tbuckley/cabot-search huggingface dataset:
Activity of NEO2734, a novel dual inhibitor of both BET and CBP-P300, in SPOP-mutated prostate cancer.
Authors: Yuqian Yan, Dejie Wang, Jian Ma, Xiaodong Pang, Dong Lin, Francis Giles, Yuzhuo Wang, Haojie Huang
Journal: Journal of Clinical Oncology (2019)

62 Background: We have previously reported that mutations in SPOP promote bromodomain and extra-terminal motif (BET) protein upregulation and BET inhibitor resistance in prostate cancer (Zhang et al., Nature Medicine 23(9):1055-1062, 2017). Other studies indicate that histone acetyltransferases (HATs) such as P300 are also upregulated in SPOP-mutated prostate cancer (Blattner et al., Cancer Cell 31: 436-451, 2017). Methods: We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. We examined the anti-cancer effect of NEO2734 (Epigene Therapeutics Inc), a novel dual inhibitor of both BET and CBP-P300, in prostate cancer using cell line, organoid and patient-derived xenografts (PDX) as working models. Results: We demonstrated that while prostate cancer cell lines expressing F133V, the most frequent SPOP mutant, are very resistant to both BET inhibitor JQ1 and CBP/P300 inhibitor CPI-637, they are very sensitive to simultaneous cotreatment with JQ1 and CPI-637. Similarly, we demonstrated that F133V mutant cells are also very sensitive to NEO2734. We established PDX and organoid models from a patient with prostate cancer expressing a novel SPOP mutation Q165P. Computer simulation analysis reveals that the Q165P mutation causes larger conformational fluctuation, indicating that the structure of Q165P is less stable than that of wild type SPOP. Accordingly, co-immunoprecipitation assay showed that Q165P mutation impaired the dimerization ability of SPOP. We further showed that the Q165P mutant organoid was very sensitive to NEO2734 in vitro and the Q165P mutant PDX was very sensitive to NEO2734 in mice. Conclusions: These PDX-based pre-clinical studies indicate that the inhibition of both BET and CBP-P300, either by co-administration of two agents, or by treatment with the dual inhibitor, NEO2734, is effective in SPOP-mutated prostate cancer. These data provide a strong rationale for the inclusion of patients with SPOP-mutated prostate cancer in clinical studies of NEO2734.
The value of uncertainty: An active inference perspective
Authors: Giovanni Pezzulo, Karl J. Friston
Journal: Behavioral and Brain Sciences (2019)

Abstract We discuss how uncertainty underwrites exploration and epistemic foraging from the perspective of active inference: a generic scheme that places pragmatic (utility maximization) and epistemic (uncertainty minimization) imperatives on an equal footing – as primary determinants of proximal behavior. This formulation contextualizes the complementary motivational incentives for reward-related stimuli and environmental uncertainty, offering a normative treatment of their trade-off.
Management of Patients With Severe Aortic Stenosis With Transcatheter Valve Replacement
Authors: AbdulRahman Dia, Adam S. Cifu, Atman P. Shah
Journal: JAMA (2019)

This JAMA Clinical Guidelines Synopsis summarizes the 2017 focused update of the American College of Cardiology/American Heart Association (AHA/ACC) guideline on management of patients with severe aortic stenosis focusing on surgical vs transcatheter valve replacement (TAVR).
Heroin addiction engages negative emotional learning brain circuits in rats
Authors: Stephanie A. Carmack, Robin J. Keeley, Janaina C. M. Vendruscolo, Emily G. Lowery-Gionta, Hanbing Lu, George F. Koob, Elliot A. Stein, Leandro F. Vendruscolo
Journal: Journal of Clinical Investigation (2019)

Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.
Mouse venous thrombosis upon silencing of anticoagulants depends on tissue factor and platelets, not FXII or neutrophils
Authors: Marco Heestermans, Salam Salloum-Asfar, Tom Streef, El Houari Laghmani, Daniela Salvatori, Brenda M. Luken, Sacha S. Zeerleder, Henri M. H. Spronk, Suzanne J. Korporaal, Daniel Kirchhofer, Gerry T. M. Wagenaar, Henri H. Versteeg, Pieter H. Reitsma, Thomas Renné, Bart J. M. van Vlijmen
Journal: Blood (2019)
One-Day Low-Dose Etoposide Is an Effective Chemomobilization Regimen with Minimal Toxicity for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Multicenter Study from Tertiary Hospitals in Korea
Authors: Yong Park, Dae Sik Kim, Ka-Won Kang, Byung-Hyun Lee, Eun Sang Yu, Min Ji Jeon, Hojoon Choi, Se Ryeon Lee, Hwa Jung Sung, Chul Won Choi, Kihyun Kim, Byung Soo Kim, Seok Jin Kim
Journal: Blood (2018)
Real-World Data of Nivolumab in Classical Hodgkin Lymphoma: Results from the Italian Expanded Access Programme
Authors: Armando Santoro, Francesco D'alo', Pier Luigi Zinzani, Luigi Rigacci, Francesco Angrilli, Paolo Corradini, Francesco Lanza, Giorgina Specchia, Maria Cantonetti, Nicola Cascavilla, Caterina Patti, Brunangelo Falini, Felicetto Ferrara, Barbara Botto, Catello Califano, Livio Trentin, Marco Gobbi, Anna Vanazzi, Diana Giannarelli, Antonello Pinto
Journal: Blood (2017)
Targeting the Second Bromodomain (BDII) of BET Family with Abbv-744 Results in Robust Anti-Leukemia Activity in AML Models with Excellent In Vivo Tolerability
Authors: Tianyu Cai, Vinitha Mary Kuruvilla, Tamar Uziel, Qi Zhang, Lina Han, Antonio Cavazos, Yu Shen, Marina Y. Konopleva, Xiaoyu Lin, Xin Lu, Lu Zhang
Journal: Blood (2018)
Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea
Authors: Julio Rosenstock, Dale Allison, Andreas L. Birkenfeld, Thalia Marie Blicher, Srikanth Deenadayalan, Jacob Bonde Jacobsen, Pierre Serusclat, Rafael Violante, Hirotaka Watada, Melanie Davies
Journal: JAMA (2019)

Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy.To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes.Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized.Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved.The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight.Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin.Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting.ClinicalTrials.gov Identifier: NCT02607865.
EPR19-067: Effectiveness of Breast Cancer Awareness Campaign on Internet Search Activity Compared to Other Gynecological Malignancies
Authors: Akriti Gupta Jain, Abdul Kareem Khan, Ranjeet Kumar, Mohammed Wazir, Syed Askari Hasan, Umair Majeed
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Breast Cancer (BC) is common, with 1 in 8 U.S. women (12.4%) developing invasive breast cancer in their lifetime. BC is associated with the most awareness campaigns with pink ribbon as its symbol. October was earmarked as the breast cancer awareness month (CAM) in 1985. Cervical (CC) and ovarian cancers (OC) are associated with a high mortality as well and have awareness months dedicated to them. The aim of these awareness drives is to change public attitude and help in early detection and ultimately prevention of various cancers. Internet search activity can be used as a method to gauge interest and awareness in the masses. We aimed to assess the popularity of BC compared to other gynecological cancers, including OC and CC. Methods: We compared the relative frequency of search terms “Breast Cancer,” “Ovarian Cancer,” and “Cervical Cancer” between January 1, 2004 and December 31, 2017 (n=168 months) using Google Trends, a public web facility of Google Inc. The software designates a reference value of 100 for the point of highest popularity and it provides relative monthly popularity scores for all the terms, which we termed as comparative interest scores (CIS). Within each cancer, average CIS was then compared for their respective awareness months (n=14 months; October for BC, September for OC, and January for CC) to the remaining months (n=154 months). Results: The mean CIS for BC was significantly higher during its CAM, 70.5 as compared to other months 35.9; p&lt;0.001. However, for CC mean CIS during January (7.4) was not different compared to the other months (7.4); P= 1.00. And for OC, CIS was significantly higher during its CAM (9.2) compared to other months (7.7); P =.0002. The peak of highest popularity for breast cancer was observed during October 2004 and all peaks corresponded to the CAM; other smaller peaks were seen during significant news events associated with BC, all of which surpassed OC and CC in those months. Overall BC CIS were significantly higher compared to CC ( P &lt;.001) and OC ( P &lt;.001). Conclusions: We conclude that BC awareness campaigns have succeeded in increasing internet search activity during its CAM but ovarian and cervical cancer campaigns especially when compared to breast cancer have not been as successful. There is still a need to increase awareness among masses. Google trends data also tells us which states in US have more internet search activity compared to others which can be used to target the relatively unaware public.
QIM19-117: Reducing Diagnostic Delays: Impact of a Novel Cancer Diagnostic Service
Authors: Luke Arney, Ryan Leib, Louise Schneider, Cori Kostick, Kerry Kilbridge, Ramin Khorasani, Oreofe Odejide, Lindsay C. Carter
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Although timeliness of care was one of the aims of quality improvement in the Institute of Medicine’s 2001 “Crossing the Quality Chasm” report, a significant proportion of patients with cancer still experience delays in diagnosis and treatment. For example, in a study of 3,831 older adults diagnosed with myeloma in the United States, the median time between the first myeloma-related symptom and diagnosis was 99 days (Friese CR, Leukemia &amp; Lymphoma 2009). Such delays are associated with substantial anxiety, poor patient-reported outcomes, and increased cost. Methods : A novel adult cancer diagnostic service (CDS) was established by the Dana-Farber/Brigham and Women’s Cancer Center in October 2017. The clinic is embedded in the Department of Medicine at the Brigham and Women’s Hospital, with the aim of expediting the cancer diagnostic work-up and treatment for clinically complex patients with symptoms concerning for cancer, but for whom the next diagnostic steps are unclear. This clinic is comprised of an internist, a physician assistant, and a practice assistant. The clinic staff conduct a weekly phone conference with a multidisciplinary team—including a solid tumor oncologist, a hematologic oncologist, and a radiologist—to discuss the work-up for each patient. For every patient evaluated who receives a cancer diagnosis, we measure the diagnostic interval (days from CDS referral to diagnosis date). We define diagnosis date as the date the pathologic report is signed. We also measure the interval between CDS referral and first oncology appointment. Results: From the inception of the CDS to October 1, 2018, 221 patients were seen in the clinic and 91 (41.2%) were diagnosed with cancer. The top 3 cancer diagnoses were lymphoma (31%), gastrointestinal cancers (20%), and lung cancer (19%; Figure 1). The median number of days from CDS referral to diagnosis was 14 days (interquartile range [IQR], 10, 21; Table 1). Finally, the median time between referral to CDS and first oncology appointment was 20 days (IQR, 14, 27). Conclusion: This novel cancer diagnostic service substantially shorted the diagnostic trajectory (∼2 weeks) compared to existing literature with median diagnostic intervals often lasting more than 3 months (Friese CR, Leukemia &amp; Lymphoma 2009). Our findings suggest that a cancer diagnostic care model, grounded in internal medicine, with engagement of oncologists and radiologists, has significant potential to improve delays in cancer diagnostic care.
Transcriptomic expression profiling identifies ITGBL1, an epithelial to mesenchymal transition (EMT)-associated gene, is a promising recurrence prediction biomarker in colorectal cancer
Authors: Takatoshi Matsuyama, Toshiaki Ishikawa, Naoki Takahashi, Yasuhide Yamada, Masamichi Yasuno, Tatsuyuki Kawano, Hiroyuki Uetake, Ajay Goel
Journal: Molecular Cancer (2019)

The current histopathological risk-stratification criteria in colorectal cancer (CRC) patients following a curative surgery remain inadequate. In this study, we undertook a systematic, genomewide, biomarker discovery approach to identify and validate key EMT-associated genes that may facilitate recurrence prediction in CRC. Genomewide RNA expression profiling results from two datasets (GSE17538; N = 173 and GSE41258; N = 307) were used for biomarker discovery. These results were independently validated in two, large, clinical cohorts (testing cohort; N = 201 and validation cohort; N = 468). We performed Gene Set Enrichment Analysis (GSEA) for understanding the function of the candidate markers, and evaluated their correlation with the mesenchymal CMS4 subtype. We identified integrin subunit beta like 1 (ITGBL1) as a promising candidate biomarker, and its high expression associated with poor overall survival (OS) in stage I-IV patients and relapse-free survival (RFS) in stage I-III patients. Subgroup validation in multiple independent patient cohorts confirmed these findings, and demonstrated that high ITGBL1 expression correlated with shorter RFS in stage II patients. We developed a RFS prediction model which robustly predicted RFS (the area under the receiver operating curve (AUROC): 0.74; hazard ratio (HR): 2.72) in CRC patients. ITGBL1 is a promising EMT-associated biomarker for recurrence prediction in CRC patients, which may contribute to improved risk-stratification in CRC.
Familial Aggregation and Coaggregation of Suicide Attempts and Comorbid Mental Disorders in Adults
Authors: Elizabeth D. Ballard, Lihong Cui, Caroline Vandeleur, Enrique Castelao, Carlos A. Zarate, Martin Preisig, Kathleen Ries Merikangas
Journal: JAMA Psychiatry (2019)

Clarification of the joint influence of familial patterns of suicide attempts and comorbid mental disorders can enhance the understanding and prevention of suicide attempts.To investigate the familial patterns of suicide attempts and comorbid mental disorders and their associations in a 2-site family study of mood and anxiety disorders.Data were obtained from 2 parallel community-based family studies conducted in the United States (National Institute of Mental Health [NIMH] study) and in Lausanne, Switzerland (PsyCoLaus study), on the comorbidity of mood and anxiety disorders. The study sample comprised 1119 adult probands and 5355 first-degree relatives. Data were collected and analyzed from October 2004 to December 2016.Lifetime suicide attempt and mental disorders in first-degree relatives, obtained through direct interviews or family history reports.The study included 1119 adult probands (675 female [60.3%] and a mean [SD] age of 50 [12.0] years) and 5355 first-degree relatives (2752 female [51.4%] and a mean [SD] age of 52 [1.5] years). Of these participants, 90 (8.0%) of 1119 probands and 199 (3.7%) of 5355 relatives had a lifetime history of suicide attempt. Those with such a history had higher rates of all mental disorders, a greater number of disorders, and statistically significantly poorer current and lifetime global functioning. After adjustment for age and sex, a statistically significant association between suicide attempts in probands and in relatives was found at the NIMH site (OR, 2.6; 95% CI, 1.5-4.7), at the Lausanne site (OR, 3.1; 95% CI, 1.6-6.0), and in the combined data (OR, 2.9; 95% CI, 1.9-4.5). All mood disorder subtypes and substance use disorders were statistically significantly associated with suicide attempts. The familial association between lifetime suicide attempts in probands and relatives was not statistically significant for the combined sample (OR, 1.6; 95% CI, 1.0-2.7) after adjustment for comorbid conditions in probands and relatives. Social anxiety disorder in probands was associated with suicide attempts in relatives (OR, 2.4; 95% CI, 1.7-3.5) after controlling for comorbid mood, anxiety, and substance use disorders.Familiality of suicide attempts appears to be explained by a history of mental disorders among those with suicide attempts; the novel finding of a common familial diathesis for suicide attempts and social anxiety, particularly in combination with mood disorders, has heuristic value for future research and may be a risk marker that can inform prevention efforts.
Get court approval or face criticism when taking non routine samples, judge warns doctors
Authors: Clare Dyer
Journal: BMJ (2019)

A senior judge has warned doctors that they could face severe criticism from the court or even damages claims for breaches of human rights if they take bodily samples from patients who lack capacity to consent without a court order.1

Lord Justice Baker published his judgment to remind practitioners that the court has a duty judge available 24 hours a day, seven days a week, year round to deal with urgent applications by telephone.

Patients who lack capacity to consent may have samples taken without a …
Association of Influenza-like Illness Activity With Hospitalizations for Heart Failure
Authors: Sonja Kytömaa, Sheila Hegde, Brian Claggett, Jacob A. Udell, Wayne Rosamond, Jonathan Temte, Kristin Nichol, Jacqueline D. Wright, Scott D. Solomon, Orly Vardeny
Journal: JAMA Cardiology (2019)

<h3>Importance</h3> Influenza is associated with an increased risk of cardiovascular events, but to our knowledge, few studies have explored the temporal association between influenza activity and hospitalizations, especially those caused by heart failure (HF). <h3>Objective</h3> To explore the temporal association between influenza activity and hospitalizations due to HF and myocardial infarction (MI). We hypothesized that increased influenza activity would be associated with an increase in hospitalizations for HF and MI among adults in the community. <h3>Design, Setting, and Participants</h3> As part of the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) study, a population-based study with hospitalizations sampled from 4 US communities, data were collected from 451 588 adults aged 35 to 84 years residing in the ARIC communities from annual cross-sectional stratified random samples of hospitalizations during October 2010 to September 2014. <h3>Exposures</h3> Monthly influenza activity, defined as the percentage of patient visits to sentinel clinicians for influenza-like illness by state, as reported by the Centers for Disease Control and Prevention Surveillance Network. <h3>Main Outcomes and Measures</h3> The monthly frequency of MI hospitalizations (n = 3541) and HF hospitalizations (n = 4321), collected through community surveillance and adjudicated as part of the ARIC Study. <h3>Results</h3> Between October 2010 and September 2014, 2042 (47.3%) and 1599 (45.1%) of the sampled patients who were hospitalized for HF and MI, respectively, were women and 2391 (53.3%) and 2013 (57.4%) were white, respectively. A 5% monthly absolute increase in influenza activity was associated with a 24% increase in HF hospitalization rates, standardized to the total population in each community, within the same month after adjusting for region, season, race/ethnicity, sex, age, and number of MI/HF hospitalizations from the month before (incidence rate ratio, 1.24; 95% CI, 1.11-1.38;<i>P</i> &lt; .001), while overall influenza activity was not significantly associated with MI hospitalizations (incidence rate ratio, 1.02; 95% CI, 0.90-1.17;<i>P</i> = .72). Influenza activity in the months before hospitalization was not associated with either outcome. Our model suggests that in a month with high influenza activity, approximately 19% of HF hospitalizations (95% CI, 10%-28%) could be attributable to influenza. <h3>Conclusions and Relevance</h3> Influenza activity was temporally associated with an increase in HF hospitalizations across 4 influenza seasons. These data suggest that influenza may contribute to the risk of HF hospitalization in the general population.