tbuckley/cabot-search huggingface dataset:
Altruism, collective rationality, and extreme self-sacrifice
Authors: Andrew M. Colman, Briony D. Pulford
Journal: Behavioral and Brain Sciences (2018)

Abstract Puzzlement about extreme self-sacrifice arises from an unarticulated assumption of psychological egoism, according to which people invariably act in their own self-interests. However, altruism and collective rationality are well established experimentally: people sometimes act to benefit others or in the interests of groups to which they belong. When such social motives are sufficiently strong, extreme self-sacrifice presents no special problem of explanation and does not require out-group threats.
Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage.
Authors: Marcus Smith Noel, Andrea Wang-Gillam, Allyson J. Ocean, Sant P. Chawla, Giuseppe Del Priore, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2019)

200 Background: SM-88 (tyrosine derivative [Td], mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy that utilizes the Warburg Effect in combination with oxidative stress to cause tumor cell death. It is well suited for pancreas cancer because of its ability to penetrate tumors and be tolerated by debilitated patients. Methods: Patients progressed on at least one line of chemotherapy are eligible for either low versus high dose single agent SM-88 in the dose selecting first stage of this trial. The primary endpoint of the study is response rate by BICR (NCT03512756). Results: As of Sept 23, 36 subjects with initial stage II 26%, III 33%, or IV 41%, were randomized between an active Td dose (430 mg/d) and 920 mg/d. Mean age was 64.9 (45.6 - 84.1); BMI 24.2 (16.8 - 36.7); female 45.5%, white 93.1%, black 4.5%; median of 3 prior lines (range 1 - 6); baseline median albumin, neutrophil lymphocyte ratio, alk phos and 19.9 were 3.8 g/dl (2.6 - 9.6), 4 (1 - 141), 179.5 (54 - 661) and 5089 (4 - 651, 696) respectively. The regimen was well tolerated with no treatment related grade 4 or 5 events; 55.6% of treated subjects (20/36) had 94 AEs, with 18.0% (17/94) being at least possibly treatment related, of which three were grade 3 (arthralgia, fatigue and asthenia). CTCs at baseline were detected in 97% (mean 93.1 cells/4 ml) and fell in 69% (11/16) evaluable subjects from 141.4 to a nadir of 30.7/4 ml (median reduction 77% [3% - 97%]). 22.2% (2/9) evaluable subjects showed CA19.9 declines, both of which also showed CTC declines. 83% of subjects have remained on treatment a median of 4.7 wks (1 - 18.7); 6 were eligible for the initial scheduled assessment at 2 months; 3 of 4 evaluable subjects (75%) had RECIST or PET SUV responses. Lesion SUVs decreased an average of 24.1% (8.3 - 35.7%). EORTC QLQ-C30, -PAN26 and correlative assays were obtained including IGF, leptin, genomics, NLR, and others. Conclusions: SM-88 has demonstrated unconfirmed monotherapy efficacy signals with no meaningful toxicity in a preliminary assessment of this ongoing trial. With additional follow up a dose will be selected for expansion Clinical trial information: NCT03512756.
Fatal Dysfunction and Fragmentation of Thrombin-Stimulated Platelets
Authors: Oleg V. Kim, Tatiana A. Nevzorova, Elmira R. Mordakhanova, Izabella A. Andrianova, Giang Le Minh, Mark S. Alber, Olga Vagin, Rustem I. Litvinov, John W. Weisel
Journal: Blood (2018)
The effect of the Alive &amp; Thrive initiative on exclusive breastfeeding in rural Burkina Faso: a repeated cross-sectional cluster randomised controlled trial
Authors: Jenny A Cresswell, Rasmané Ganaba, Sophie Sarrassat, Henri Somé, Abdoulaye Hama Diallo, Simon Cousens, Veronique Filippi
Journal: The Lancet Global Health (2019)

BackgroundThe benefits of exclusive breastfeeding on mortality, health, and development of children have been well documented. In Burkina Faso, the Alive & Thrive initiative combined interpersonal communication and community mobilisation activities with the aim of improving knowledge, beliefs, skills, and, ultimately, breastfeeding outcomes. The objective of this study was to determine the effect of the Alive & Thrive initiative on exclusive breastfeeding in Boucle du Mouhoun, Burkina Faso.MethodsWe did a cluster-randomised trial with data collected with two independent, population-representative, cross-sectional surveys: a baseline survey done before the start of the initiative implementation and an endline survey done 2 years later. Rural villages in Boucle du Mouhoun, Burkina Faso, were randomly allocated by use of computer generated pseudo-random numbers, and women were eligible for participation if they had a livebirth in the 12 months preceding the survey and resided in a village selected for the study. The primary outcome was exclusive breastfeeding among infants younger than 6 months. Masking was not possible for the intervention implementation. All women who participated in the trial were included in the analysis population. The trial is registered with ClinicalTrials.gov, number NCT02435524.FindingsBetween June 2 and July 28, 2015, 2288 mothers participated in the baseline survey and between June 12 and July 25, 2017, 2253 mothers participated in the endline survey. At endline, there was a risk difference of 38·9% (95% CI 32·2–45·6, p<0·001) between the reported prevalence of exclusive breastfeeding in the intervention group and that of the control group.InterpretationA multidimensional intervention deliverable at scale in a low-income setting resulted in substantial increases in mothers' optimal breastfeeding knowledge and beliefs and in reported exclusive breastfeeding practices. However, it is possible that the findings might have been influenced by social desirability bias.FundingBill & Melinda Gates Foundation, London School of Hygiene & Tropical Medicine.
Increased Mac 2-Binding Protein Glycan Isomer (M2BPGi) Would Predict Late Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation
Authors: Yu Akahoshi, Hideki Nakasone, Koji Kawamura, Miki Sato, Misato Kikuchi, Yukiko Misaki, Kazuki Yoshimura, Ayumi Gomyo, Aki Tanihara, Masaharu Tamaki, Machiko Kusuda, Hidenori Wada, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda
Journal: Blood (2018)
Measurement of Myofilament-Localized Calcium Dynamics in Adult Cardiomyocytes and the Effect of Hypertrophic Cardiomyopathy Mutations
Authors: Alexander J. Sparrow, Kolja Sievert, Suketu Patel, Yu-Fen Chang, Connor N. Broyles, Frances A. Brook, Hugh Watkins, Michael A. Geeves, Charles S. Redwood, Paul Robinson, Matthew J. Daniels
Journal: Circulation Research (2019)

Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here, we develop and characterize genetically encoded Ca2+ indicators restricted to the myofilament to directly visualize Ca2+ changes in the sarcomere.To produce and validate myofilament-restricted Ca2+ imaging probes in an adenoviral transduction adult cardiomyocyte model using drugs that alter myofilament function (MYK-461, omecamtiv mecarbil, and levosimendan) or following cotransduction of 2 established hypertrophic cardiomyopathy disease-causing mutants (cTnT [Troponin T] R92Q and cTnI [Troponin I] R145G) that alter myofilament Ca2+ handling.When expressed in adult ventricular cardiomyocytes RGECO-TnT (Troponin T)/TnI (Troponin I) sensors localize correctly to the sarcomere without contractile impairment. Both sensors report cyclical changes in fluorescence in paced cardiomyocytes with reduced Ca2+ on and increased Ca2+ off rates compared with unconjugated RGECO. RGECO-TnT/TnI revealed changes to localized Ca2+ handling conferred by MYK-461 and levosimendan, including an increase in Ca2+ binding rates with both levosimendan and MYK-461 not detected by an unrestricted protein sensor. Coadenoviral transduction of RGECO-TnT/TnI with hypertrophic cardiomyopathy causing thin filament mutants showed that the mutations increase myofilament [Ca2+] in systole, lengthen time to peak systolic [Ca2+], and delay [Ca2+] release. This contrasts with the effect of the same mutations on cytoplasmic Ca2+, when measured using unrestricted RGECO where changes to peak systolic Ca2+ are inconsistent between the 2 mutations. These data contrast with previous findings using chemical dyes that show no alteration of [Ca2+] transient amplitude or time to peak Ca2+.RGECO-TnT/TnI are functionally equivalent. They visualize Ca2+ within the myofilament and reveal unrecognized aspects of small molecule and disease-associated mutations in living cells.
Abstract 16449: Exosome-Derived miRNAs Mediate Cardiomyocyte-Adipocyte Communication and Suppress High Molecule Adiponectin Production by Regulating ER Function After Myocardial Ischemia/Reperfusion
Authors: Gan Lu, Dina Xie, Wayne B Lau, Zheyi Yan, Wenjun Yan, Rui Guo, Yajing Wang, Xin L Ma
Journal: Circulation (2017)

Despite years of significant effort, it remains unclear how injured cardiomyocytes disrupt gene synthesis in adipocytes. We recently demonstrate cardiac ischemia/reperfusion (I/R) injury markedly releases exosomes. In our current discovery-based study, we determined the specific effect of cardiac-derived exosomes upon gene expression. By investigating genes regulating various cellular processes (including inflammation, lipid biosynthesis, lipolysis, glycometabolism, β oxidation, adipokine, apoptosis and ER stress), we demonstrate that cardiac-derived exosomes upregulated 1 cytokine and 5 ER stress genes (CHOP, Gadd34), and decreased the expression of 2 ER stress genes (EDEM1, DERL1) in adipose tissue in vivo. To further investigate the dysregulation of ER stress, ERp44 and DsBA-L1 was measured. Cardiac I/R-derived exosomes suppressed expression of both ERp44 and DsBA-L1 in vitro and in vivo, supporting the role of exosome-induced ER stress in target cells. In 3T3L1 cells subjected to cardiac I/R-derived e...
Outcome of Patients with Non–Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors
Authors: Lizza E.L. Hendriks, Clemence Henon, Edouard Auclin, Laura Mezquita, Roberto Ferrara, Clarisse Audigier-Valette, Julien Mazieres, Corentin Lefebvre, Audrey Rabeau, Sylvestre Le Moulec, Sophie Cousin, Boris Duchemann, Cecile le Pechoux, Angela Botticella, Samy Ammari, Anas Gazzah, Caroline Caramella, Julien Adam, Emmanuèle Lechapt, David Planchard, Dirk De Ruysscher, Anne-Marie Dingemans, Benjamin Besse
Journal: Journal of Thoracic Oncology (2019)
CAR T Cells: A Snapshot on the Growing Options to Design a CAR
Authors: Astrid Holzinger, Hinrich Abken
Journal: HemaSphere (2019)

Adoptive cell therapy of malignant diseases with chimeric antigen receptor (CAR) modified T cells rapidly advanced from pre-clinical models to commercial approvals within 2 decades. CARs redirect patient's T cells towards cancer cells and activate the engineered cells for a cytolytic attack resulting in the destruction of the cognate target cell. CAR T cells have demonstrated their powerful capacities in inducing complete and lasting remissions of leukemia/lymphoma in an increasing number of trials worldwide. Since the early 90's, the design of CARs went through various steps of optimization until the very recent developments which include CARs with logic gating in the recognition of antigen patterns on target cells and TRUCKs with a target recognition induced delivery of immune modulating agents. Here we review the generations in CAR design, the impact of specific modifications, the strategies to improve the safety of CAR T cell therapy, and the challenges to adapt the CAR design for broader applications.
Abstract 9850: Cardioprotective Role of Zofenopril in Hypertensive Patients With Acute Myocardial Infarction: A Pooled Individual Data Analysis of Four Randomized, Double-blind, Controlled, Prospective Studies
Authors: Claudio Borghi, Stefano Omboni, Giorgio Reggiardo, Stefano Bacchelli, Daniela Degli Esposti, Ettore Ambrosioni
Journal: Circulation (2015)

Introduction: the SMILE (Survival of Myocardial Infarction Long-term Evaluation) studies demonstrated that early administration of zofenopril following acute myocardial infarction (AMI) is prognostically beneficial compared to placebo or other angiotensin-converting enzyme inhibitors (ACE-inhibitors). Hypothesis: In the present meta-analysis of individual data of four SMILE studies we evaluated the cumulative efficacy of zofenopril on cardiovascular (CV) morbidity and mortality in the subgroup of hypertensive patients. Methods: 1880 (53.1%) of the 3542 patients had a positive history for hypertension. 449 hypertensives and 486 normotensives were treated with placebo (SMILE 1 and 3), 980 and 786 with zofenopril 30-60 mg/die (all four studies), 451 and 390 with lisinopril 5-10 mg/die (SMILE 2) or ramipril 10 mg/die (SMILE 4). Treatment was continued for 6 to 48 weeks. For the purpose of this pooled analysis the primary study endpoint was set to 1-year combined occurrence of death or hospitalization for CV causes. Results: the risk of CV events was significantly reduced by 35% with zofenopril vs. placebo [HR: 0.65; 95% CI: 0.49-0.86; p=0.003) in hypertensive patients and by 41% in normotensive patients (0.59; 0.44-0.79; p=0.0001). The other ACE-inhibitors reduced CV morbidity and mortality as well, though the reduction (-17%) was not statistically significant vs. placebo either in hypertensives (0.83; 0.57-1.21; p=0.338) or normotensives (reduction: -24%; HR: 0.76; 0.50-1.15; p=0.194). Treatment with zofenopril of hypertensive and normotensive patients was associated with a non-statistically significant reduction in the risk of CV outcomes as compared to the other ACE-inhibitors (hypertensives: 0.78; 0.60-1.01; p=0.062; normotensives: 0.77; 0.55-1.10; p=0.1509. Conclusions: in high-risk cardiac patients with arterial hypertension, zofenopril treatment is associated with a clinically relevant reduction in long-term CV morbidity and mortality, compared to placebo, with an efficacy similar to that of other ACE-inhibitors, such as lisinopril and ramipril.
Therapeutic Antisense Oligonucleotides Are Coming of Age
Authors: C. Frank Bennett
Journal: Annual Review of Medicine (2019)

The first published description of therapeutic applications of antisense oligonucleotide (ASO) technology occurred in the late 1970s and was followed by the founding of commercial companies focused on developing antisense therapeutics in the late 1980s. Since the late 1980s, there has been steady progress in improving the technology platform, taking advantage of advances in oligonucleotide chemistry and formulations as well as increased understanding of the distribution and safety of ASOs. There are several approved ASO drugs and a broad pipeline in development. In addition, advances in understanding human disease, including the genetic basis for most monogenic diseases and the availability of the full human genome sequence, have created numerous therapeutic applications for the technology. I summarize the state of the technology and highlight how advances in the technology position ASOs to be an important contributor to future medicines.
Clinical and Computed Tomography Angiographic Predictors of Coronary Lesions That Later Progressed to Chronic Total Occlusion
Authors: Jeehoon Kang, Eun Ju Chun, Hee Jeong Park, Young-Seok Cho, Jin Joo Park, Si-Hyuck Kang, Young Jin Cho, Yeonyee E. Yoon, Il-Young Oh, Chang-Hwan Yoon, Jung-Won Suh, Tae-Jin Youn, In-Ho Chae, Dong-Ju Choi
Journal: JACC. Cardiovascular imaging (2019)
LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis
Authors: Yi Xie, Allison C. Ostriker, Yu Jin, Haidi Hu, Ashley J. Sizer, Gang Peng, Aaron H. Morris, Changwan Ryu, Erica L. Herzog, Themis Kyriakides, Hongyu Zhao, Alan Dardik, Jun Yu, John Hwa, Kathleen A. Martin
Journal: Circulation (2019)

Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis.We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy.LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
5-Hydroxymethylcytosines of Circulating Cell-Free DNA and Prognosis in Diffuse Large B-Cell Lymphoma
Authors: Brian C.-H. Chiu, Zhou Zhang, Qiancheng You, Elizabeth Stepniak, Paige Bracci, Rudyard I Chiu, Xu Zhang, Girish Venkataraman, Sonali M. Smith, Chuan He, Wei Zhang
Journal: Blood (2018)
How Safe Is Safe Enough for Space and Health Care?
Authors: James P. Bagian
Journal: JAMA Neurology (2019)

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Recommendation to include hydroxyethyl (meth)acrylate in the British baseline patch test series
Authors: S. Rolls, M.M. Chowdhury, S. Cooper, P. Cousen, A.M. Flynn, S.A. Ghaffar, C.M. Green, A. Haworth, C. Holden, G.A. Johnston, K. Naidoo, D.I. Orton, C. Reckling, R.A. Sabroe, M. Scorer, N.M. Stone, D. Thompson, S. Wakelin, M. Wilkinson, D.A. Buckley
Journal: British Journal of Dermatology (2019)

(Meth)acrylates are potent sensitizers and a common cause of allergic contact dermatitis (ACD). The frequency of (meth)acrylate ACD has increased with soaring demand for acrylic nails. A preliminary audit has suggested a significant rate of positive patch tests to (meth)acrylates using aimed testing in patients providing a clear history of exposure. To date, (meth)acrylates have not been routinely tested in the baseline patch test series in the U.K. and Europe.To determine whether inclusion of 2-hydroxyethyl methacrylate (2-HEMA) 2% in petrolatum (pet.) in the baseline series detects cases of treatable (meth)acrylate ACD.During 2016-2017, 15 U.K. dermatology centres included 2-HEMA in the extended baseline patch test series. Patients with a history of (meth)acrylate exposure, or who tested positive to 2-HEMA, were selectively tested with a short series of eight (meth)acrylate allergens.In total 5920 patients were consecutively patch tested with the baseline series, of whom 669 were also tested with the (meth)acrylate series. Overall, 102 of 5920 (1·7%) tested positive to 2-HEMA and 140 (2·4%) to at least one (meth)acrylate. Had 2-HEMA been excluded from the baseline series, (meth)acrylate allergy would have been missed in 36 of 5920 (0·6% of all patients). The top (meth)acrylates eliciting a positive reaction were 2-HEMA (n = 102, 1·7%), 2-hydroxypropyl methacrylate (n = 61, 1·0%) and 2-hydroxyethyl acrylate (n = 57, 1·0%).We recommend that 2-HEMA 2% pet. be added to the British baseline patch test series. We also suggest a standardized short (meth)acrylate series, which is likely to detect most cases of (meth)acrylate allergy.
Correction: Drug-Resistant Brain Metastases: A Role for Pharmacology, Tumor Evolution, and Too-Late Therapy
Authors: Thomas Stricker, Carlos L. Arteaga
Journal: Cancer Discovery (2019)

In the original version of this article (1), the stated disclosure of the author Carlos L. Arteaga is incorrect. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.