strategies are needed to improve health outcomes for socially vulnerable patients.
Associations of Clinical and Social Risk Factors With Racial Differences in Premature Cardiovascular Disease
Authors: Shah Nilay S. , Ning Hongyan , Petito Lucia C. , Kershaw Kiarri N. , Bancks Michael P. , Reis Jared P. , Rana Jamal S. , Sidney Stephen , Jacobs David R. , Kiefe Catarina I. , Carnethon Mercedes R. , Lloyd-Jones Donald M. , Allen Norrina B. , Khan Sadiya S. 
Published: July 2022

Background:
Racial differences in cardiovascular disease (CVD) are likely related to differences in clinical and social factors. The relative contributions of these factors to Black-White differences in premature CVD have not been investigated.

Methods:
In Black and White adults aged 18 to 30 years at baseline in the CARDIA study (Coronary Artery Risk Development in Young Adults), the associations of clinical, lifestyle, depression, socioeconomic, and neighborhood factors across young adulthood with racial differences in incident premature CVD were evaluated in sex-stratified, multivariable-adjusted Cox proportional hazards models using multiply imputed data assuming missing at random. Percent reduction in the β estimate (log-hazard ratio [HR]) for race quantified the contribution of each factor group to racial differences in incident CVD.

Results:
Among 2785 Black and 2327 White participants followed for a median 33.9 years (25th–75th percentile, 33.7–34.0), Black (versus White) adults had a higher risk of incident premature CVD (Black women: HR, 2.44 [95% CI, 1.71–3.49], Black men: HR, 1.59 [1.20–2.10] adjusted for age and center). Racial differences were not statistically significant after full adjustment (Black women: HR, 0.91 [0.55–1.52], Black men: HR 1.02 [0.70–1.49]). In women, the largest magnitude percent reduction in the β estimate for race occurred with adjustment for clinical (87%), neighborhood (32%), and socioeconomic (23%) factors. In men, the largest magnitude percent reduction in the β estimate for race occurred with an adjustment for clinical (64%), socioeconomic (50%), and lifestyle (34%) factors.

Conclusions:
In CARDIA, the significantly higher risk for premature CVD in Black versus White adults was statistically explained by adjustment for antecedent multilevel factors. The largest contributions to racial differences were from clinical and neighborhood factors in women, and clinical and socioeconomic factors in men.
Differences in Comorbidities Explain Black–White Disparities in Outcomes After Femoropopliteal Endovascular Intervention
Authors: Krawisz Anna K. , Natesan Sahana , Wadhera Rishi K. , Chen Siyan , Song Yang , Yeh Robert W. , Jaff Michael R. , Giri Jay , Julien Howard , Secemsky Eric A. 
Published: July 2022

Background:
Black adults have a higher incidence of peripheral artery disease and limb amputations than White adults in the United States. Given that peripheral endovascular intervention (PVI) is now the primary revascularization strategy for peripheral artery disease, it is important to understand whether racial differences exist in PVI incidence and outcomes.

Methods:
Data from fee-for-service Medicare beneficiaries ≥66 years of age from 2016 to 2018 were evaluated to determine age- and sex-standardized population-level incidences of femoropopliteal PVI among Black and White adults over the 3-year study period. Patients’ first inpatient or outpatient PVIs were identified through claims codes. Age- and sex-standardized risks of the composite outcome of death and major amputation within 1 year of PVI were examined by race.

Results:

Black adults underwent 928 PVIs per 100 000 Black beneficiaries compared with 530 PVIs per 100 000 White beneficiaries (risk ratio, 1.75 [95% CI, 1.73–1.77];
P
<0.01). Black adults who underwent PVI were younger (mean age, 74.5 years versus 76.4 years;
P
<0.01), were more likely to be female (52.8% versus 42.7%;
P<
0.01), and had a higher burden of diabetes (70.6% versus 56.0%;
P
<0.01), chronic kidney disease (67.5% versus 56.6%;
P<
0.01), and heart failure (47.4% versus 41.7%;
P<
0.01) than White adults. When analyzed by indication for revascularization, Black adults were more likely to undergo PVI for chronic limb-threatening ischemia than White adults (13 023 per 21 352 [61.0%] versus 59 956 per 120 049 [49.9%];
P<
0.01). There was a strong association between Black race and the composite outcome at 1 year (odds ratio, 1.21 [95% CI, 1.16–1.25]). This association persisted after adjustment for socioeconomic status (odds ratio, 1.08 [95% CI, 1.03–1.13]) but was eliminated after adjustment for comorbidities (odds ratio, 0.96 [95% CI, 0.92–1.01]).

Conclusions:
Among fee-for-service Medicare beneficiaries, Black adults had substantially higher population-level PVI incidence and were significantly more likely to experience adverse events after PVI than White adults. The association between Black race and adverse outcomes appears to be driven by a higher burden of comorbidities. This analysis emphasizes the critical need for early identification and aggressive management of peripheral artery disease risk factors and comorbidities to reduce Black–White disparities in the development and progression of peripheral artery disease and the risk of adverse events after PVI.
Disparities in Cardiovascular Mortality Between Black and White Adults in the United States, 1999 to 2019
Authors: Kyalwazi Ashley N. , Loccoh Eméfah C. , Brewer LaPrincess C. , Ofili Elizabeth O. , Xu Jiaman , Song Yang , Joynt Maddox Karen E. , Yeh Robert W. , Wadhera Rishi K. 
Published: July 2022

Background:
Black adults experience a disproportionately higher burden of cardiovascular risk factors and disease in comparison with White adults in the United States. Less is known about how sex-based disparities in cardiovascular mortality between these groups have changed on a national scale over the past 20 years, particularly across geographic determinants of health and residential racial segregation.

Methods:
We used CDC WONDER (Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research) to identify Black and White adults age ≥25 years in the United States from 1999 to 2019. We calculated annual age-adjusted cardiovascular mortality rates (per 100 000) for Black and White women and men, as well as absolute rate differences and rate ratios to compare the mortality gap between these groups. We also examined patterns by US census region, rural versus urban residence, and degree of neighborhood segregation.

Results:
From 1999 to 2019, age-adjusted mortality rates declined overall for both Black and White adults. There was a decline in age-adjusted cardiovascular mortality among Black (602.1 to 351.8 per 100 000 population) and White women (447.0 to 267.5), and the absolute rate difference (ARD) between these groups decreased over time (1999: ARD, 155.1 [95% CI, 149.9–160.3]; 2019: ARD, 84.3 [95% CI, 81.2–87.4]). These patterns were similar for Black (824.1 to 526.3 per 100 000) and White men (637.5 to 396.0; 1999: ARD, 186.6 [95% CI, 178.6–194.6]; 2019: ARD, 130.3 [95% CI, 125.6–135.0]). Despite this progress, cardiovascular mortality in 2019 was higher for Black women (rate ratio, 1.32 [95% CI, 1.30–1.33])— especially in the younger (age <65 years) subgroup (rate ratio, 2.28 [95% CI, 2.23–2.32])—as well as for Black men (rate ratio, 1.33 [95% CI, 1.32–1.34]), compared with their respective White counterparts. There was regional variation in cardiovascular mortality patterns, and the Black-White gap differed across rural and urban areas. Cardiovascular mortality rates among Black women and men were consistently higher in communities with high levels of racial segregation compared with those with low to moderate levels.

Conclusions:
During the past 2 decades, age-adjusted cardiovascular mortality declined significantly for Black and White adults in the United States, as did the absolute difference in death rates between these groups. Despite this progress, Black women and men continue to experience higher cardiovascular mortality rates than their White counterparts.