tbuckley/cabot-search huggingface dataset:
Abstract 249: ERBB2 and beta-1-Adrenergic Receptor Cross-talk Underlies Cardiac Dysfunction
Authors: Manveen K Gupta, Kate Stenson, Kathleen Gabrielson, Sathyamangla V Naga Prasad
Journal: Circulation Research (2019)

ERBB2 is a member of the EGFR growth factor receptor family and a primary target for anti-cancer treatment in patients diagnosed with breast cancer. ERBB2 targeting is known to cause cardiotoxicity, resulting in cardiac dilation while, less is understood about the underlying mechanisms. Studies have shown a direct co-relationship between beta2-adrenergic receptors (β2ARs) and ERBB2 in the cardiac hypertrophy wherein increased ERBB2 expression is associated with elevated β2ARs. Given the key role of β1ARs in cardiac function, we assessed potential cross-talk between ERBB2 and β1ARs. Towards this end, we have used a transgenic mouse model of cardiomyocyte-specific overexpression of microRNA-7 (miR-7 Tg) that abrogates ERBB2 expression in the adult cardiomyocytes and associated with cardiac dilation. Radio-ligand binding in miR-7 Tg hearts showed selective increase in β1AR density with no changes in the β2ARs. In contrast, cardiomyocyte-specific overexpression of ERBB2 results cardiac hypertrophy and is associated with significant increase in β2AR density with no changes in β1ARs. These observations show that ERBB2 expression may differentially regulate β1AR versus β2AR providing a unique role for ERBB2 in cardiac physiology. Further, ERBB2 expression is elevated in an age-dependent manner in C57BL6 mice that may account for hypertrophic response. Consistently, miR-7 Tg mice have age-dependent cardiac dilation consistent with the loss in the ERBB2 expression. To test for such a role, C57BL6 mice were administered vehicle, AG1875 (EGFR inhibitor) or AG825 (ERBB2 inhibitor) for two weeks to assess for changes in cardiac function. Administration of AG825 resulted significant cardiac dysfunction and dilation compared to AG1875 or vehicle controls, conferring the idea that inhibition of ERBB2 and not EGFR that mediates deleterious remodeling. Proteomic analysis showed dramatic differences in the associated proteins following AG825 compared to vehicle or AG1478 and our presentation will elucidate the results on how homeostatic ERBB2 signaling and expression is key for cardiac function and how chemotherapeutic inhibition of ERBB2 underlies deleterious pathways leading to cardiotoxicity.
Proteomic Analysis Identifies HSP70 As a Novel Target Therapy to Polycythemia Vera
Authors: Miguel Gallardo, Marisol Fernandez, Alberto Paradela, Oscar Toldos, Rosa-Maria Garcia-Martin, Santiago Barrio, Rosa M. Ayala, Enriqueta Albizua, Inmaculada Rapado, Ana Jimenez, Marisa Candelas, Florinda Gilsanz, Joaquín Martínez-López
Journal: Blood (2011)
Creatine uptake regulates CD8 T cell antitumor immunity
Authors: Stefano Di Biase, Xiaoya Ma, Xi Wang, Jiaji Yu, Yu-Chen Wang, Drake J. Smith, Yang Zhou, Zhe Li, Yu Jeong Kim, Nicole Clarke, Angela To, Lili Yang
Journal: The Journal of Experimental Medicine (2019)

T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine supplementation with a PD-1/PD-L1 blockade treatment showed synergistic tumor suppression efficacy. We further demonstrated that creatine acts as a “molecular battery” conserving bioenergy to power T cell activities. Therefore, our results have identified creatine as an important metabolic regulator controlling antitumor T cell immunity, underscoring the potential of creatine supplementation to improve T cell–based cancer immunotherapies.
High-Risk AML, Including Flt3ITD+, Exhibits Resistance To Conventional Cytarabine Induction Associated With Diminished ENT1 and p16INK Expression: Evidence For Epigenetic Repression and HDAC Inhibitor Modulated De-Repression
Authors: H. Scott Boswell, Sushil Gupta, Rui Gao, Katie J Sargent, Larry D. Cripe, Mehdi Nassiri, Hamid Sayar, Yan Liu
Journal: Blood (2013)
Abstract 337: Cell-Substrate Adhesion Regulates Early Steps of Myofibrillogenesis in Human Cardiomyocytes
Authors: Abigail C Neininger, Nilay Taneja, Dylan T Burnette
Journal: Circulation Research (2019)

Forces generated by myofibrils within cardiomyocytes must be balanced by adhesion to the extracellular matrix proteins and to other cardiomyocytes for proper heart function. Loss of this force balance results in cardiomyopathies and heart failure. Using a sarcomere assembly assay we previously developed utilizing human induced pluripotent stem cell-derived cardiomyocytes, we show coupling of focal adhesions to myofibrils during early steps of de novo myofibrillogenesis is essential for myofibril maturation. Increasing the extent of adhesion by inhibition of Focal adhesion kinase (FAK), a known regulator of adhesion dynamics, or by increasing the concentration of fibronectin on which the cardiomyocytes are cultured, led to precocious myofibril formation. Decreasing the extent of adhesion by siRNA-mediated FAK knockdown or by decreasing the concentration of fibronectin attenuated myofibrillogenesis. In each case, increased or decreased adhesion extent inversely correlated with rate of retrograde flow of myofibril precursors known as muscle stress fibers (AKA, non-muscle stress fiber-like structures or pre-myofibrils). This suggests a relationship between cell-substrate adhesion and substrate coupling to muscle stress fibers, facilitating their maturation into myofibrils. Taken together, our findings implicate a role for classical mechano-transduction in the assembly of sarcomere containing myofibrils.
Contemporary analysis of bone mineral density in men initiating androgen deprivation therapy for prostate cancer.
Authors: Jason Hu, Armen G. Aprikian, Marie Vanhuyse, Alice Dragomir
Journal: Journal of Clinical Oncology (2019)

38 Background: Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) treatment, however several side-effects are associated with its long-term use. Notably, loss of bone mineral density (BMD) is accelerated which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to properly assess baseline fracture risk. The objective was to examine the proportion of BMD testing in men initiating long-term ADT in Quebec. Methods: The cohort consists of men extracted from Quebec public healthcare insurance administrative databases who were diagnosed with PCa from 2001-2012 and treated by ADT for at least one continuous year. The primary study outcome was the receipt of baseline BMD testing (defined as a BMD test identified in the period from 6 months prior to and up to 12 months after ADT initiation). Multivariable generalized linear mixed with a logit link was performed to identify variables associated with baseline BMD testing accounting for physician clustering. Results: We identified 7,069 patients, of which 887 (12.6%) underwent baseline BMD testing. Baseline BMD testing varied by year of ADT initiation, from 7.7% in 2001-2003 to 12.3% in 2013-2012. Following multivariable analyses, later years of ADT initiation (2004-2006, 2007-2009, 2010-2012, 2013-2015) remained associated with higher odds of baseline BMD testing compared to the earlier years (2001-2003) (ORs ranging from 1.43-1.88; p &lt; 0.001). Conversely, age &gt; 80 (OR 0.73; 95% CI 0.57-0.94; p = 0.001), greater Charlson comorbidity score (OR 0.51; 95%CI 0.34-0.75; p = 0.001), and rural residence (OR 0.60; 95%CI 0.48-0.75; p &lt; 0.001) were associated with lower odds of baseline BMD testing. Conclusions: In our study population, rates of baseline BMD testing in men initiating ADT are low, although the rates increased over the course of the study period. Potential gaps identified in baseline BMD testing include older, more comorbid patients, and rural residence. Additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.
Assessment of Accuracy of an Artificial Intelligence Algorithm to Detect Melanoma in Images of Skin Lesions
Authors: Michael Phillips, Helen Marsden, Wayne Jaffe, Rubeta N. Matin, Gorav N. Wali, Jack Greenhalgh, Emily McGrath, Rob James, Evmorfia Ladoyanni, Anthony Bewley, Giuseppe Argenziano, Ioulios Palamaras
Journal: JAMA Network Open (2019)

A high proportion of suspicious pigmented skin lesions referred for investigation are benign. Techniques to improve the accuracy of melanoma diagnoses throughout the patient pathway are needed to reduce the pressure on secondary care and pathology services.To determine the accuracy of an artificial intelligence algorithm in identifying melanoma in dermoscopic images of lesions taken with smartphone and digital single-lens reflex (DSLR) cameras.This prospective, multicenter, single-arm, masked diagnostic trial took place in dermatology and plastic surgery clinics in 7 UK hospitals. Dermoscopic images of suspicious and control skin lesions from 514 patients with at least 1 suspicious pigmented skin lesion scheduled for biopsy were captured on 3 different cameras. Data were collected from January 2017 to July 2018. Clinicians and the Deep Ensemble for Recognition of Malignancy, a deterministic artificial intelligence algorithm trained to identify melanoma in dermoscopic images of pigmented skin lesions using deep learning techniques, assessed the likelihood of melanoma. Initial data analysis was conducted in September 2018; further analysis was conducted from February 2019 to August 2019.Clinician and algorithmic assessment of melanoma.Area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity of the algorithmic and specialist assessment, determined using histopathology diagnosis as the criterion standard.The study population of 514 patients included 279 women (55.7%) and 484 white patients (96.8%), with a mean (SD) age of 52.1 (18.6) years. A total of 1550 images of skin lesions were included in the analysis (551 [35.6%] biopsied lesions; 999 [64.4%] control lesions); 286 images (18.6%) were used to train the algorithm, and a further 849 (54.8%) images were missing or unsuitable for analysis. Of the biopsied lesions that were assessed by the algorithm and specialists, 125 (22.7%) were diagnosed as melanoma. Of these, 77 (16.7%) were used for the primary analysis. The algorithm achieved an AUROC of 90.1% (95% CI, 86.3%-94.0%) for biopsied lesions and 95.8% (95% CI, 94.1%-97.6%) for all lesions using iPhone 6s images; an AUROC of 85.8% (95% CI, 81.0%-90.7%) for biopsied lesions and 93.8% (95% CI, 91.4%-96.2%) for all lesions using Galaxy S6 images; and an AUROC of 86.9% (95% CI, 80.8%-93.0%) for biopsied lesions and 91.8% (95% CI, 87.5%-96.1%) for all lesions using DSLR camera images. At 100% sensitivity, the algorithm achieved a specificity of 64.8% with iPhone 6s images. Specialists achieved an AUROC of 77.8% (95% CI, 72.5%-81.9%) and a specificity of 69.9%.In this study, the algorithm demonstrated an ability to identify melanoma from dermoscopic images of selected lesions with an accuracy similar to that of specialists.
Abstract 527: Cardiac Fibroblast Ablation in Chronic Fibrosis
Authors: April Stempien-Otero, Deri Helterline, Steve Farris
Journal: Circulation Research (2019)

Cardiac fibrosis is a common feature of heart failure independent of etiology. Although much is known about initiation of fibrosis in acute injury, factors leading to the persistence of fibrosis are poorly understood. We sought to determine if cardiac fibroblasts are necessary for the persistence of fibrosis by ablating resident cardiac fibroblasts in a mouse model of cardiac fibrosis. Methods: We generated mice with inducible ablation of cardiac fibroblasts (fb) by crossing the tcf21-cre gene into a MerCreMer-DTA mouse. These mice were then crossed into SR-uPA transgene which promotes diffuse interstitial fibrosis by 12 weeks of age. Control tcf21-DTA and tcf-21-DTA-SRuPA mice were treated with tamoxifen for 1-4 weeks to activate DTA and ablate cardiac fibroblasts. Echocardiography, histology and qPCR of isolated fb and macrophages (mac) was performed. Results: Treatment of wildtype tcf21-DTA mice with tamoxifen for 1-4 weeks resulted in a decrease in alpha-SMA positive cells in the heart but no change in left ventricular size or function. There was no excess mortality. Hearts showed no evidence of increased inflammation or fibrosis. Tcf21-DTA-SRuPA mice were viable but exhibited increased mortality starting at 10 days following initiation of tamoxifen. There were no changes in echocardiographic parameters, histologic inflammation or fibrosis. Fb had no change in expression of Col1a1 normalized to GAPDH. However, mac from Tcf21-DTA-SRuPA mice had a significant decrease in expression of M2 genes Arg1 and YM1. Conclusion: Ablation of fibroblasts was toxic to mice with established fibrosis, without changes in cardiac structure or function. Mac phenotype shifted from pro-fibrotic/M2 to pro-inflammatory/M1 with fibroblast ablation. These data point to important compensatory mechanisms that may maintain fibrosis in the heart.
Prediction of acute care service utilization for patients with hematologic malignancies.
Authors: Kai Zu, Kristina Greenwood, Joyce Lamori, Besa Smith, Tyler C Smith, Alaina Lee
Journal: Journal of Clinical Oncology (2019)

312 Background: Improving the ability to predict which patients are at increased risk for acute care services subsequent to hospitalization can lead to more effective interventions and quality care. This study evaluated the performance of risk models to predict 30-day acute service utilization among adult inpatients with newly diagnosed hematologic malignancies. The study explored the impact of medical complications on potentially preventable service utilization, aligned with specifications for proposed measure OP-35 from the CMS Hospital Outpatient Quality Reporting Program. Methods: The study included 933 unique adult patients admitted to four acute care inpatient facilities within a non-profit community based healthcare system during calendar years 2012 to 2017. Risk models integrated a comprehensive set of data elements using clinical information from electronic medical records and facility oncology registries. Predictive models were constructed using a multivariable logistic regression, with calculation of standardized coefficients to rank order variables with the greatest impact on unplanned readmissions. Exploratory data mining techniques were conducted to augment classification of at-risk patients. Results: The mean age of study participants was 65 years and 55.1% were male. In order of prevalence, the types of hematologic malignancy were lymphoma (48.7%), leukemia (35.2%), myeloma (14.0%), and mixed types (2.1%). Approximately one fifth of patients received unplanned acute care services within 30 days after the index hospitalization (lymphoma = 23.1%, myeloma = 22.1%, leukemia = 18.6%). Among the risk models, the most influential predictors included initial length of stay, severity of illness, and consult for social work. Overall, 56.6% of patients who were readmitted within 30 days of hospitalization presented with one or more symptoms associated with the CMS medical complication measure, including cytopenia, infection, negative hydration, and/or pain. Conclusions: Optimizing quality care in a value-based health care environment requires proactive approaches such as risk prediction models for identifying patients who can benefit most from care transition interventions.
Abstract 511: Regulation of p53 Protein Levels Drives Activation of Cardiac Fibroblasts in Response to Pressure Overload
Authors: Ryan M Burke, Pearl Quijada, Adwiteeya Misra, Ronald A Dirkx, Brian Kang, Christine S Moravec, Eric M Small
Journal: Circulation Research (2019)

Heart disease is accompanied by the accumulation of resident cardiac fibroblasts (CF) that subsequently become myofibroblasts and secrete copious amounts of extracellular matrix (ECM), impeding cardiac function and driving the progression of heart failure. Understanding the mechanisms coordinating CF accumulation and myofibroblast activation may reveal novel therapeutic strategies to block pathologic fibrosis. We recently found that s mall pr oline r ich protein 2b (SPRR2B) drives CF proliferation in response to pathological cues by facilitating MDM2-dependent proteasomal degradation of p53. Surprisingly, although Sprr2b gene deletion or targeted mutation of the USP7/MDM2 interacting domain in mice ( Sprr2b-KO and Sprr2b-USP m , respectively) stimulated the expression of p53-dependent cell cycle arrest genes, mutant animals also developed excessive fibrosis in LV pressure overload. The development of fibrosis in Sprr2b mutant mice was traced primarily to a more robust myofibroblast activation response, providing evidence that CF accumulation and myofibroblast activation may be mutually antagonistic. To investigate the contribution p53 to CF accumulation and fibrosis in mouse heart disease models, we deleted floxed p53 alleles specifically in adult CF using the tamoxifen-inducible Tcf21 MerCreMer mouse line (called p53-CKO). Surprisingly, while p53-CKO animals display exaggerated accumulation of Tcf21 + /PDGFRα + CF in response to left ventricle pressure overload, we observed a biphasic physiological response; initially, p53-CKO animals are resistant to systolic functional decline, only developing more severe fibrosis and functional decline than littermate controls at later time points. Time course studies using primary adult mouse CF revealed that p53 positively correlates with myofibroblast activation, while reduction in p53 levels correlates with accelerated cell cycle and the suppression of myofibroblast activation until the subsequent induction of p16/19 - Rb-mediated cell cycle arrest. Taken together, this study offers detailed insight into the transition of CF from a proliferative to an activated state that may accelerate the development of anti-fibrotic strategies.
Understanding the factors influencing doctors’ intentions to report patient safety concerns: a qualitative study
Authors: Antonia Rich, Rowena Viney, Ann Griffin
Journal: Journal of the Royal Society of Medicine (2019)

To investigate doctors' intentions to raise a patient safety concern by applying the socio-psychological model 'Theory of Planned Behaviour'.Qualitative semi-structured focus groups and interviews.Training venues across England (North West, South East and South West).Sampling was purposeful to include doctors from differing backgrounds and grades.Perceptions of raising a patient safety concern.While raising a concern was considered an appropriate professional behaviour, there were multiple barriers to raising a concern, which could be explained by the Theory of Planned Behaviour. Negative attitudes operated due to a fear of the consequences, such as becoming professionally isolated. Disapproval for raising a concern was encountered at an interpersonal and organisational level. Organisational constraints of workload and culture significantly undermined the raising of a concern. Responses about concerns were often side-lined or not taken seriously, leading to demotivation to report. This was reinforced by high-profile cases in the media and the negative treatment of whistle-blowers. While regulator guidance acted as an enabler to justify raising a concern, doctors felt disempowered to raise a concern about people in positions of greater power, and ceased to report concerns due to a perceived lack of action about concerns raised previously.Intentions to raise a concern were complex and highly contextual. The Theory of Planned Behaviour is a useful model to aid understanding of the factors which influence the decision to raise a concern. Results point to implications for policymakers, including the need to publicise positive stories of whistle-blowers and providing greater support to doctors.
Dexrazoxane Use in Pediatric Patients with Acute Lymphoblastic or Myeloid Leukemia: Analysis of a National Cohort of Patients in the Pediatric Health Information Systems Database From 1999 to 2009
Authors: Dana Sepe, Brian T. Fisher, Alix E. Seif, Yuan-Shung V. Huang, Yimei Li, Richard Aplenc
Journal: Blood (2011)
Association Between Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, and Suicide
Authors: Muhammad Mamdani, Tara Gomes, Simon Greaves, Selina Manji, David N. Juurlink, Mina Tadrous, Sidney H. Kennedy, Tony Antoniou
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs. <h3>Objective</h3> To examine the association between suicide and exposure to ARBs compared with ACEIs. <h3>Design, Setting, and Participants</h3> This population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date. <h3>Exposures</h3> Use of an ACEI or ARB. <h3>Main Outcomes and Measures</h3> Conditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs. <h3>Results</h3> Nine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (27.0%) were exposed to ARBs, and 704 (73.0%) were exposed to ACEIs. Among controls, 741 (19.2%) were exposed to ARBs, and 3115 (80.8%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98). <h3>Conclusions and Relevance</h3> The use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.
Interleukin (IL)-1 Beta and IL-6 Activated Acute and Chronic Myelogenous Leukemia-Derived Myofibroblasts to Express Leukemia-Specific Transcripts
Authors: Takuji Matsuo, Haruko Tashiro, Ritsu Sumiyoshi, Tadashi Yamamoto, Kensuke Matsumoto, Jun Ooi, Naoki Shirafuji
Journal: Blood (2018)
Nonmyeoablative Allogeneic Conditioning with Bendamustine in Combination with Fludarabine and Rituximab for Lymphoid Malignancies: Immunosuppression without Myelosuppression and without Acute Gvhd
Authors: Issa F Khouri, Rima M Saliba, Martin Korbling, Amin M Alousi, Uday R Popat, Paolo Anderlini, Stefan O Ciurea, Partow Kebriaei, Muzaffar H. Qazilbash, Richard Champlin, Roland L Bassett
Journal: Blood (2011)
Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Relapsed/Refractory Acute Myeloid Leukemia
Authors: Muhammad Umair Mushtaq, Sibgha Gull Chaudhary, Guru Subramanian Guru Murthy, Aric C. Hall, Ehab L. Atallah, Ryan J. Mattison
Journal: Blood (2018)