tbuckley/cabot-search huggingface dataset:
Cardiomyocyte-derived small extracellular vesicles can signal eNOS activation in cardiac microvascular endothelial cells to protect against Ischemia/Reperfusion injury
Authors: Guihao Chen, Chuansheng Xu, Thomas G. Gillette, Tongyi Huang, Peisen Huang, Qing Li, Xiangdong Li, Qinfeng Li, Yu Ning, Ruijie Tang, Cunrong Huang, Yuyan Xiong, Xiaqiu Tian, Jun Xu, Junyan Xu, Liping Chang, Cong Wei, Chen Jin, Joseph A. Hill, Yuejin Yang
Journal: Theranostics (2020)

Rationale: The crosstalk between cardiac microvascular endothelial cells (CMECs) and cardiomyocytes (CMs) has emerged as a key component in the development of, and protection against, cardiac diseases. For example, activation of endothelial nitric oxide synthase (eNOS) in CMECs, by therapeutic strategies such as ischemic preconditioning, plays a critical role in the protection against myocardial ischemia/reperfusion (I/R) injury. However, much less is known about the signals produced by CMs that are able to regulate CMEC biology. Here we uncovered one such mechanism using Tongxinluo (TXL), a traditional Chinese medicine, that alleviates myocardial ischemia/reperfusion (I/R) injury by activating CMEC eNOS. The aim of our study is to identify the signals produced by CMs that can regulate CMEC biology during I/R. Methods:Ex vivo, in vivo, and in vitro settings of ischemia-reperfusion were used in our study, with the protective signaling pathways activated in CMECs identified using genetic inhibition (p70s6k1 siRNA, miR-145-5p mimics, etc.), chemical inhibitors (the eNOS inhibitor, L-NNA, and the small extracellular vesicles (sEVs) inhibitor, GW4869) and Western blot analyses. TritonX-100 at a dose of 0.125% was utilized to inactivate the eNOS activity in endothelium to investigate the role of CMEC-derived eNOS in TXL-induced cardioprotection. Results: We found that while CMEC-derived eNOS activity was required for the cardioprotection of TXL, activation of eNOS in CMECs by TXL did not occur directly. Instead, eNOS activation in CMECs required a crosstalk between CMs and CMECs through the uptake of CM-derived sEVs. We further demonstrate that TXL induced CM-sEVs contain increased levels of Long Intergenic Non-Protein Coding RNA, Regulator Of Reprogramming (Linc-ROR). Upon uptake into CMECs, linc-ROR downregulates its target miR-145-5p leading to activation of the eNOS pathway by facilitating the expression of p70s6k1 in these cells. The activation of CMEC-derived eNOS works to increase survival in both the CMECs and the CMs themselves. Conclusions: These data uncover a mechanism by which the crosstalk between CMs and CMECs leads to the increased survival of the heart after I/R injury and point to a new therapeutic target for the blunting of myocardial I/R injury.
Tissue Engineering: In Situ Forming, Silanized Hyaluronic Acid Hydrogels with Fine Control Over Mechanical Properties and In Vivo Degradation for Tissue Engineering Applications (Adv. Healthcare Mater. 19/2020)
Authors: Killian Flegeau, Claire Toquet, Gildas Rethore, Cyril d'Arros, Léa Messager, Boris Halgand, Davy Dupont, Florent Autrusseau, Julie Lesoeur, Joëlle Veziers, Pascal Bordat, Anthony Bresin, Jérôme Guicheux, Vianney Delplace, Hélène Gautier, Pierre Weiss
Journal: Advanced Healthcare Materials (2020)

In article number 2000981 by Pierre Weiss and co-workers, an in situ forming, single-component hyaluronic acid hydrogel is reported based on the pH-triggered condensation of silanols into siloxanes. In vitro, cytocompatible hydrogels with tunable mechanical properties are obtained by tuning the crosslink density. In vivo, the hydrogel's degradability can be adapted, while elicitating minimum inflammation. Silanized hyaluronic gels are potent minimally invasive vehicles for tissue engineering.
The impact of within-visit and pre-visit decision aids for localized prostate cancer on patient knowledge.
Authors: Jon Charles Tilburt, Joel E Pacyna, Kristin Cina, Daniel G. Petereit, Judith Salmon Kaur, Elizabeth M. Storrrick, David Zahrieh, Amylou C. Dueck, Simon P. Kim
Journal: Journal of Clinical Oncology (2020)

151 Background: Decision aids (DAs) for prostate cancer treatment can improve knowledge and reduce decisional conflict, but the relative effect of pre-visit and within-visit DAs is not known, and effect sizes for minority populations has not been estimated. Methods: We conducted a 3-arm, patient-level-RCT in specialty urology and radiation oncology practices in Ohio, South Dakota, and Alaska, test the effect of pre-consultation and with-in consultation decision aids on patient knowledge immediately after specialty consultation compared to usual care. We used linear regression to estimate effects of each intervention arm, including the respective standard error, two-sided 95% confidence interval, and two-sided P value for testing the study’s hypotheses. Results: 103 patients were recruited and randomized to receive either the pre-visit decision aid, within-visit decision aid, or neither decision aids (usual care). In 2017 and 20018, we accrued similar numbers of men to pre-consultation aid (n = 37), during-consultation aid (n = 33) and usual care arms, respectively (n = 33). The median (range) age in years was 64 [49, 81]; 67.6% were White, 15.7% were Black or African American, 16.7% were American Indian or Alaska Native, and 1% were not reported. 47.6%, 45.6%, and 6.8% had a baseline clinical stage of T1, T2, and T3, respectively. The median [range] prostate specific antigen (PSA) was 8.0 [2.4, 53.7]. There were no clinically notable imbalances. We obtained usable data on 102 of the 103 patient-participants. The pre-visit decision aid arm showed a mean knowledge effect of 0.694 (0.636, 0.753). The within-visit decision arm showed a very similar mean knowledge effect of 0.686 (0.625, 0.748). The usual care arm showed a mean knowledge effect of 0.644 (0.582,0.705). The linear regression model showed, that, compared with usual care, neither intervention effect achieved statistical significance in the primary analysis (p = 0.24, 0.330, for pre-visit and within-visit, respectively). Conclusions: Modest knowledge gains of pre-visit and during-visit decision aids for prostate cancer treatment were not statistically significant. Clinical trial information: NCT03182998 .
Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort
Authors: Paola Nicoletti, Daniel F. Carr, Sarah Barrett, Laurence McEvoy, Peter S. Friedmann, Neil H. Shear, Matthew R. Nelson, Anca M. Chiriac, Natalia Blanca-López, José A. Cornejo-García, Francesco Gaeta, Alla Nakonechna, Maria J. Torres, Cristiano Caruso, Rocco L. Valluzzi, Aris Floratos, Yufeng Shen, Rebecca K. Pavlos, Elizabeth J. Phillips, Pascal Demoly, Antonino Romano, Miguel Blanca, Munir Pirmohamed
Journal: Journal of Allergy and Clinical Immunology (2020)

β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE.We sought to identify genetic predisposing factors for immediate reactions to β-lactam antibiotics.Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort.Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams.HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.
Feasibility of and associated cost savings from transitioning to therapeutic biosimilar use in a large community oncology network.
Authors: Garrett Young, Kathy McGee, Leah Owens, Stacey McCullough, Edward Arrowsmith, Stacey L Poole, Mary Catherine Marsden, Aaron J. Lyss, Stephen Matthew Schleicher, Sylvia S. Richey, Natalie R. Dickson, Lee S. Schwartzberg
Journal: Journal of Clinical Oncology (2020)

9 Background: The use of biosimilar drugs in the treatment of cancer offer an opportunity for oncology providers to decrease total cost of care while preserving quality. However, it remains unclear whether providers and patients may resist biosimilar use due to concerns over safety and efficacy. Our national network of 5 practices with over 100 clinics committed to a conversion to therapeutic biosimilars for trastuzumab and bevacizumab after their introduction in July 2019. Methods: Common steps to foster therapeutic biosimilar conversion included frequent communication from medical directors to providers and staff, incorporation of biosimilars into default treatment regimen orders, providing clinical teams lists identifying candidates for conversion, and tracking reasons why biosimilar switch did not occur. Most practices prioritized converting patients initiating new treatments, then later transitioning patients receiving maintenance therapy. This phased approach was taken to ensure that prior authorization and patient consent could be obtained prior to conversion. Rates of biosimilar use were calculated by comparing the number of administrations for which a biosimilar was given to the total number of administrations for which a biosimilar could have been given. Cost savings were calculated by comparing the difference in Medicare allowed rates for each originator and biosimilar drug pair at the time of administration. Results: Biosimilar use increased over time at all practices, from 0% to an average of 67% for trastuzumab and 78% for bevacizumab. The decrease in cost attributed to the use of biosimilars in the study period totaled over $4.4 million. Challenges to biosimilar use included physician preference for the originator drug, difference in preferred agents across payers, and challenges with biosimilar drug storage. Patients rarely had concerns over efficacy and safety. Conclusions: Therapeutic biosimilar adoption in a large oncology network is feasible and can lead to significant cost savings. [Table: see text]
Impacts of Different Renal Function Estimation Formulas on Dosing of DOACs and Clinical Outcomes
Authors: Yi-Hsin Chan, Tze-Fan Chao, Hsin-Fu Lee, Yung-Hsin Yeh, Chih-Hsin Yeh, Ya-Chi Huang, Shang-Hung Chang, Chi-Tai Kuo, Gregory Y.H. Lip, Shih-Ann Chen
Journal: Journal of the American College of Cardiology (2020)
The impact of a cancer diagnosis on worker productivity: Results from a survey of cancer patients and caregivers.
Authors: Suepattra Grace May, Kevin Chiu, Joanna P. MacEwan, Katalin Bognar, Desi Peneva, Lauren Zhao, Candice Yong, Suvina Amin, Katharine Batt, Bjorn Bolinder, James Baumgardner
Journal: Journal of Clinical Oncology (2020)

144 Background: Traditional approaches to capturing health-related productivity loss--e.g. the human capital method--focus only on the foregone wages of affected patients, overlooking the losses caregivers can incur. Thus, the value of lost productivity is often underestimated. This study comprehensively estimates and describes work-related productivity losses due to a cancer diagnosis among working-age (18-65) breast cancer (BC) and non-small cell lung cancer (NSCLC) patients and their unpaid caregivers in the United States. Methods: A cross-sectional survey of BC and NSCLC patients and caregivers measured loss associated with time absent from work (absenteeism) and reduced effectiveness (presenteeism). Respondents reported pre- and post-cancer diagnosis income, hours worked, and time to complete tasks. Exploratory multivariable analyses examined correlations between respondents’ clinical and demographic characteristics—including industry of employment—and post-diagnosis productivity. Results: Of 204 patients (104 BC, 100 NSCLC) and 200 caregivers (100 BC, 100 NSCLC) who completed the survey, 319 participants (162 BC, 157 NSCLC) working ≥40 weeks/year pre-diagnosis were included in the analysis. Over a third of the NSCLC (33%) and BC (43%) patients left the workforce post-diagnosis, whereas 15% of caregivers left. Estimated mean annual productivity loss equaled $125,975 ($50,328 using traditional method) for NSCLC patients and $120,404 ($37,445 using traditional method) for BC. For caregivers, estimated mean annual productivity loss was $97,062 ($39,751 using traditional method) for NSCLC and $123,669 ($33,410 using traditional method) for BC. Exploratory analyses found that greater patient age and later stage at diagnosis were correlated with greater absenteeism. Conclusions: Although patients typically experience greater absenteeism, productivity loss incurred by caregivers is also substantial. Our results underscore the importance of holistic approaches to understanding the broad impact of cancer on both patients and their caregivers.
The effect of body mass index (BMI) on survival in patients with breast cancer and obesity-associated conditions.
Authors: Keenan B. Caddell, Yi Ren, Anuyuga Sampathkumar, Chandra A. Almond, Oluwatomi L. Ladipo, Colin E. Champ, Laura Horst Rosenberger, Rachel Adams Greenup, Jennifer Kay Plichta, Gayle DiLalla, Carolyn S. Menendez, Lisa Tolnitch, Eun-Sil Shelley Hwang, Terry Hyslop, Oluwadamilola Motunrayo Fayanju
Journal: Journal of Clinical Oncology (2020)

203 Background: Previous studies have demonstrated an association between body mass index (BMI) and survival after breast cancer diagnosis, but the direction and strength of this relationship is inconsistent. Comorbidities that are more common in patients who are obese (BMI≥30) – including diabetes (DM), hypertension (HTN), and hyperlipidemia (HLD) – are often conflated with obesity with regard to their effects on breast cancer outcomes. We sought to determine the effect of BMI on overall survival (OS) among women with breast cancer after controlling for obesity-associated conditions. Methods: Women≥18y diagnosed with stage 0-IV breast cancer at an academic institution from Jan 2014-Jul 2016 and with known BMI at diagnosis were identified. χ 2 and ANOVA tests were used to compare intergroup differences. BMI was categorized as normal (&lt;25), overweight (25-29.9), class 1 obesity (30-34.9), and class 2/3 obesity (≥35). Unadjusted OS by BMI class was estimated with the Kaplan-Meier method. Cox proportional hazards models were used to estimate the association of BMI with OS after adjusting for covariates including obesity-associated conditions. Results: 1027 patients were included (median follow-up 46.8 mos): 296 (28.9%) were overweight, 227 (22.1%) had class 1 obesity, and 207 (20.2%) had class 2/3 obesity. Non-Hispanic (NH) black women were overrepresented among obese patients, making up 25% (n=257) of all patients but 37.5% of obese patients. Rates of DM, HTN, and HLD increased with increasing BMI (all p&lt;0.01). Unadjusted OS differed significantly by BMI class, with overweight women having the worst 5-year OS (log-rank p=0.02). After adjustment, BMI continued to be associated with OS, with overweight women having significantly worse OS vs normal-weight women, but there was no significant association between obesity and OS (Table). Conclusions: Despite higher rates of DM, HTN, and HLD with increasing BMI, a diagnosis of obesity was not associated with worse OS in women with breast cancer but being overweight was, suggesting the need for a more nuanced understanding of body composition, obesity-associated conditions, and their respective potential impact on breast cancer outcomes. [Table: see text]
<i>KALRN</i>mutations promote antitumor immunity and immunotherapy response in cancer
Authors: Mengyuan Li, Yuxiang Ma, You Zhong, Qian Liu, Canping Chen, Lei Qiang, Xiaosheng Wang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background kalirin RhoGEF kinase ( KALRN ) is mutated in a wide range of cancers. Nevertheless, the association between KALRN mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer. Methods We explored the correlation between KALRN mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between KALRN mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy. Results Antitumor immune signatures were more enriched in KALRN -mutated than KALRN -wildtype cancers. Moreover, KALRN mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in KALRN -mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in KALRN -mutated versus KALRN -wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in KALRN -mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between KALRN mutations and increased antitumor immunity was associated with the fact that KALRN mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors. Conclusions The KALRN mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.
Evaluation of Hospital Performance Using the Excess Days in Acute Care Measure in the Hospital Readmissions Reduction Program
Authors: Rishi K. Wadhera, Karen E. Joynt Maddox, Nihar R. Desai, Bruce E. Landon, Muthiah Vaduganathan MD, Lauren G. Gilstrap, Changyu Shen, Robert W. Yeh
Journal: Annals of Internal Medicine (2020)

The Hospital Readmissions Reduction Program (HRRP) has penalized hospitals with higher 30-day readmission rates more than $3 billion to date. Clinicians and policy experts have raised concerns that the 30-day readmission measure used in this program provides an incomplete picture of performance because it does not capture all hospital encounters that may occur after discharge. In contrast, the excess days in acute care (EDAC) measure, which currently is not used in the HRRP, captures the full spectrum of hospital encounters (emergency department, observation stay, inpatient readmission) and their associated lengths of stay within 30 days of discharge. This study of 3173 hospitals that participated in the HRRP in fiscal year 2019 compared performance on the readmission and EDAC measures and evaluated whether using the EDAC measure would change hospitals' penalty status for 3 conditions targeted by the HRRP. Overall, only moderate agreement was found on hospital performance rankings by using the readmission and EDAC measures (weighted κ statistic: heart failure, 0.45 [95% CI, 0.42 to 0.47]; acute myocardial infarction [AMI], 0.37 [CI, 0.35 to 0.40]; and pneumonia, 0.50 [CI, 0.47 to 0.52]). Under the HRRP, the penalty status of 769 (27.0%) of 2845 hospitals for heart failure, 581 (28.3%) of 2055 for AMI, and 724 (24.9%) of 2911 for pneumonia would change if the EDAC measure were used instead of the readmission measure to evaluate performance. Fewer small and rural hospitals would receive penalties. The Centers for Medicare & Medicaid Services should consider using the EDAC measure, which provides a more comprehensive picture of postdischarge hospital use, rather than the 30-day readmission measure to evaluate health care system performance under federal quality, reporting, and value-based programs.
Opioid prescribing practices in adolescent and young adults with sarcomas.
Authors: Melissa Beauchemin, Rohit Raghunathan, Melissa Kate Accordino, Jason Dennis Wright, Justine Kahn, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2020)

136 Background: Adolescents and young adults (AYAs) with sarcoma undergo procedures that can result in acute and chronic pain. Adult cancer patients are at increased risk of chronic opioid use, and AYAs are vulnerable to misuse. However, opioid prescribing practices in AYAs with sarcoma are not known. We described opioid prescribing during active therapy and identify factors associated with continued opioid prescription post-treatment in AYAs with newly diagnosed sarcoma. Methods: Patients 10–26 years who were diagnosed with sarcoma between 2008–2016 were identified using IBM Marketscan database. Included subjects received anti-cancer therapy (chemotherapy, procedures, and/or radiation) within 30 days of diagnosis and were continuously enrolled in one insurance plan (commercial or Medicaid) &gt;12-months both before diagnosis and after last therapy. Primary outcome was opioid use, defined as at least one opioid prescription during the 12 months following treatment completion. Covariates included age, sex, insurance, treatment type, mental health (MH) and substance use (SU) diagnoses. Results: We included 1,349 patients, 75% had commercial insurance, 21% had a previous MH, and 4% had previous SU diagnosis. 63% of subjects used opioids during treatment and 28% received at least 1 prescription in the year post-therapy. Medicaid insurance was associated with 60% higher likelihood of opioid use during treatment and those with prior use were three-times more likely to continue post- therapy. Conclusions: Opioid prescriptions in AYAs with sarcoma are common during treatment. A significant proportion of patients continue to receive opioids post-therapy, particularly those with a history of use pre-diagnosis. Medicaid insurance and MH disorder are also associated with continued use post-therapy. Further research is needed to establish safe and effective opioid prescribing practices in AYAs with sarcoma. [Table: see text]