tbuckley/cabot-search huggingface dataset:
GSK3β-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression
Authors: Hisae Yoshitomi, Kun Y. Lee, Ke Yao, Seung Ho Shin, Tianshun Zhang, Qiushi Wang, Souren Paul, Eunmiri Roh, Joohyun Ryu, Hanyong Chen, Faisal Aziz, Abhijit Chakraborty, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2020)

Abstract The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3β promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box−/− WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. Significance: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3β-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.
Matters of Life and Death: An Experimental Study Investigating Psychological Interventions to Encourage the Readiness for End-of-Life Conversations
Authors: Pia von Blanckenburg, Nico Leppin, Katharina Nagelschmidt, Carola Seifart, Winfried Rief
Journal: Psychotherapy and Psychosomatics (2020)

Talking about death and dying is evoking discomfort in many persons, resulting in avoidance of this topic. However, end-of-life discussions can alleviate distress and uncertainties in both old and young adults, but only a minority uses this option in palliative care. Even in healthy populations, talking about death is often seen as alleviative and worthwhile, but rarely initiated.To investigate different psychological interventions (a) encouraging the readiness for end-of-life discussions and (b) changing death attitudes in healthy adults of different ages.168 participants were randomized to four different interventions (IG1: value-based intervention with end-of-life perspective, IG2: motivation-based intervention with end-of-life perspective, IG3: combination of IG1 and IG2, CG: control group). Primary outcome was the readiness to engage in end-of-life topics. Secondary outcomes were fear of death, fear of dying and death acceptance. Assessments took place before, directly after the intervention and at 2 weeks of follow up.IG2 and IG3 reported significantly more changes in the readiness to engage in end-of-life discussions than the CG (F[5.61, 307] = 4.83, p < 0.001, ηp2 = 0.081) directly after the intervention. The effect of IG3 remained stable at the follow-up. There were no significant effects of the interventions on end-of-life fears or death acceptance. Acceptability of the interventions was very high.Short interventions can be useful to encourage end-of-life discussions and could be integrated in health care programs. The efficacy and effectiveness of these short interventions in palliative patients are currently examined.
COVID-19 INDUCED LIVER FUNCTION ABNORMALITY
Authors: S. Li, J. Li Li, Z. Zhang, L. Tan, T. Shao, M. Li, X. Li, J. A. Holmes, W. Lin, M. Han
Journal: Hepatology (2020)

Background: Coronavirus disease 2019 (COVID-19) is a novel infectious disease that may cause fever, dry cough, fatigue and shortness of breath The impact of COVID-19 on liver function is not well described Methods: The Second People's Hospital of Fuyang City in China has admitted a total of 159 patients with confirmed COVID-19 since the outbreak from January 2020 to March 2020 We analyzed the incidence of liver function test (LFT) abnormality in these patients with confirmed COVID-19 infection  Results: We found that the overall frequency of LFT abnormality was 17 6%  Frequency of LFT abnormality was significantly greater in patients with severe/critical (SC) COVID-19 compared to those with mild/moderate (MM) COVID-19 (32 4% vs 11 6%, p=0 011) Among patients with LFT abnormality, the median age was significantly higher in the SC group compared to the MM group (52 vs 39 years, p=0 021) Conclusion: COVID-19 is frequently associated with mild liver function abnormality, particularly in individuals with severe/critical COVID-19 who were older Liver function should be monitored carefully during infection, with judicious use of hepatotoxic agents where possible and avoidance of prolonged hypotension to minimize liver injury in older patients
SARS-CoV-2 Transmission among Marine Recruits during Quarantine
Authors: Andrew G. Letizia, Irene Ramos, Ajay Obla, Carl Goforth, Dawn L. Weir, Yongchao Ge, Marcas M. Bamman, Jayeeta Dutta, Ethan Ellis, Luis Estrella, Mary-Catherine George, Ana S. Gonzalez-Reiche, William D. Graham, Adriana van de Guchte, Ramiro Gutierrez, Franca Jones, Aspasia Kalomoiri, Rhonda Lizewski, Stephen Lizewski, Jan Marayag, Nada Marjanovic, Eugene V. Millar, Venugopalan D. Nair, German Nudelman, Edgar Nunez, Brian L. Pike, Chad Porter, James Regeimbal, Stas Rirak, Ernesto Santa Ana, Rachel S.G. Sealfon, Robert Sebra, Mark P. Simons, Alessandra Soares-Schanoski, Victor Sugiharto, Michael Termini, Sindhu Vangeti, Carlos Williams, Olga G. Troyanskaya, Harm van Bakel, Stuart C. Sealfon
Journal: New England Journal of Medicine (2020)

BackgroundThe efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults.MethodsWe investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections.ResultsA total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon.ConclusionsAmong Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons. (Funded by the Defense Health Agency and others.)
Abstract 285: Resuscitation Practices of Cardiac Arrest in Children with Cardiac Disease in Cardiac Intensive Care Units Compared to Pediatric Intensive Care Units
Authors: Tanya Perry, Tia T Raymond, Joanna Fishbein, Michael G Gaies, Todd Sweberg
Journal: Circulation (2020)

Introduction: Hospitalized children with critical cardiac disease experience cardiac arrest more than any other disease type. Varying models are devoted to caring for this population, including pediatric intensive care units (PICU) and dedicated cardiac intensive care units (CICU). The process of CPR delivery has not been evaluated in CICUs in comparison to PICUs. Hypothesis: There will be no difference in cardiac arrest resuscitation practices between unit types. Methods: We analyzed patients &lt;18 years from the American Heart Association Get with the Guidelines-Resuscitation database (GWTG-R) with an illness category of medical or surgical cardiac disease who received CPR in a CICU or PICU from 2014 to 2018. Events were assessed for compliance with GWTG-R achievement measures of time to first chest compressions ≤ 1 minute, time to IV/IO epinephrine ≤ 5 minutes, time to first shock ≤ 2 minutes for VF/pulseless VT first documented rhythm, and confirmation of endotracheal tube (ETT) placement in trachea. Results: CPR practices were evaluated on 866 patients, 687 CICU and 179 PICU (55% male and 65% neonatal). Surgical cardiac disease was present in 56%. Cardiac malformations were present in 81% (45% cyanotic 29% acyanotic). Pulseless arrest was the initial event in 41% with a shockable rhythm in 14%. Return of spontaneous circulation occurred in 86% and survival to hospital discharge in 58%. Univariate analysis comparing resuscitation practice is shown in Table 1. ECPR use was the only variable noted to be significantly different between units (CICU 22% vs PICU 6%, P&lt;0.01). On multivariate analysis, there were no differences in GWTG-R achievement measures between ICU types for ETT placement confirmation, time to IV/IO epinephrine dose, time to first chest compression to first shock (P&gt;0.05). Conclusion: Despite differences in infrastructure, process, and provider expertise, there were no differences in cardiac arrest resuscitation practice between CICUs and PICUs.
Analysis of Mitochondrial Metabolic Profile As a Predictor of Clinical Aggressiveness of Acute Myeloid Leukemia
Authors: Praveen Ramakrishnan Geethakumari, Rasmi G Nair, Geetha Jagannathan, Diana Whitaker-Menezes, Zhao Lin, Neal Flomenberg, Dolores Grosso, Jerald Gong, Guldeep Uppal, Ubaldo Martinez-Outschoorn
Journal: Blood (2017)
Abstract 13538: Trends in Utilization and Outcomes of Mechanical Circulatory Support for Patients With Myocarditis
Authors: Jonathan B Edelson, Alicia Kamesh, Jen Faerber, Antara Mondal, Heather M Griffis, Danielle S Burstein, Carol A Wittlieb-Weber, Kimberly Y Lin, Christopher Mascio, James W Gaynor, Jonthan Chen, Stephanie M Fuller, Matthew J O'Connor, Edo Birati, Joseph W Rossano
Journal: Circulation (2020)

Introduction: Outcomes of mechanical circulatory support (MCS) to treat myocarditis are not well described. Hypothesis: We hypothesize that MCS is increasingly utilized for the treatment of myocarditis and is associated with high morbidity and mortality. Methods: This study utilized admissions from the National Inpatient Sample (NIS) from 2012-2016. Patient-encounters with myocarditis were identified using ICD-9/10 codes. Weighted population estimate outcomes comparing encounters with MCS or without MCS were calculated. Mode of MCS was examined and trends in MCS treatment, mortality and morbidity were assessed using logistic regression models. Results: Of the 48,965 encounters for myocarditis between 2012 and 2016, 1,910 patients died (3.9%) and 255 (0.5%) underwent transplant. MCS was used in 2,215 patients (4.5%): extra corporeal membrane oxygenation (ECMO) in 590, durable ventricular assist device (VAD) in 150, temporary VAD (tVAD) in 320, and intra-aortic balloon pump (BP) in 770. Over 5 years there was no change in the frequency of MCS and mortality in MCS patients remained stable (p for trends &gt;0.3 ). However, the use of ECMO increased from 23.2% in 2012 to 38.5% in 2016 while BP use decreased from 60.9% to 26.4% (p trend for both &lt;0.05). Mortality (25.5% vs 2.9%), infection (32.7% vs 11.7%), stroke (10.2% vs 2.2%), bleeding events (16.0% vs 2.2%) and arrhythmia (58.9% vs 29.0%), were higher in MCS (p for all &lt;0.0001). Incidence of mortality, stroke, and bleeding differed by mode of MCS support {ECMO (31.2%, 15.3%, 23.7%), BP (18.2%, 4.6%, 7.8%), tVAD (26.6%, 4.7%, 7.8%) and VAD (6.7%, 6.7%, 16.7%) (p for all &lt;0.05)} with ECMO having the highest number of complications. Conclusion: MCS is utilized in 5% of patients with myocarditis. ECMO has become the most common support modality, but its use is associated with significant morbidity and mortality. Further evaluation of how patient characteristics influence the MCS type utilized and their impact on outcomes is needed.
Abstract 15924: Identification of Gender- and Age-specific Top Predictors of Hospitalization Due to Heart Failure Using Machine Learning in TOPCAT
Authors: Gauri Dandi, Nuha Gani, Zyannah Mallick, Avantika Banerjee, Ian Atkinson, Victoria Xin, Khizar Qureshi, Natalie Lewis, Nayab Mahmood, Noah Hasan, Scout Hayashi, Nowreen Haq, Amit Dey, Anwar Husain, Yves D Rosenberg, Ahmed A Hasan
Journal: Circulation (2020)

Background: NHLBI supported Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) (NCT00094302) investigated whether treatment with spironolactone reduces hospitalization due to heart failure (hHF) in 3,445 adults with prior heart failure and a left ventricular ejection fraction over 45%. We reused publicly available individual patient-level data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) on the American TOPCAT cohort (n=1767) to identify gender and age groups specific baseline (bl) predictors of hHF. Methods: The subjects were stratified into subgroups based on gender (male and female) and age (50-59, 60-69, 70-79, 80-90). Random Survival Forest (RSF), a non-parametric ML approach, evaluated 172 bl variables as predictors of hHF. Top 10 predictors were subsequently included in a multivariate Cox proportional hazards model. Results: The top 10 predictors of hHF are shown in Figure 1. Overall, renal and hematological biomarkers appeared prominently in the top 10 predictors for these patients. While liver markers were among top predictors for hHF in males, diabetes treatment and diabetic complications were top predictors for females. Also, diabetic treatment was a top predictor among age group 50-59, diabetic complications were top predictors among age groups 50-59 and 70-79, liver markers were top predictors among age groups 70-79, and race and years of smoking were top predictors among age group 60-69. Importantly, the use of potassium sparing diuretic at bl was the top predictor among age group 80-90. Conclusion: Using ML, we uncovered in an unbiased fashion, otherwise overlooked bl predictors of hHF in a large, international, multi-center trial like TOPCAT. Thus, ML can help to identify similarities and differences of disease and treatment outcomes among gender, race, ethnicity, and age specific subgroups and advance precision medicine.
Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care
Authors: Hanny Al-Samkari
Journal: Blood (2020)

Hereditary hemorrhagic telangiectasia (HHT) management is evolving because of the emergence and development of antiangiogenic therapies to eliminate bleeding telangiectasias and achieve hemostasis. This progress is reflected in recent clinical recommendations published in the Second International Guidelines for the Diagnosis and Treatment of HHT, in which systemic therapies including antiangiogenics and antifibrinolytics are now recommended as standard treatment options for bleeding. This review highlights the new recommendations especially relevant to hematologists in managing bleeding, anticoagulation, and anemia in patients with HHT.
Abstract 14697: Nt-probnp and Outcomes in Patients With and Without Heart Failure Hospitalized With Severe Covid-19 Pneumonia
Authors: Jeanwoo Yoo, Prabhjot Grewal, Aikaterini Papamanoli, Azad Mojahedi, Jacquelyn Nakamura, Jenny Fung, Joshua Abata, Simrat Dhaliwal, Robin Jacob, Jessica Hotelling, Nikitha Karkala, Stella T Tsui, Sahil Rawal, Alexandra Coritsidis, Luis Marcos, Michelle Bloom, Hal Skopicki, Andreas P Kalogeropoulos
Journal: Circulation (2020)

Introduction: The value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in hospitalized patients with severe coronavirus disease 2019 (COVID-19) is unclear. Hypothesis: Elevated NT-proBNP is associated with worse prognosis in hospitalized COVID-19 patients regardless of history of HF. Methods: We evaluated the in-hospital course of 469 adults admitted to Stony Brook University Hospital, NY, from March 1 to April 15, 2020 with severe COVID-19 pneumonia (need for high-flow O 2 ). We excluded patients who required mechanical ventilation (MV) or died within 24h of admission. We used Cox regression models to examine the association of admission NT-proBNP with mortality and the composite of death or MV. Results: Admission NT-proBNP was available in 399 patients (85.1%) of this cohort. Table 1 summarizes the patient characteristics according to history of HF (41/399 [10.3%]). After a median of 13 days (8-22), 107 patients (26.8%) died and 86 additional patients (21.6%) required MV and survived. Both HF (HR 3.65; 95%CI 2.32-5.77; P&lt;0.001) and admission NT-proBNP (HR per log-2 [doubling] 1.35; 95%CI 1.27-1.44; P&lt;0.001) were strongly associated with mortality. In models adjusting for age, sex, race, body mass index, hypertension, diabetes, coronary artery disease, atrial fibrillation, chronic lung disease, chronic kidney disease, and baseline 0 2 saturation, every log-2 higher admission NT-proBNP was associated with 28% higher mortality in patients with HF (HR 1.28; 95%CI 1.02-1.61; P=0.037) and 26% higher mortality in patients without HF (HR 1.26; 95%CI 1.14-1.40; P&lt;0.001), P for interaction 0.92. Admission NT-proBNP was also associated with the composite of death or MV in the entire cohort (adjusted HR per log-2 1.09; 95%CI 1.02-1.17; P=0.017). Conclusions: In these high-risk COVID-19 patients, admission NT-proBNP was strongly predictive of mortality regardless of HF. Elevated NT-proBNP may thus identify patients in need of cardioprotective measures.
Mesenchymal Bmp3b expression maintains skeletal muscle integrity and decreases in age-related sarcopenia
Authors: Akiyoshi Uezumi, Madoka Ikemoto-Uezumi, Heying Zhou, Tamaki Kurosawa, Yuki Yoshimoto, Masashi Nakatani, Keisuke Hitachi, Hisateru Yamaguchi, Shuji Wakatsuki, Toshiyuki Araki, Mitsuhiro Morita, Harumoto Yamada, Masashi Toyoda, Nobuo Kanazawa, Tatsu Nakazawa, Jun Hino, So-ichiro Fukada, Kunihiro Tsuchida
Journal: Journal of Clinical Investigation (2020)

Age-related sarcopenia constitutes an important health problem associated with adverse outcomes. Sarcopenia is closely associated with fat infiltration in muscle, which is attributable to interstitial mesenchymal progenitors. Mesenchymal progenitors are nonmyogenic in nature but are required for homeostatic muscle maintenance. However, the underlying mechanism of mesenchymal progenitor-dependent muscle maintenance is not clear, nor is the precise role of mesenchymal progenitors in sarcopenia. Here, we show that mice genetically engineered to specifically deplete mesenchymal progenitors exhibited phenotypes markedly similar to sarcopenia, including muscle weakness, myofiber atrophy, alterations of fiber types, and denervation at neuromuscular junctions. Through searching for genes responsible for mesenchymal progenitor-dependent muscle maintenance, we found that Bmp3b is specifically expressed in mesenchymal progenitors, whereas its expression level is significantly decreased during aging or adipogenic differentiation. The functional importance of BMP3B in maintaining myofiber mass as well as muscle-nerve interaction was demonstrated using knockout mice and cultured cells treated with BMP3B. Furthermore, the administration of recombinant BMP3B in aged mice reversed their sarcopenic phenotypes. These results reveal previously unrecognized mechanisms by which the mesenchymal progenitors ensure muscle integrity and suggest that age-related changes in mesenchymal progenitors have a considerable impact on the development of sarcopenia.
Biomedical engineering approaches to enhance therapeutic delivery for malignant glioma
Authors: Phoebe McCrorie, Catherine E. Vasey, Stuart J. Smith, Maria Marlow, Cameron Alexander, Ruman Rahman
Journal: Journal of Controlled Release (2020)

We review the challenges of next-generation therapeutics for both systemic and localised delivery to brain tumours and discuss how recent engineering advances may be used to enhance brain penetration of systemic delivery therapies. The unmet clinical need which drug delivery seeks to address is discussed with reference to the therapy obstacles that the intra-tumour heterogeneity of glioma present. The unmet chemistry and biomedical engineering challenge to develop controlled release therapeutics is appraised, with commentary on current success/failures in systemic carrier-mediated delivery, including receptor-targeted, cell-based, blood-brain-barrier disrupting and MRI-guided focused ultrasound. Localised therapeutic delivery is a relatively under-studied research avenue and is discussed with reference to existing technologies in preclinical development. These include convection-enhanced delivery, alternative catheter delivery, and neuro-surgically applied delivery systems such as polymeric hydrogels and interstitial spray. A myriad of nano-scale therapeutic delivery systems is emerging as potential future medicines for malignant brain tumours. Such biomedically-engineered systems will increasingly feature in next-generation neuro-oncological clinical trials to deliver repurposed and experimental therapeutics, aimed at achieving therapeutic drug concentrations in the brain, with associated mortality and morbidity benefits for patients.
Response to Comment on Zhou et al. Cost-effectiveness of Diabetes Prevention Interventions Targeting High-risk Individuals and Whole Populations: A Systematic Review. Diabetes Care 2020;43:1593–1616
Authors: Xilin Zhou, Ping Zhang
Journal: Diabetes Care (2020)

We thank Sathish et al. (1) for their interest in our systematic review on the cost-effectiveness of interventions to prevent type 2 diabetes (T2D) among high-risk individuals and whole populations (2). Sathish et al. provided additional evidence from India and Bangladesh on the cost-effectiveness of T2D prevention interventions for low- and middle-income countries (LMICs). These new studies, along with one earlier study from India (3) and two studies from China (4,5), provide direct evidence from LMICs that in-person lifestyle interventions are indeed cost-effective.

The cost-effectiveness results presented in studies cited by Sathish et al. would be …