bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance to Pyrrolobenzodiazepine Dimers Is Associated with SLFN11 Downregulation and Can Be Reversed through Inhibition of ATR
Authors: Mao Shenlan , Chaerkady Raghothama , Yu Wen , D’Angelo Gina , Garcia Andrew , Chen Hong , Barrett Allison M. , Phipps Sandrina , Fleming Ryan , Hess Sonja , Koopmann Jens-Oliver , Dimasi Nazzareno , Wilson Susan , Pugh Kathryn , Cook Kimberly , Masterson Luke A. , Gao Changshou , Wu Herren , Herbst Ronald , Howard Philip W. , Tice David A. , Cobbold Mark , Harper Jay 
Published: March 2021

Abstract
Resistance to antibody–drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance to pyrrolobenzodiazepine (PBD)-conjugated ADCs have not been well characterized and thus, this study was designed to investigate development of resistance to PBD dimer warheads and PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations of SG3199, the PBD dimer released from the PBD drug-linker tesirine. 361-PBDr cells were over 20-fold less sensitive to SG3199 compared with parental cells and were cross-resistant to other PBD warhead and ADCs conjugated with PBDs. Proteomic profiling revealed that downregulation of Schlafen family member 11 (SLFN11), a putative DNA/RNA helicase, sensitizing cancer cells to DNA-damaging agents, was associated with PBD resistance. Confirmatory studies demonstrated that siRNA knockdown of SLFN11 in multiple tumor cell lines conferred reduced sensitivity to SG3199 and PBD-conjugated ADCs. Treatment with EPZ011989, an EZH2 inhibitor, derepressed SLFN11 expression in 361-PBDr and other SLFN11-deficient tumor cells, and increased sensitivity to PBD and PBD-conjugated ADCs, indicating that the suppression of SLFN11 expression is associated with histone methylation as reported. Moreover, we demonstrated that combining an ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, AZD6738, with SG3199 or PBD-based ADCs led to synergistic cytotoxicity in either resistant 361-PBDr cells or cells that SLFN11 was knocked down via siRNA. Collectively, these data provide insights into potential development of resistance to PBDs and PBD-conjugated ADCs, and more importantly, inform strategy development to overcome such resistance.
Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells
Authors: Zhang Yida , He Lile , Sadagopan Ananthan , Ma Tao , Dotti Gianpietro , Wang Yufeng , Zheng Hui , Gao Xin , Wang Dian , DeLeo Albert B. , Fan Song , Sun Ruochuan , Yu Ling , Zhang Liyuan , Wang Gongxian , Ferrone Soldano , Wang Xinhui 
Published: March 2021

Abstract

Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cell–mediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer.

Significance:
We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.
Very High Coronary Artery Calcium (≥1000) and Association With Cardiovascular Disease Events, Non–Cardiovascular Disease Outcomes, and Mortality
Authors: Peng Allison W. , Dardari Zeina A. , Blumenthal Roger S. , Dzaye Omar , Obisesan Olufunmilayo H. , Iftekhar Uddin S.M. , Nasir Khurram , Blankstein Ron , Budoff Matthew J. , Bødtker Mortensen Martin , Joshi Parag H. , Page John , Blaha Michael J. 
Published: March 2021

Background:
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.

Methods:
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).

Results:

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 mm
2
), 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.

Conclusions:
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 Role of Sensory Qualities in Renaissance Natural History: The Case of Mattioli’s Herbal
Authors: Strnadová Lucie 
Published: March 2021

Abstract
The aim of this paper is to show how sensory qualities were used to identify, observe, and describe plants in the sixteenth century. Mattioli’s herbal is an example of Renaissance natural history, which was based on Dioscorides’ classical text. Each step of constructing a chapter of the herbal required a different approach to sensory qualities. The identification of the plants described by Dioscorides called for detailed philological work and a good knowledge of the meaning of each term used for tastes, smells or colours. Descriptions were compared with living plants, while all plant parts and their properties had to be thoroughly examined. Taste was an important tool in establishing an affinity of a new plant with a plant from Dioscorides’ text, because gustatory qualities were regarded as closely related to plant nature. Visual qualities such as shape and colour were then especially useful in distinguishing varieties of particular plants.
António Vieira: A Jesuit Missionary to the Portuguese Jews of Amsterdam
Authors: Muhana Adma 
Published: March 2021

Abstract
Between the years 1646 and 1648, António Vieira maintained close contact with the Portuguese-Jewish community of Amsterdam, in particular with Menasseh ben Israel, a rabbi of Portuguese-converso origin. Under interrogation by the Inquisition, Vieira characterized this period of his life as the one in which he began to elaborate his messianic thesis of the so-called Fifth Empire. Unlike ben Israel, however, Vieira maintained that the Fifth Empire would arrive when the Jews recognized Christ as the messiah. Moreover, commanded by a Portuguese emperor-king, these Fifth Empire Christianized Jews would have their own political state, king, and cultural ceremonies. Always a missionary, Vieira argued that Jews would convert to the Catholic faith without the use of force as long as their idiosyncratic expectations were accepted, much like the Asian peoples and Indians of the New World, who, despite having been converted by the Jesuits, maintained some of their customs, beliefs, and institutions.
Contrast medium protocols in routine chest CT: a survey study
Authors: Henning Mette Karen , Aaløkken Trond Mogens , Johansen Safora 
Published: March 2021

Background Administration of contrast medium (CM) is an important image quality factor in computed tomography (CT) of the chest. There is no clear evidence or guidelines on CM strategies for chest CT, thus a consensus approach is needed. Purpose To survey the potential impact on differences in chest CT protocols, with emphasis on strategies for the administration of CM. Material and Methods A total of 170 respondents were included in this survey, which used two different approaches: (i) an online survey was sent to the members of the European Society of Thoracic Imaging (ESTI); and (ii) an email requesting a copy of their CT protocol was sent to all hospitals in Norway, and university hospitals in Sweden and Denmark. The survey focused on factors affecting CM protocols and enhancement in chest CT. Results The overall response rate was 24% (n = 170): 76% of the respondents used a CM concentration of ≥350 mgI/mL; 52% of the respondents used a fixed CM volume strategy. Fixed strategies for injection rate and delay were also the most common approach, practiced by 73% and 57% of the respondents, respectively. The fixed delay was in the range of 20–90 s. Of the respondents, 56% used flexible tube potential strategies (kV). Conclusion The chest CT protocols and CM administration strategies employed by the respondents vary widely, affecting the image quality. The results of this study underline the need for further research and consensus guidelines related to chest CT.
Magnetic Resonance Imaging Provides Useful Diagnostic Information Following Equivocal Ultrasound in Children With Suspected Appendicitis
Authors: Komanchuk Jelena , Martin Dori-Ann , Killam Rory , Eccles Robin , Brindle Mary E. , Khanafer Ijab , Joffe Ari R. , Blackwood Jaime , Yu Weiming , Gupta Priya , Sethi Sanjay , Moorjani Vijay , Thompson Graham 
Published: March 2021

Purpose: In Canada, ultrasonography is the primary imaging modality for children with suspected appendicitis, yet equivocal studies are common. Magnetic resonance imaging provides promise as an adjunct imaging strategy. The primary objective of this study was to determine the proportion of children with suspected appendicitis and equivocal ultrasound where magnetic resonance imaging determined a diagnosis. Methods: A prospective consecutive cohort of children aged 5-17 years presenting to a tertiary pediatric Emergency Department with suspected appendicitis were enrolled. Participants underwent diagnostic and management strategies according to our local suspected appendicitis pathway, followed by magnetic resonance (Siemens Avanto 1.5 Tesla) imaging. Sub-specialty pediatric radiologists reported all images. Results: Magnetic resonance imaging was performed in 101 children with suspected appendicitis. The mean age was 11.9 (SD 3.4) years and median Pediatric Appendicitis Score was 6 [IQR 4,8]. Ultrasonography was completed in 98/101 (97.0%). Of 53/98 (54.1%) with equivocal ultrasound, magnetic resonance imaging provided further diagnostic information in 41 (77.4%; 10 positive, 31 negative; 12 remained equivocal). Secondary findings of appendicitis on magnetic resonance imaging in children with equivocal ultrasound included abdominal free fluid (24, 45.3%), peri-appendiceal fluid (12, 22.6%), intraluminal appendiceal fluid (9, 17.0%), fat stranding (8, 15.1%), appendicolith (2, 3.8%), and peri-appendiceal abscess (1, 1.9%). The observed agreement between magnetic resonance imaging results and final diagnosis was 94.9% (kappa = 0.89).
Embedding an Advanced Pharmacy Technician in an Adult Specialty Pulmonary Clinic to Complete Prior Authorizations Improves Efficiency and Provider Satisfaction
Authors: Jones Emily M. , Francart Suzanne J. , Amerine Lindsey B. 
Published: March 2021

Purpose: The purpose of this study is to assess the impact of a clinic embedded Medication Assistance Program (MAP) specialist on the prescription benefit prior authorization (PA) process and provider satisfaction in an adult pulmonary clinic. Methods: In this mixed methods study, a retrospective cohort analysis was done to determine the turnaround time for the PA process from initial referral to approval or final denial in an adult pulmonary clinic. Additionally, a pre- and post-implementation survey to providers was conducted to assess provider satisfaction and perceptions around the prescription benefit PA process. The first study aim assessed PA efficiency by summarizing PA approval rate and PA turnaround time using descriptive statistics. Any prescriptions written by a clinic provider requiring a PA during the timeframe of June 2018 through August 2018 were included. The second study aim assessed change in provider satisfaction, analyzed via the Mann-Whitney U test. Results: The MAP specialist completed 110 PAs over 3 months for 110 unique patients. Median turnaround time was 3 hours, with 76% of PAs approved in less than 24 hours. Initial approval rate was 82.7%, and overall approval rate following the appeals process was 87.3%. A significant difference between the pre- and post-survey responses were identified in 2 of the 17 questions. Conclusion: Implementation of a clinic embedded MAP specialist to complete PAs demonstrated an efficient process while also improving provider satisfaction.
Medication Therapy Management for Texas MediCAID Patients With Asthma and Chronic Obstructive Pulmonary Disease—A Pilot Study
Authors: Nduaguba Sabina , Barner Jamie C. , Makhinova Tatiana , Roberson Kim 
Published: March 2021

Background: Pharmacists can play an important role in providing medication therapy management (MTM) services, which focus on appropriate medication use. This pilot study aimed to describe pharmacists’ MTM service provision, results/outcomes of pharmacists’ recommendations and resolution/acceptance rate among patients with high-risk asthma and/or chronic obstructive pulmonary disease (COPD). Methods: This was a prospective descriptive study of MTM services provided by community pharmacists to Texas Medicaid patients (5-63 years) with “high risk” asthma or COPD. Patients received in-person and telephone consultations that included medication review, asthma control test assessment, and education on adherence and proper medication/device use. Data extracted from MTM software was used to describe: reasons for MTM services, type of pharmacists’ interventions, outcomes of pharmacists’ recommendations and acceptance rate. Results: Twenty-eight pharmacists provided 139 MTM interventions with 63 patients (2.2 interventions per patient). The most frequent intervention reason was complex drug therapy (53.2%), underuse of medication (8.6%), need for drug therapy (8.6%), new or changed prescription therapy (6.5%), and administration technique (5.0%). The resolution rate was 77.7%. Patient and prescriber, respectively, refused recommendation in 12% and 6% of the interventions. Outcomes included comprehensive medication review (46.7%), improved adherence (6.5%), therapeutic success (6.5%), improved administration technique (5.0%), and initiation of new therapy (5.0%). Conclusion: Through the provision of MTM, pharmacists were able to identify and intervene with medication-related problems. These interventions are instrumental in helping patients better manage their asthma/COPD. The high resolution rate was encouraging. Larger scale studies are needed to assess clinical and economic outcomes.
Pulmonary Histopathology Findings in Patients With STAT3 Gain of Function Syndrome
Authors: Cortes-Santiago Nahir , Forbes Lisa , Vogel Tiphanie P , Silva-Carmona Manuel , Hicks John , Guillerman R Paul , Thatayatikom Akaluck , Patel Kalyani 
Published: March 2021

Introduction and Aim Multiorgan autoimmunity and interstitial lung disease (ILD) are reported in patients with STAT3 GOF syndrome. Results We present lung histopathology findings in 3 such children, two of whom underwent wedge biopsies with adequate diagnostic material. Wedge biopsies showed interstitial cellular expansion with linear and nodular aggregates of CD8 positive T lymphocytes, plasma cells, and histiocytes; consistent with lymphocytic interstitial pneumonia pattern (LIP). CD4+ T cells and CD20+ B cells were present but infrequent in the interstitium. FOXP3 cells ranged from 0-5%. Focal interstitial and intraalveolar histiocytes were also seen. Neutrophils and eosinophils were rare/absent. Non-occlusive peribronchial lymphoid aggregates showed equal T and B cells; likely reactive in nature. Pulmonary vessels appeared normal without vasculitis or hypertensive change. There was no interstitial or subepithelial fibrosis or organizing pneumonia. Interlobular septa and visceral pleura were unremarkable. Conclusion Children with multi-system autoimmune disorders with ILD should be investigated for STAT3 GOF syndrome. Lung wedge biopsies are more informative than transbronchial biopsies, if a tissue sampling is indicated. CD8 dominant T cell inflammation seems to be a key driver of ILD. Although interstitial fibrosis was not seen in our small sample, longer follow up is needed to understand the natural history.
A Panel Evaluation of the Changes in the General Public’s Social-Media-Following of United States’ Public Health Departments during COVID-19 Pandemic
Authors: Khokhar Areej , Spaulding Aaron , Niazi Zuhair , Ailawadhi Sikander , Manochakian Rami , Chanan-khan Asher , Niazi Shehzad , Sher Taimur 
Published: March 2021

Importance: Social media is widely used by various segments of society. Its role as a tool of communication by the Public Health Departments in the U.S. remains unknown. Objective: To determine the impact of the COVID-19 pandemic on social media following of the Public Health Departments of the 50 States of the U.S. Design, Setting, and Participants: Data were collected by visiting the Public Health Department web page for each social media platform. State-level demographics were collected from the U.S. Census Bureau. The Center for Disease Control and Prevention was utilized to collect information regarding the Governance of each State’s Public Health Department. Health rankings were collected from “America’s Health Rankings” 2019 Annual report from the United Health Foundation. The U.S. News and World Report Education Rankings were utilized to provide information regarding the public education of each State. Exposure: Data were pulled on 3 separate dates: first on March 5th (baseline and pre-national emergency declaration (NED) for COVID-19), March 18th (week following NED), and March 25th (2 weeks after NED). In addition, a variable identifying the total change across platforms was also created. All data were collected at the State level. Main Outcome: Overall, the social media following of the state Public Health Departments was very low. There was a significant increase in the public interest in following the Public Health Departments during the early phase of the COVID-19 pandemic. Results: With the declaration of National Emergency, there was a 150% increase in overall public following of the State Public Health Departments in the U.S. The increase was most noted in the Midwest and South regions of the U.S. The overall following in the pandemic “hotspots,” such as New York, California, and Florida, was significantly lower. Interesting correlations were noted between various demographic variables, health, and education ranking of the States and the social media following of their Health Departments. Conclusion and Relevance: Social media following of Public Health Departments across all States of the U.S. was very low. Though, the social media following significantly increased during the early course of the COVID-19 pandemic, but it still remains low. Significant opportunity exists for Public Health Departments to improve social media use to engage the public better.
Effectiveness of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled Clinical Trials
Authors: Nie Liu-yan , Zhao Kun , Ruan Jiaqi , Xue Jing 
Published: March 2021

Background: The effectiveness of platelet-rich plasma (PRP) injections for knee osteoarthritis and the effects of leukocyte-poor PRP (LP-PRP) versus leukocyte-rich PRP (LR-PRP) are still controversial. Purpose: To assess the effectiveness of different PRP injections through a direct and indirect meta-analysis of randomized controlled trials. Study Design: Systematic review; Level of evidence, 1. Methods: A systematic literature search of electronic databases (PubMed, Cochrane Library, and EMBASE) was performed to locate randomized controlled trials published through March 2019 that compared PRP with control treatment. A random-effects meta-analysis was conducted to synthesize the evidence, and meta-regression analyses were conducted to determine the influence of trial characteristics. An indirect comparison was performed to assess the effects of LP-PRP and LR-PRP compared with hyaluronic acid (HA). Results: A total of 21 trials were included. A clinically important benefit for pain relief was seen for intra-articular PRP compared with intra-articular saline (standardized mean difference [SMD] = –1.38 [95% CI, –2.07 to –0.70]; P < .0001; I 2 = 37%) and corticosteroid solution injection (SMD = –2.47 [95% CI, –3.34 to –1.61]; P < .00001; I 2 = 47%). As a result of heterogeneity ( I 2 = 89%), there was no conclusive effect compared with HA, even though the pooling effect provided clinically relevant pain relief (SMD = –0.59 [95% CI, –0.97 to –0.21]; P = .003). Indirect meta-analysis showed that there was no significant difference between LR-PRP and LP-PRP. Conclusion: PRP injections are beneficial for pain relief and functional improvement in knee osteoarthritis. Larger, randomized high-quality studies are needed to compare the effects of LP-PRP and LR-PRP.