tbuckley/cabot-search huggingface dataset:
Occult blood in faeces: a window into health beyond the colorectum?
Authors: Uri Ladabaum
Journal: Gut (2018)

After decades of research, testing for occult blood in faeces is firmly established as a method to screen for colorectal cancer (CRC). Such testing is based on the relatively simple premise that asymptomatic CRCs, and some CRC precursors, may lose small amounts of blood into faeces. The provocative study by Libby et al in Gut ,1 which reports the associations between a positive guaiac faecal occult blood test (gFOBT) result and all-cause as well as non-CRC mortality in the National Health Service Tayside Board area of Scotland, suggests that occult blood in faeces may be telling us more than we might have thought. If the eye is the window to the soul, is a faecal test the window to general health?

The current study confirms and expands on the observations of Chen et al , who reported a gradient relationship between all-cause mortality and faecal haemoglobin (f-Hb) concentration in population-based screening programmes in Keelung and Tainan, Taiwan.2 Chen et al and Libby et al found associations between occult blood in faeces and CRC mortality, which is not surprising. However, in the study by Chen et al , with median follow-up of 3.5 years and longest follow-up of 8 years, the adjusted HRs for all-cause mortality ranged from 1.15 (95% CI 1.07 to 1.24) to 1.67 (95% CI 1.54 to 2.07) for persons with f-Hb concentrations of 20–49 and ≥450 ng Hb/mL, respectively (trend test p<0.0001), compared with the reference group of 1–19 ng Hb/mL (whose risk did not differ from that of persons with undetectable f-Hb). …
Exposure to improved nutrition from conception to age 2 years and adult cardiometabolic disease risk: a modelling study
Authors: Nicole D Ford, Jere R Behrman, John F Hoddinott, John A Maluccio, Reynaldo Martorell, Manuel Ramirez-Zea, Aryeh D Stein
Journal: The Lancet Global Health (2018)

BackgroundLow-income and middle-income countries with populations that are chronically undernourished in early life are undergoing a nutrition transition and are experiencing an epidemic of cardiometabolic disease. These dual burdens are thought to be causally related; therefore, the extent to which improvements in early-life nutrition can offset adult-onset disease is important. The aim of this study was to examine whether improvement of protein-energy nutrition from conception to age 2 years can attenuate the risk of cardiometabolic disease.MethodsWe followed up a cohort of 2392 individuals born between Jan 1, 1962, and Feb 28, 1977, in four villages in Guatemala who had participated in a cluster-randomised protein-energy nutritional supplementation (Atole) trial. Of 1661 participants available for follow-up from Feb 26, 2015, to April 29, 2017, we studied 683 women and 456 men. We assessed cardiometabolic disease risk at ages 37–54 years using anthropometry, fasting and post-challenge glucose, fasting lipid concentrations, and blood pressure. We used generalised linear and logistic regression modelling to estimate the effect of Atole from conception to age 2 years (the first 1000 days) on cardiometabolic disease risk.FindingsExposure to Atole from conception to age 2 years was associated with increased fatness (body-mass index [BMI, 1·30 kg/m2, 95% CI 0·14 to 2·46], body fat [1·47%, −0·01 to 2·94], and obesity [odds ratio 1·99, 1·16 to 3·41]), and reduced odds of diabetes (odds ratio 0·47, 0·22 to 0·99). We found stratum heterogeneity by sex in pooled models for BMI (1·06 kg/m2, 95% CI −0·60 to 2·71, for women vs 1·56, 0·07 to 3·05, for men), waist circumference (1·54 cm, −2·31 to 5·40, for women vs 4·38, 0·61 to 8·15, for men), waist-to-height ratio (0·01, −0·02 to 0·04, for women vs 0·02, 0·00 to 0·04, for men), and body fat (0·75%, −1·07 to 2·57, for women vs 2·61, 0·18 to 5·04, for men). p values for interaction of sex and exposure to Atole from conception to age 2 years were 0·06, 0·07, 0·04, and 0·09, respectively.InterpretationImproved protein-energy nutrition from conception to the 2nd birthday reduced the odds of diabetes at ages 37–54 years; however, this protein-energy supplementation also increased the risk of obesity and several obesity-related conditions. Our findings suggest a mixed ability of protein-energy nutritional supplementation in early life to prevent adult cardiometabolic disease incidence in the context of high childhood stunting and high adult overweight and obesity.FundingNational Institutes of Health.
Obesity-Associated Heart Failure as a Theoretical Target for Treatment With Mineralocorticoid Receptor Antagonists
Authors: Milton Packer
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Despite their clinical benefits, mineralocorticoid receptor antagonists are greatly underprescribed by most practitioners who treat patients with chronic heart failure. A novel approach to encouraging the use of these drugs is to enhance awareness about the intimate link between aldosterone and obesity. <h3>Observations</h3> There is a strong association between abdominal obesity and circulating levels of aldosterone, and markers of abdominal obesity identify patients most likely to benefit from mineralocorticoid receptor antagonism. In a trial of patients with heart failure and a reduced ejection fraction, patients with an increased waist circumference exhibited an approximately 50% reduction in the risk of a primary end point. The magnitude of benefit was more than twice as great in patients with abdominal obesity than in those with a normal waist circumference, and patients with abdominal obesity tolerated treatment better than nonobese patients. Similarly, in a trial of patients with heart failure and a preserved ejection fraction, those who were most likely to have abdominal obesity (identified by their level of natriuretic peptides) were most likely to demonstrate a benefit of treatment with spironolactone, exhibiting an approximately 80% reduction in the risk of a primary end point (based on a small number of events). <h3>Conclusions and Relevance</h3> Although these analyses are post hoc, their concordance and strong biological foundation suggests that abdominal obesity may identify patients who respond most favorably to mineralocorticoid receptor antagonism. Given the easy availability of its measurement, targeting patients with an increased waist circumference could enhance the adoption of these important drugs for the treatment of chronic heart failure in clinical practice.
Phase Ib Results of the Rational Combination of Selumetinib and Cyclosporin A in Advanced Solid Tumors with an Expansion Cohort in Metastatic Colorectal Cancer
Authors: Anuradha Krishnamurthy, Arvind Dasari, Anne M. Noonan, Janice M. Mehnert, Albert C. Lockhart, Stephen Leong, Anna Capasso, Mark N. Stein, Hanna K. Sanoff, James J. Lee, Aaron Hansen, Usha Malhotra, Sarah Rippke, Daniel L. Gustafson, Todd M. Pitts, Kim Ellison, S. Lindsey Davis, Wells A. Messersmith, S. Gail Eckhardt, Christopher H. Lieu
Journal: Cancer Research (2018)

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program-approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib "run-in" to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expansion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation.Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies. Cancer Res; 78(18); 5398-407. ©2018 AACR.
As Safe as Possible (ASAP): A Brief App-Supported Inpatient Intervention to Prevent Postdischarge Suicidal Behavior in Hospitalized, Suicidal Adolescents
Authors: Betsy D. Kennard, Tina Goldstein, Aleksandra A. Foxwell, Dana L. McMakin, Kristin Wolfe, Candice Biernesser, Alexandra Moorehead, Antoine Douaihy, Lucas Zullo, Erin Wentroble, Victoria Owen, Jamie Zelazny, Satish Iyengar, Giovanna Porta, David Brent
Journal: American Journal of Psychiatry (2018)

Objective: The authors report on a pilot study of an inpatient intervention for suicidal adolescents, As Safe as Possible (ASAP), supported by a smartphone app (BRITE) to reduce suicide attempts following hospital discharge. Method: Across two sites, 66 adolescents hospitalized for suicidal ideation (N=26) or a recent suicide attempt (N=40) were randomly assigned to the ASAP intervention program plus treatment as usual or to treatment as usual alone. ASAP, which focuses on emotion regulation and safety planning, is a 3-hour intervention delivered on the inpatient unit. The BRITE app prompted participants to rate their level of emotional distress on a daily basis and provided personalized strategies for emotion regulation and safety planning. A blind, independent evaluator assessed suicide attempts following hospital discharge and suicidal ideation at 4, 12, and 24 weeks after discharge. Results: The ASAP intervention did not have a statistically significant effect on suicide attempt, although findings were in the hypothesized direction for occurrence of an attempt (16% compared with 31%; χ2=1.86, df=1, g=−0.36) and time to an attempt (hazard ratio=0.49, 95% CI=0.16, 1.47). Past history of a suicide attempt was a significant moderator of treatment outcome, with a stronger, albeit nonsignificant, effect of the ASAP intervention among participants with a history of suicide attempt (hazard ratio=0.23, 95% CI=0.05, 1.09). There were no treatment effects on suicidal ideation. The majority of participants (70%) used the BRITE app (median usage, 19 times). Participants reported high satisfaction with both the intervention and the app. Conclusions: The ASAP intervention program shows promise in reducing the incidence of postdischarge suicide attempts among adolescents hospitalized for suicidality and merits further study.
MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma
Authors: Scott J. Rodig, Daniel Gusenleitner, Donald G. Jackson, Evisa Gjini, Anita Giobbie-Hurder, Chelsea Jin, Han Chang, Scott B. Lovitch, Christine Horak, Jeffrey S. Weber, Jason L. Weirather, Jedd D. Wolchok, Michael A. Postow, Anna C. Pavlick, Jason Chesney, F. Stephen Hodi
Journal: Science Translational Medicine (2018)

Loss of membrane MHC class I protein expression in most of tumor cells in advanced melanomas predicts primary resistance to anti–CTLA-4, but not anti-PD1, treatment.
Predicting the clinical impact of human mutation with deep neural networks
Authors: Laksshman Sundaram, Hong Gao, Samskruthi Reddy Padigepati, Jeremy F. McRae, Yanjun Li, Jack A. Kosmicki, Nondas Fritzilas, Jörg Hakenberg, Anindita Dutta, John Shon, Jinbo Xu, Serafim Batzoglou, Xiaolin Li, Kyle Kai-How Farh
Journal: Nature Genetics (2018)
Coronary Vasospasm Induced in Transgenic Mouse With Increased Phospholipase C-δ1 Activity
Authors: ShujiShibutani, TomohiroOsanai, ToshihiroAshitate, ShigekiSagara, KeiIzumiyama, YukoYamamoto, KenjiHanada, TakashiEchizen, HirofumiTomita, TakeshiFujita, TakeshiMiwa, HiroakiMatsubara, YoshimiHomma, KenOkumura
Journal: Circulation (2012)

Background—We reported that phospholipase C (PLC)-δ1 activity was enhanced 3-fold in patients with coronary spastic angina. We detected variant PLC-δ1 with replacement of arginine 257 by histidine (R257H) showing increased enzymatic activity. We tested the hypothesis that increased PLC-δ1 activity causes enhanced coronary vasomotility. Methods and Results—We generated transgenic (TG) mice with human R257H variant PLC-δ1 in vascular smooth muscle cells. PLC enzymatic activity in the coronary artery was increased by 2.57 and 1.89 times, respectively, in homozygous and heterozygous TG compared with wild-type (WT) mice. ST elevation after ergometrine occurred in 17 of 18 homozygous TG, 6 of 20 heterozygous TG, and 3 of 22 WT mice (P<0.01, homozygous TG versus WT; P<0.05, homozygous TG versus heterozygous TG; P=NS, heterozygous TG versus WT). ST elevation was associated with bradyarrhythmias in homozygous TG mice. Focal coronary artery narrowing was documented with the microvascular filling technique in 3 of 5...
Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates
Authors: Xiaorong Gu, Quteba Ebrahem, Reda Z. Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej Przychodzen, Zhenbo Hu, Ramesh Balusu, Claudiu V. Cotta, David Wald, Christian Argueta, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty Carraway, Bo T. Porse, Jaroslaw Maciejewski, Babal K. Jha, Yogen Saunthararajah
Journal: Journal of Clinical Investigation (2018)

Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU.1 into cytoplasm with it. CEBPA and RUNX1, the master transcription factors that collaborate with PU.1 to activate granulomonocytic lineage fates, remained nuclear; but without PU.1, their coregulator interactions were toggled from coactivators to corepressors, repressing instead of activating more than 500 granulocyte and monocyte terminal differentiation genes. An inhibitor of nuclear export, selinexor, by locking mutant NPM1/PU.1 in the nucleus, activated terminal monocytic fates. Direct depletion of the corepressor DNA methyltransferase 1 (DNMT1) from the CEBPA/RUNX1 protein interactome using the clinical drug decitabine activated terminal granulocytic fates. Together, these noncytotoxic treatments extended survival by more than 160 days versus vehicle in a patient-derived xenotransplant model of NPM1/FLT3-mutated AML. In sum, mutant NPM1 represses monocyte and granulocyte terminal differentiation by disrupting PU.1/CEBPA/RUNX1 collaboration, a transforming action that can be reversed by pharmacodynamically directed dosing of clinical small molecules.
A novel disease-causing synonymous exonic mutation in GATA2 affecting RNA splicing
Authors: Claudia Wehr, Katja Grotius, Silvia Casadei, Dorothee Bleckmann, Sebastian F. N. Bode, Björn C. Frye, Maximilian Seidl, Suleyman Gulsuner, Mary-Claire King, Mary-Beth Percival, Colin C. Pritchard, Tom Walsh, David Wu, Siobán Keel, Ulrich Salzer
Journal: Blood (2018)
Dendritic cell-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites elicits enhanced anti-cancer immune response in glioblastoma
Authors: Tong-Fei Li, Ke Li, Quan Zhang, Chao Wang, Yuan Yue, Zhuo Chen, Shen-Jun Yuan, Xin Liu, Yu Wen, Min Han, Naoki Komatsu, Yong-Hong Xu, Li Zhao, Xiao Chen
Journal: Biomaterials (2018)
Knockdown of long non-coding RNA NEAT1 inhibits glioma cell migration and invasion via modulation of SOX2 targeted by miR-132
Authors: Ke Zhou, Chi Zhang, Hui Yao, Xuewen Zhang, Youxin Zhou, Yanjun Che, Yulun Huang
Journal: Molecular Cancer (2018)

A better understanding of the molecular mechanism involving lncRNA-miRNA-mRNA network underlying glioma genesis is beneficial to the treatment of glioma. This study was designed to investigate the role of lncRNA NEAT1, miR-132 and SOX2 interaction in glioma.Microarray analysis was conducted to identify the differentially expressed lncRNAs in glioma tissues. The expression levels of NEAT1, miR-132 and SOX2 were determined by qRT-PCR and western blot. Proliferation of glioma cells was detected by MTT assay, while migration and invasion were determined by transwell assay. The target relationships were predicted by miRcode algorithm, and confirmed by dual luciferase reporter gene assay.NEAT1 was up-regulated in glioma. Knockdown of NEAT1 inhibited glioma cells' viability, migration and invasion. MiR-132 was down-regulated while SOX2 was up-regulated in glioma cells. NEAT1 negatively regulated the expression of miR-132 in glioma while miR-132 targeted SOX2 to down-regulate its expression.NEAT1 promoted glioma development by promoting SOX2 expression through suppressing miR-132.
Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With <i>IKZF1</i> Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study
Authors: Allen Eng Juh Yeoh, Yi Lu, Winnie Hui Ni Chin, Edwynn Kean Hui Chiew, Evelyn Huizi Lim, Zhenhua Li, Shirley Kow Yin Kham, Yiong Huak Chan, Wan Ariffin Abdullah, Hai Peng Lin, Lee Lee Chan, Joyce Ching Mei Lam, Poh Lin Tan, Thuan Chong Quah, Ah Moy Tan, Hany Ariffin
Journal: Journal of Clinical Oncology (2018)

Purpose Although IKZF1 deletion ( IKZF1del) confers a higher risk of relapse in childhood B-cell acute lymphoblastic leukemia (B-ALL), it is uncertain whether treatment intensification will reverse this risk and improve outcomes. The Malaysia-Singapore ALL 2010 study (MS2010) prospectively upgraded the risk assignment of patients with IKZF1del to the next highest level and added imatinib to the treatment of all patients with BCR- ABL1 fusion. Patients and Methods In total, 823 patients with B-ALL treated in the Malyasia-Singapore ALL 2003 study (MS2003; n = 507) and MS2010 (n = 316) were screened for IKZF1del using the multiplex ligation-dependent probe amplification assay. The impact of IKZF1del on the 5-year cumulative incidence of relapse (CIR) was compared between the two studies. Results Patient characteristics were similar in both cohorts, including IKZF1del frequencies (59 of 410 [14.4%] v 50 of 275 [18.2%]; P = .2). In MS2003, where IKZF1del was not used in risk assignment, IKZF1del conferred a significantly higher 5-year CIR (30.4% v 8.1%; P = 8.7 × 10-7), particularly in the intermediate-risk group who lacked high-risk features (25.0% v 7.5%; P = .01). For patients with BCR-ABL1-negative disease, IKZF1del conferred a higher 5-year CIR (20.5% v 8.0%; P = .01). In MS2010, the 5-year CIR of patients with IKZF1del significantly decreased to 13.5% ( P = .05) and no longer showed a significant difference in patients with BCR-ABL1-negative disease (11.4% v 4.4%; P = .09). The 5-year overall survival for patients with IKZF1del improved from 69.6% in MS2003 to 91.6% in MS2010 ( P = .007). Conclusion Intensifying therapy for childhood B-ALL with IKZF1del significantly reduced the risk of relapse and improved overall survival. Incorporating IKZF1del screening significantly improved treatment outcomes in contemporary ALL therapy.
Older People With Disabilities Overlooked in Humanitarian Response
Authors: M.J. Friedrich
Journal: JAMA (2018)

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Review: SMART reduces asthma exacerbations compared with other controller and relief therapy regimens
Authors: Professor Francis Thien
Journal: Annals of Internal Medicine (2018)

Source Citation Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting beta-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319:1485-96. 29554195.