tbuckley/cabot-search huggingface dataset:
One Clever Macrophage Checkpoint
Authors: Alberto Mantovani, Raffaella Bonecchi
Journal: Clinical Cancer Research (2019)

Abstract Macrophages are a key component of the tumor microenvironment (TME). Blocking Clever-1, a molecule expressed in M2-like macrophages, unleashed macrophage and T-cell–mediated antitumor immunity. Myeloid checkpoints including Clever-1 hold promise as alternative or complementary immunotherapy strategies. See related article by Viitala et al., p. 3289
Transcriptomics of atopy and atopic asthma in white blood cells from children and adolescents
Authors: Yale Jiang, Olena Gruzieva, Ting Wang, Erick Forno, Nadia Boutaoui, Tao Sun, Simon K. Merid, Edna Acosta-Pérez, Inger Kull, Glorisa Canino, Josep M. Antó, Jean Bousquet, Erik Melén, Wei Chen, Juan C. Celedón
Journal: European Respiratory Journal (2019)

Early allergic sensitisation (atopy) is the first step in the development of allergic diseases such as atopic asthma later in life. Genes and pathways associated with atopy and atopic asthma in children and adolescents have not been well characterised.A transcriptome-wide association study (TWAS) of atopy and atopic asthma in white blood cells (WBCs) or whole blood was conducted in a cohort of 460 Puerto Ricans aged 9-20 years (EVA-PR study) and in a cohort of 250 Swedish adolescents (BAMSE study). Pathway enrichment and network analyses were conducted to further assess top findings, and classification models of atopy and atopic asthma were built using expression levels for the top differentially expressed genes (DEGs).In a meta-analysis of the study cohorts, both previously implicated genes (e.g. IL5RA and IL1RL1) and genes not previously reported in TWASs (novel) were significantly associated with atopy and/or atopic asthma. Top novel genes for atopy included SIGLEC8 (p=8.07×10-13), SLC29A1 (p=7.07×10-12) and SMPD3 (p=1.48×10-11). Expression quantitative trait locus analyses identified multiple asthma-relevant genotype-expression pairs, such as rs2255888/ALOX15 Pathway enrichment analysis uncovered 16 significantly enriched pathways at adjusted p<0.01, including those relevant to T-helper cell type 1 (Th1) and Th2 immune responses. Classification models built using the top DEGs and a few demographic/parental history variables accurately differentiated subjects with atopic asthma from nonatopic control subjects (area under the curve 0.84).We have identified genes and pathways for atopy and atopic asthma in children and adolescents, using transcriptome-wide data from WBCs and whole blood samples.
Hospital Responses to the End of Life Option Act
Authors: Cindy L. Cain, Barbara A. Koenig, Helene Starks, Judy Thomas, Lindsay Forbes, Sara McCleskey, Neil S. Wenger
Journal: JAMA Internal Medicine (2019)

This survey study of statewide California hospitals evaluates the prevalence and institutional characteristics of hospitals and health systems that have either implemented or opted out of the state’s End of Life Option Act.
Allogeneic hematopoietic stem cell transplant outcomes for patients with dominant negative IKZF1/IKAROS mutations
Authors: Erinn S. Kellner, Christa Krupski, Hye Sun Kuehn, Sergio D. Rosenzweig, Nao Yoshida, Seiji Kojima, David Boutboul, Sylvain Latour, Vincent Barlogis, Claire Galambrun, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Rebecca A. Marsh
Journal: Journal of Allergy and Clinical Immunology (2019)
Women’s Attitudes Toward Invasive and Noninvasive Testing When Facing a High Risk of Fetal Down Syndrome
Authors: Valerie Seror, Olivier L’Haridon, Laurence Bussières, Valérie Malan, Nicolas Fries, Michel Vekemans, Laurent J. Salomon, Yves Ville
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Noninvasive prenatal testing (NIPT) using cell-free DNA in maternal blood is increasingly common compared with invasive testing (IT) in routine antenatal detection of Down syndrome (DS). <h3>Objective</h3> To assess attitudes and decision making in pregnant women facing a risk of fetal DS greater than 1 in 250 as established by combined first trimester screening at 11 to 14 weeks of gestation. <h3>Design, Setting, and Participants</h3> Survey study in which data were collected from pregnant women at high risk of fetal DS participating in a randomized clinical trial. Data were collected from April 8, 2014, to April 7, 2016, in 57 prenatal diagnosis centers in France. Data were analyzed in 2018. <h3>Interventions</h3> Data on attitudes were collected prior to offering randomization between NIPT and IT, whereas data on decision making and test results were collected as part of the clinical trial. <h3>Main Outcome and Measures</h3> The primary outcome related to attitudes. A hierarchical cluster analysis was conducted to identify clusters with contrasting attitudes. Logistic regression analyses were used to identify factors associated with attitudes. <h3>Results</h3> All 2436 consecutive women to whom the study was proposed (mean [SD] age, 36.3 [5.0] years) answered the questionnaire: 515 (21.1%) expressed preference toward IT with complete karyotyping, whereas 1843 (75.7%) favored NIPT with almost certain but limited information. Hierarchical cluster analysis yielded 4 different clusters that mainly differed in attitudes toward risk taking and extent of information seeking. Factors likely associated with attitudes driven by risk aversion were mostly age and religious beliefs (adjusted odds ratio [aOR], 1.03; 95% CI, 1.00-1.05;<i>P</i> = .03 and aOR, 1.62; 95% CI, 1.29-2.04;<i>P</i> &lt; .001, respectively), whereas higher nuchal translucency measurements by ultrasonography were associated with attitudes driven by ambiguity aversion (aOR, 1.67; 95% CI, 1.27-2.20;<i>P</i> &lt; .001). For attitudes involving both risk and ambiguity aversion at different extents, lower education was associated with highly valuing all possibilities of getting information on pregnancy, whereas higher education was associated with highly valuing information on fetal DS as a primary concern (aOR, 0.54; 95% CI, 0.44-0.67;<i>P</i> &lt; .001 and aOR, 1.44; 95% CI, 1.20-1.74;<i>P</i> &lt; .001, respectively). In all, decision making was in line with attitudes. <h3>Conclusions and Relevance</h3> Aversion to risk of fetal loss related to IT and aversion to ambiguity generated by incomplete information from NIPT played a major role in shaping attitudes and decision making. Informed decision making should require pregnant women at high risk of DS to receive extensive information on targeted abnormalities by both tests.
Self care interventions for sexual and reproductive health and rights: costs, benefits, and financing
Authors: Michelle Remme, Manjulaa Narasimhan, David Wilson, Moazzam Ali, Lavanya Vijayasingham, Fatima Ghani, Pascale Allotey
Journal: BMJ (2019)

<b>Michelle Remme and colleagues</b> argue that if costs to users are considered and their financing is right, self care interventions for sexual and reproductive health can improve equity and efficiency
The motility regulator flhDC drives intracellular accumulation and tumor colonization of Salmonella
Authors: Vishnu Raman, Nele Van Dessel, Owen M. O’Connor, Neil S. Forbes
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> <i>Salmonella</i> have potential as anticancer therapeutic because of their innate tumor specificity. In clinical studies, this specificity has been hampered by heterogeneous responses. Understanding the mechanisms that control tumor colonization would enable the design of more robust therapeutic strains. Two mechanisms that could affect tumor colonization are intracellular accumulation and intratumoral motility. Both of these mechanisms have elements that are controlled by the master motility regulator <i>flhDC</i>. We hypothesized that 1<i>) overexpressing flhDC in Salmonella increases intracellular bacterial accumulation in tumor cell masses,</i> and <i>2) intracellular accumulation of Salmonella drives tumor colonization in vitro</i>. <h3>Methods</h3> To test these hypotheses, we transformed <i>Salmonella</i> with genetic circuits that induce <i>flhDC</i> and express green fluorescent protein after intracellular invasion. The genetically modified <i>Salmonella</i> was perfused into an <i>in vitro</i> tumor-on-a-chip device. Time-lapse fluorescence microscopy was used to quantify intracellular and colonization dynamics within tumor masses. A mathematical model was used to determine how these mechanisms are related to each other. <h3>Results</h3> Overexpression of <i>flhDC</i> increased intracellular accumulation and tumor colonization 2.5 and 5 times more than control <i>Salmonella</i>, respectively (P &lt; 0.05). Non-motile <i>Salmonella</i> accumulated in cancer cells 26 times less than controls (P &lt; 0.001). Minimally invasive, <i>ΔsipB</i>, <i>Salmonella</i> colonized tumor masses 2.5 times less than controls (P &lt; 0.05). When <i>flhDC</i> was selectively induced after penetration into tumor masses, <i>Salmonella</i> both accumulated intracellularly and colonized tumor masses 2 times more than controls (P &lt; 0.05). Mathematical modeling of tumor colonization dynamics demonstrated that intracellular accumulation increased retention of <i>Salmonella</i> in tumors by effectively causing the bacteria to bind to cancer cells and preventing leakage out of the tumors. These results demonstrated that increasing intracellular bacterial density increased overall tumor colonization and that <i>flhDC</i> could be used to control both. <h3>Conclusions</h3> This study demonstrates a mechanistic link between motility, intracellular accumulation and tumor colonization. Based on our results, we envision that therapeutic strains of <i>Salmonella</i> could use inducible <i>flhDC</i> to drive tumor colonization. More intratumoral bacteria would enable delivery of higher therapeutic payloads into tumors and would improve treatment efficacy.
CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene
Authors: Shuying Shen, Yizheng Wu, Junxin Chen, Ziang Xie, Kangmao Huang, Gangliang Wang, Yute Yang, Weiyu Ni, Zhijun Chen, Peihua Shi, Yan Ma, Shunwu Fan
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Circular RNAs (circRNA) expression aberration has been identified in various human diseases. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of osteoarthritis (OA). Methods CircRNA deep sequencing was performed to the expression of circRNAs between OA and control cartilage tissues. The regulatory and functional role of CircSERPINE2 upregulation was examined in OA and was validated in vitro and in vivo, downstream target of CircSERPINE2 was explored. RNA pull down, a luciferase reporter assay, biotin-coupled microRNA capture and fluorescence in situ hybridisation were used to evaluate the interaction between CircSERPINE2 and miR-1271-5 p, as well as the target mRNA, E26 transformation-specific-related gene (ERG). The role and mechanism of CircSERPINE2 in OA was also explored in rabbit models. Results The decreased expression of CircSERPINE2 in the OA cartilage tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix (ECM). Mechanistically, CircSERPINE2 acted as a sponge of miR-1271-5 p and functioned in human chondrocytes (HCs) through targeting miR-1271-5 p and ERG. Intra-articular injection of adeno-associated virus-CircSERPINE2-wt alleviated OA in the rabbit model. Conclusions Our results reveal an important role for a novel circRNA-CircSERPINE2 in OA progression. CircSERPINE2 overexpression could alleviate HCs apoptosis and promote anabolism of ECM through miR-1271-ERG pathway. It provides a potentially effective therapeutic strategy for OA progression.
The Intersection between Tumor Angiogenesis and Immune Suppression
Authors: Osama E. Rahma, F. Stephen Hodi
Journal: Clinical Cancer Research (2019)

Both immune checkpoint inhibitors (ICI) and antiangiogenesis agents have changed the landscape of cancer treatment in the modern era. While antiangiogenesis agents have demonstrated activities in tumors with high vascularization, including renal cell carcinoma and colorectal cancer, the effect of ICIs has been seen mainly in immunologically recognized tumors, with highly immune-infiltrative lymphocytes. The main challenge in the drug development of ICIs is moving their activities to noninflamed tumors and overcoming resistance that is driven, in part, by the immune-suppressive microenvironment. Angiogenesis factors drive immune suppression by directly suppressing the antigen-presenting cells as well as immune effector cells or through augmenting the effect of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM). Those suppressive immune cells can also drive angiogenesis, creating a vicious cycle of impaired immune activation. The combination of bevacizumab and ipilimumab was the first to show the promising effect of antiangiogenesis and ICIs. A plethora of similar combinations has entered the clinic since then, confirming the promising effects of such approach.
Peptide Receptor Radionuclide Therapy Combined With Chemotherapy in Patients With Neuroendocrine Tumors
Authors: Anna Yordanova, Harriet Ahrens, Georg Feldmann, Peter Brossart, Florian C. Gaertner, Christian Fottner, Matthias M. Weber, Hojjat Ahmadzadehfar, Mathias Schreckenberger, Matthias Miederer, Markus Essler
Journal: Clinical Nuclear Medicine (2019)

Purpose Combinations of therapies may enhance therapeutic effects without significantly increasing the incidence of adverse events. However, there are few data regarding survival after concomitant chemotherapy and peptide receptor radionuclide therapy (PRRT) with [ 177 Lu]Lu-octreotate in patients with neuroendocrine tumors (NETs). Thus, we explored the outcome of this combination of therapies. Methods Fifteen patients with somatostatin receptor–positive, rapidly progressive G2/G3 NETs during chemotherapy or PRRT alone from 2 German cancer centers were included in the retrospective analysis. The patients received a combination of PRRT and chemotherapy with temozolomide (n = 3) or temozolomide plus capecitabine (n = 12). To evaluate the effects of the combined treatment, we assessed the responses, survival, and adverse events. Results The cumulative administered activity of [ 177 Lu]Lu-octreotate had a median of 21.3 GBq after 3 cycles of combination therapy. The patients exhibited a median progression-free survival of 7.1 months and a median overall survival of 25.3 months. The clinical benefit (objective response and stable disease) rates were as follows: 55% of patients according to CT, 38% in [ 18 F]F-FDG PET/CT, and 44% in [ 68 Ga]Ga-DOTATOC PET/CT. One patient with rapidly progressing liver metastases experienced grade 4 liver failure according to the Common Terminology Criteria for Adverse Events (version 5.0). Four other patients (27%) experienced significantly elevated (grade 3) liver parameters. Conclusions According to different imaging modalities, the combination of PRRT and temozolomide +/− capecitabine led to disease control in 38% to 55% of the progressive NETs after PRRT or chemotherapy alone failed. The overall survival in this extensively pretreated group of patients was nearly 25 months. The majority of patients did not experience any serious adverse events.
Combined THC and CBD to treat pain in EB
Authors: N.H.B. Schräder, J.C. Duipmans, B. Molenbuur, A. Wolff, M.F. Jonkman
Journal: British Journal of Dermatology (2019)

EB is blistering condition, in which even minor knocks and friction can cause the skin to blister or ulcer. There are three main types reflecting the severity and location on the body of the blistering, EB simplex, junctional EB, and dystrophic EB. Pain is an extremely debilitating symptom of all the sub‐types of EB. Daily use of opioids, a class of drug which includes powerful painkillers such as morphine, is the current mainstay of EB pain relief. Opioids often fail to effectively manage this pain and are associated with development of tolerance, meaning that with repeated use, it takes a higher dose to get the initial benefits, and addiction. In this study from the Netherlands, three adult EB patients with chronic, severe pain were treated with pharmaceutical grade cannabinoid‐based medication (CBM) oil. All three participants reported a significant reduction in pain levels experienced whilst undergoing CBM oil treatment relative to their previous drug regime. An additional benefit was reduction in itching. Cannabinoids are chemical compounds which occur naturally in the cannabis plant. Cannabis contains over 100 cannabinoids, the two most abundant being tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD, unlike THC, does not possess psychoactive properties, meaning it does not alter mood, perception and behaviour in the ways often associated with recreational use of cannabis. The CBM used in this case was a mixture of CBD and THC in an oil base, which seemed to avoid unwanted side effects such as sedation and intoxication. The treatment was administered under the tongue. The cases reported in this study indicate that there may be a role for CBM oil in EB treatment, if these initial findings are confirmed in more in‐depth controlled scientific studies.
Polygenic Risk: Predicting Depression Outcomes in Clinical and Epidemiological Cohorts of Youths
Authors: Thorhildur Halldorsdottir, Charlotte Piechaczek, Ana Paula Soares de Matos, Darina Czamara, Verena Pehl, Petra Wagenbuechler, Lisa Feldmann, Peggy Quickenstedt-Reinhardt, Antje-Kathrin Allgaier, Franz Joseph Freisleder, Ellen Greimel, Tuomas Kvist, Jari Lahti, Katri Räikkönen, Monika Rex-Haffner, Eiríkur Örn Arnarson, W. Edward Craighead, Gerd Schulte-Körne, Elisabeth B. Binder
Journal: American Journal of Psychiatry (2019)

Objective: Identifying risk factors for major depression and depressive symptoms in youths could have important implications for prevention efforts. This study examined the association of polygenic risk scores (PRSs) for a broad depression phenotype derived from a large-scale genome-wide association study (GWAS) in adults, and its interaction with childhood abuse, with clinically relevant depression outcomes in clinical and epidemiological youth cohorts. Methods: The clinical cohort comprised 279 youths with major depression (mean age=14.76 years [SD=2.00], 68% female) and 187 healthy control subjects (mean age=14.67 years [SD=2.45], 63% female). The first epidemiological cohort included 1,450 youths (mean age=13.99 years [SD=0.92], 63% female). Of those, 694 who were not clinically depressed at baseline underwent follow-ups at 6, 12, and 24 months. The replication epidemiological cohort comprised children assessed at ages 8 (N=184; 49.2% female) and 11 (N=317; 46.7% female) years. All cohorts were genome-wide genotyped and completed measures for major depression, depressive symptoms, and/or childhood abuse. Summary statistics from the largest GWAS to date on depression were used to calculate the depression PRS. Results: In the clinical cohort, the depression PRS predicted case-control status (odds ratio=1.560, 95% CI=1.230–1.980), depression severity (β=0.177, SE=0.069), and age at onset (β=−0.375, SE=0.160). In the first epidemiological cohort, the depression PRS predicted baseline depressive symptoms (β=0.557, SE=0.200) and prospectively predicted onset of moderate to severe depressive symptoms (hazard ratio=1.202, 95% CI=1.045–1.383). The associations with depressive symptoms were replicated in the second epidemiological cohort. Evidence was found for an additive, but not an interactive, effect of the depression PRS and childhood abuse on depression outcomes. Conclusions: Depression PRSs derived from adults generalize to depression outcomes in youths and may serve as an early indicator of clinically significant levels of depression.
Threshold Analysis as an Alternative to GRADE for Assessing Confidence in Guideline Recommendations Based on Network Meta-analyses
Authors: David M. Phillippo, Sofia Dias, Nicky J. Welton, Deborah M. Caldwell, Nichole Taske, A.E. Ades
Journal: Annals of Internal Medicine (2019)

Guideline development requires the synthesis of evidence on several treatments of interest, typically by using network meta-analysis (NMA). Because treatment effects may be estimated imprecisely or be based on evidence lacking internal or external validity, guideline developers must assess the robustness of recommendations made on the basis of the NMA to potential limitations in the evidence. Such limitations arise because the observed estimates differ from the true effects of interest, for example, because of study biases, sampling variation, or issues of relevance. The widely used GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework aims to assess the quality of evidence supporting a recommendation by using a structured series of qualitative judgments. This article argues that GRADE approaches proposed for NMA are insufficient for the purposes of guideline development, because the influence of the evidence on the final recommendation is not taken into account. It outlines threshold analysis as an alternative approach, demonstrating the method with 2 examples of clinical guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom. Threshold analysis quantifies precisely how much the evidence could change (for any reason, such as potential biases, or simply sampling variation) before the recommendation changes, and what the revised recommendation would be. If it is judged that the evidence could not plausibly change by more than this amount, then the recommendation is considered robust; otherwise, it is sensitive to plausible changes in the evidence. In this manner, threshold analysis directly informs decision makers and guideline developers of the robustness of treatment recommendations.