tbuckley/cabot-search huggingface dataset:
Deserters on the atopic march: Risk factors, immune profile and clinical outcomes of food sensitized–tolerant infants
Authors: Lawrence E. K. Gray, Anne‐Louise Ponsonby, Fiona Collier, Martin O'Hely, Peter D. Sly, Sarath Ranganathan, Mimi L. K. Tang, John B. Carlin, Richard Saffery, Peter J. Vuillermin
Journal: Allergy (2019)

A few studies have investigated the antecedents and outcomes of infants who demonstrate IgE sensitization to foods that they clinically tolerate. Improved understanding of this sensitized-tolerant phenotype may inform strategies for the prevention of food allergy.In an Australian birth cohort (n = 1074), assembled using an unselected antenatal sampling frame, participants were categorized as nonsensitized (NS), sensitizedtolerant (ST), or food allergic (FA) based on skin prick testing and food challenge at 12 months of age. Environmental exposures were recorded throughout. Cord blood regulatory T-cell populations were measured at birth. Subsequent childhood allergic disease was assessed by parent report, clinical examination, and repeat skin prick testing.The covariates of interest varied between NS (n = 698), ST (n = 27), and FA (n = 61) groups as follows, suggesting that across these measures, the ST group was more similar to the NS than the FA group: family history of eczema NS 44.6%, ST. 44.6%, FA 65.6%; pet ownership at 12 months: NS 71.5%, ST 81.5%, FA 45.8%; eczema during the first 12 months: NS 19%, ST 32%, FA 64%; and aeroallergen sensitization at 4 years: NS 19.1%, ST 28.6%, FA 44.4%. At birth, a higher proportion of activated regulatory T cells was associated with ST (OR = 2.89, 95% CI 1.03-8.16, P = .045).Food-sensitized-tolerance in infancy appears to be associated with a similar pattern of exposures, immunity, and outcomes to nonsensitized infants. In addition, we found some evidence that an elevated proportion of activated regulatory T cells at birth was specific to the sensitized-tolerant infants, which may be relevant to suppression of clinical disease.
Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain
Authors: Jeanna M. Wheeler, Pamela McMillan, Timothy J. Strovas, Nicole F. Liachko, Alexandre Amlie-Wolf, Rebecca L. Kow, Ronald L. Klein, Patricia Szot, Linda Robinson, Chris Guthrie, Aleen Saxton, Nicholas M. Kanaan, Murray Raskind, Elaine Peskind, John Q. Trojanowski, Virginia M. Y. Lee, Li-San Wang, C. Dirk Keene, Thomas Bird, Gerard D. Schellenberg, Brian Kraemer
Journal: Science Translational Medicine (2019)

The poly(A) RNA binding proteins MSUT2 and PABPN1 regulate the accumulation of pathological tau in two mouse models of tauopathy.
Impact of early introduction of steroid on immune-checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer treated
Authors: A. De Giglio, L. Mezquita, E. Auclin, F. Blanc-Durand, L. El-Amarti, C. Caramella, G. Martinez Bernal, L. Hendriks, R. Ferrara, C. Naltet, P. Lavaud, A. Gazzah, J. Adam, D. Planchard, N. Chaput, B. Besse
Journal: Annals of Oncology (2019)
Del(6)(q22) and BCL6 Rearrangements in Primary Central Nervous System Lymphoma (PCNSL) Are Indicators of an Aggressive Clinical Course.
Authors: Francois M. Cady, Mark E. Law, Caterina Giannini, Alyx B. Porter, Brian P. O’Neill, Paul A. Decker, Paul J. Kurtin, Ellen D. Remstein, Ahmet Dogan
Journal: Blood (2007)
Mcl1 is the predominant pro-survival protein in neuroblastoma
Authors: Mark Fluchel, Agueda Lin, Kelly Goldsmith, Xueyuan Liu, Kim Davis, Ashish Bhumbla, Laura Ip, Wendy London, Michael Hogarty
Journal: Cancer Research (2007)

5138  Neuroblastoma (NB) is a common and frequently lethal childhood tumor. While many NBs are initially chemosensitive, the majority progress after acquiring chemoresistance. Bcl2-homology (BH) proteins govern mitochondrial death signaling and alterations in these pathways contribute to chemoresistance. Mcl1 is a Bcl2 homologue capable of both sequestering specific BH3 death proteins and directly repressing Bak to exert dual pro-survival effects. We previously identified gain of Mcl1 as a co-operative lesion supporting MYCN deregulation in neural cell transformation, analogous to Bcl2 supporting MYC in lymphomagenesis, and explored Mcl1 as a candidate oncogene in NB. Mcl1 maps to a region of frequent gain in NB (1q21) and was the most highly expressed pro-survival Bcl2 homologue (RNA and protein) in NB cell lines. Both Mcl1-L and Mcl1-S were present in NBs. Co-IP studies found pro-apoptotic PUMA and BIM-L bound to Mcl1 (and Bcl-Xl), but not Bcl2, in NB cell lines during steady state growth. Thus, Mcl1 tonically represses death signals constitutively present in NBs. Expression profiling of 101 primary NBs (Affymetrix) similarly demonstrated Mcl1 as the most abundant Bcl2 homologue across all NB risk groups. To validate these findings we used TaqMan to determine Mcl1 expression in 33 independent NBs (from COG): 15 (45%) were MYCN amplified and 20 (61%) high-risk by COG criteria. There was a trend toward higher Mcl1 expression in MYCN-amplified (p=0.06) and diploid NBs (p=0.09) but not with higher stage, age, or histopathology (Wilcoxon exact two-sample test). EFS nor OS was significantly correlated with Mcl1 expression by log-rank test for this cohort. In vitro knockdown of Mcl1 via siRNA resulted in increased cell death in the NB cell lines studied. Both KAN and SK-N-AS cells treated with Mcl1 siRNA demonstrated >30% reduction in viability at 72 hrs compared with GAPDH siRNA. Knockdown of Mcl1 variably potentiated chemoresponse when combined with topotecan, doxorubicin, etoposide or mafosfamide with resultant IC50 shifted ~1 log. Mcl1 protein, unlike Bcl2, has a short t1/2 and is highly regulated. In vitro data suggests that knockdown of Mcl1 can increase cell death and chemosensitivity. For these reasons, Mcl1 makes an attractive therapeutic target. We are investigating the therapeutic utility of Mcl1-Antisense to augment chemoresponsiveness in NB.
Herpesvirus‐bacteria synergistic interaction in periodontitis
Authors: Casey Chen, Pinghui Feng, Jørgen Slots
Journal: Periodontology 2000 (2019)

The etiopathogenesis of severe periodontitis includes herpesvirus-bacteria coinfection. This article evaluates the pathogenicity of herpesviruses (cytomegalovirus and Epstein-Barr virus) and periodontopathic bacteria (Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis) and coinfection of these infectious agents in the initiation and progression of periodontitis. Cytomegalovirus and A. actinomycetemcomitans/P. gingivalis exercise synergistic pathogenicity in the development of localized ("aggressive") juvenile periodontitis. Cytomegalovirus and Epstein-Barr virus are associated with P. gingivalis in adult types of periodontitis. Periodontal herpesviruses that enter the general circulation may also contribute to disease development in various organ systems. A 2-way interaction is likely to occur between periodontal herpesviruses and periodontopathic bacteria, with herpesviruses promoting bacterial upgrowth, and bacterial factors reactivating latent herpesviruses. Bacterial-induced gingivitis may facilitate herpesvirus colonization of the periodontium, and herpesvirus infections may impede the antibacterial host defense and alter periodontal cells to predispose for bacterial adherence and invasion. Herpesvirus-bacteria synergistic interactions, are likely to comprise an important pathogenic determinant of aggressive periodontitis. However, mechanistic investigations into the molecular and cellular interaction between periodontal herpesviruses and bacteria are still scarce. Herpesvirus-bacteria coinfection studies may yield significant new discoveries of pathogenic determinants, and drug and vaccine targets to minimize or prevent periodontitis and periodontitis-related systemic diseases.
Economic evaluations in ‘non-inferiority’ trials: can costs guide decisions between surgical and non-surgical interventions?
Authors: Steven M McPhail
Journal: British Journal of Sports Medicine (2019)

Have you ever wondered…‘Is physical therapy treatment (alone) just as good as arthroscopic partial meniscectomy (APM) in patients with non-obstructive partial meniscal tears?’ What would make you think it is just as good? What would you use as a measure of ‘goodness’? It is an interesting question, isn’t it? Clinical trials that test whether one treatment is not meaningfully worse than another are called ‘non-inferiority trials’, and they are an example of the increasing sophistication of study designs in the field of sport and exercise physiotherapy and medicine.

In this editorial I discuss the concept of non-inferiority using the JAMA -published 2018 ESCAPE study as the example. The Dutch surgeon and epidemiologist authors randomised 321 patients with non-obstructive partial meniscal tears and concluded that physical therapy alone was not inferior to APM in those patients.1 That was based on clinical measures—the widely used International Knee Documentation Committee (IKDC) score. But what about costs? Wouldn’t physiotherapy alone be cheaper than surgery too?

In the British Journal of Sports Medicine paper linked to this editorial, the authors of the ESCAPE trial report their economic evaluation.2 Patients randomised to the physical therapy intervention had lower healthcare and societal costs than patients randomised to APM. This, along with their incremental cost-effectiveness analyses, adds to the case that APM should not be the first-choice treatment for …
Limitation standard of toxic aconitines in Aconitum proprietary Chinese medicines using on-line extraction electrospray ionization mass spectrometry
Authors: Zi-Dong Qiu, Xu-Ya Wei, Rui-Qi Sun, Jin-Long Chen, Ting Tan, Jia-Quan Xu, Guang-Hong Cui, Tong Chen, Juan Guo, Chang-Jiang-Sheng Lai, Lu-Qi Huang
Journal: Acta Pharmaceutica Sinica B (2019)

Development of rapid analytical methods and establishment of toxic component limitation standards are of great importance in quality control of traditional Chinese medicine. Herein, an on-line extraction electrospray ionization mass spectrometry (oEESI-MS) coupled with a novel whole process integral quantification strategy was developed and applied to direct determination of nine key aconitine-type alkaloids in 20 Aconitum proprietary Chinese medicines (APCMs). Multi-type dosage forms (e.g., tablets, capsules, pills, granules, and liquid preparation) of APCM could be determined directly with excellent versatility. The strategy has the characteristics of high throughput, good tolerance of matrix interference, small amount of sample (∼0.5 mg) and reagent (∼240 μL) consumption, and short analysis time for single sample (<15 min). The results were proved to be credible by high performance liquid chromatography−mass spectrometry (LC–MS) and electrospray ionization mass spectrometry, respectively. Moreover, the limitation standard for the toxic aconitines in 20 APCMs was established based on the holistic weight toxicity (HWT) evaluation and the Chinese Pharmacopoeia severally, and turned out that HWT-based toxicity evaluation results were closer to the real clinical applications. Hence, a more accurate and reliable APCM toxicity limitation was established and expected to play an important guiding role in clinics. The current study extended the power of ambient MS as a method for the direct quantification of molecules in complex samples, which is commonly required in pharmaceutical analysis, food safety control, public security, and many other disciplines.
Extensively drug-resistant Klebsiella pneumoniae ST307 outbreak, north-eastern Germany, June to October 2019
Authors: Sebastian Haller, Rolf Kramer, Karsten Becker, Jürgen A Bohnert, Tim Eckmanns, Jörg B Hans, Jane Hecht, Claus-Dieter Heidecke, Nils-Olaf Hübner, Axel Kramer, Kathleen Klaper, Martina Littmann, Lennart Marlinghaus, Bernd Neumann, Yvonne Pfeifer, Niels Pfennigwerth, Simone Rogge, Katharina Schaufler, Andrea Thürmer, Guido Werner, Sören Gatermann
Journal: Eurosurveillance (2019)

From June to October 2019, 17 patients (six infected, 11 colonised) with an extensively drug-resistant (XDR) Klebsiella pneumoniae strain were notified from four Western Pomerania medical facilities. The XDR K. pneumoniae produced carbapenemases NDM-1 and OXA-48, and was only susceptible to chloramphenicol, tigecycline and cefiderocol. Synergistic activity was observed for the combination of aztreonam plus ceftazidime-avibactam. Genomic analyses showed all isolates belonged to K. pneumoniae sequence type 307. Control measures and further investigations are ongoing.
Abstract 13813: Identification of Six Polymorphisms as Novel Susceptibility Loci for Ischemic or Hemorrhagic Stroke by Exome-Wide Association Studies
Authors: Mitsutoshi Oguri, Kimihiko Kato, Tetsuo Fujimaki, Hideki Horibe, Jun Sakuma, Ichiro Takeuchi, Toyoaki Murohara, Yoshiki Yasukochi, Yoshiji Yamada
Journal: Circulation (2017)

Introduction: Genome-wide association studies (GWASs) in European ancestry populations have identified various genes and loci that confer susceptibility to ischemic stroke, intracerebral hemorrhage...
PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus
Authors: Xue Han, Matthew D. Vesely, Wendy Yang, Miguel F. Sanmamed, Ti Badri, Jude Alawa, Francesc López-Giráldez, Patricia Gaule, Sang Won Lee, Jian-Ping Zhang, Xinxin Nie, Ala Nassar, Agedi Boto, Dallas B. Flies, Linghua Zheng, Tae Kon Kim, Gilbert W. Moeckel, Jennifer M. McNiff, Lieping Chen
Journal: Science Translational Medicine (2019)

Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) of the skin are autoimmune diseases characterized by inappropriate immune responses against self-proteins; the key elements that determine disease pathogenesis and progression are largely unknown. Here, we show that mice lacking immune inhibitory receptor VISTA or programmed death-1 homolog (PD-1H KO) on a BALB/c background spontaneously develop cutaneous and systemic autoimmune diseases resembling human lupus. Cutaneous lupus lesions of PD-1H KO mice have clustering of plasmacytoid dendritic cells (pDCs) similar to human DLE. Using mass cytometry, we identified proinflammatory neutrophils as critical early immune infiltrating cells within cutaneous lupus lesions of PD-1H KO mice. We also found that PD-1H is highly expressed on immune cells in human SLE, DLE lesions, and cutaneous lesions of MRL/lpr mice. A PD-1H agonistic monoclonal antibody in MRL/lpr mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, chemokines, and immune cell expansion. Furthermore, PD-1H on both T cells and myeloid cells including neutrophils and pDCs could transmit inhibitory signals, resulting in reduced activation and function, establishing PD-1H as an inhibitory receptor on T cells and myeloid cells. On the basis of these findings, we propose that PD-1H is a critical element in the pathogenesis and progression of lupus, and PD-1H activation could be effective for treatment of systemic and cutaneous lupus.
Horizontal Gene Transfer Phylogenetics: A Random Walk Approach
Authors: Gur Sevillya, Daniel Doerr, Yael Lerner, Jens Stoye, Mike Steel, Sagi Snir
Journal: Molecular Biology and Evolution (2019)

Abstract The dramatic decrease in time and cost for generating genetic sequence data has opened up vast opportunities in molecular systematics, one of which is the ability to decipher the evolutionary history of strains of a species. Under this fine systematic resolution, the standard markers are too crude to provide a phylogenetic signal. Nevertheless, among prokaryotes, genome dynamics in the form of horizontal gene transfer (HGT) between organisms and gene loss seem to provide far richer information by affecting both gene order and gene content. The “synteny index” (SI) between a pair of genomes combines these latter two factors, allowing comparison of genomes with unequal gene content, together with order considerations of their common genes. Although this approach is useful for classifying close relatives, no rigorous statistical modeling for it has been suggested. Such modeling is valuable, as it allows observed measures to be transformed into estimates of time periods during evolution, yielding the “additivity” of the measure. To the best of our knowledge, there is no other additivity proof for other gene order/content measures under HGT. Here, we provide a first statistical model and analysis for the SI measure. We model the “gene neighborhood” as a “birth–death–immigration” process affected by the HGT activity over the genome, and analytically relate the HGT rate and time to the expected SI. This model is asymptotic and thus provides accurate results, assuming infinite size genomes. Therefore, we also developed a heuristic model following an “exponential decay” function, accounting for biologically realistic values, which performed well in simulations. Applying this model to 1,133 prokaryotes partitioned to 39 clusters by the rank of genus yields that the average number of genome dynamics events per gene in the phylogenetic depth of genus is around half with significant variability between genera. This result extends and confirms similar results obtained for individual genera in different manners.
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA
Authors: Boris D. Heifets, Juliana S. Salgado, Madison D. Taylor, Paul Hoerbelt, Daniel F. Cardozo Pinto, Elizabeth E. Steinberg, Jessica J. Walsh, Ji Y. Sze, Robert C. Malenka
Journal: Science Translational Medicine (2019)

The extensively abused recreational drug (±)3,4-methylenedioxymethamphetamine (MDMA) has shown promise as an adjunct to psychotherapy for treatment-resistant psychiatric disease. It is unknown, however, whether the mechanisms underlying its prosocial therapeutic effects and abuse potential are distinct. We modeled both the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain region-specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We demonstrate in mice that MDMA acting at the serotonin transporter within the nucleus accumbens is necessary and sufficient for MDMA's prosocial effect. MDMA's acute rewarding properties, in contrast, require dopaminergic signaling. MDMA's prosocial effect requires 5-HT1b receptor activation and is mimicked by d-fenfluramine, a selective serotonin-releasing compound. By dissociating the mechanisms of MDMA's prosocial effects from its addictive properties, we provide evidence for a conserved neuronal pathway, which can be leveraged to develop novel therapeutics with limited abuse liability.
A Bayesian Implementation of the Multispecies Coalescent Model with Introgression for Phylogenomic Analysis
Authors: Tomáš Flouri, Xiyun Jiao, Bruce Rannala, Ziheng Yang
Journal: Molecular Biology and Evolution (2019)

Abstract Recent analyses suggest that cross-species gene flow or introgression is common in nature, especially during species divergences. Genomic sequence data can be used to infer introgression events and to estimate the timing and intensity of introgression, providing an important means to advance our understanding of the role of gene flow in speciation. Here, we implement the multispecies-coalescent-with-introgression model, an extension of the multispecies-coalescent model to incorporate introgression, in our Bayesian Markov chain Monte Carlo program Bpp. The multispecies-coalescent-with-introgression model accommodates deep coalescence (or incomplete lineage sorting) and introgression and provides a natural framework for inference using genomic sequence data. Computer simulation confirms the good statistical properties of the method, although hundreds or thousands of loci are typically needed to estimate introgression probabilities reliably. Reanalysis of data sets from the purple cone spruce confirms the hypothesis of homoploid hybrid speciation. We estimated the introgression probability using the genomic sequence data from six mosquito species in the Anopheles gambiae species complex, which varies considerably across the genome, likely driven by differential selection against introgressed alleles.
Image Gallery: Cerebral and subcutaneous sparganosis
Authors: B.L. Adler, G.H. Kim, D.D. Kim
Journal: British Journal of Dermatology (2019)

DEAR EDITOR, A 59-year-old Korean woman with (a) multifocal brain lesions on magnetic resonance imaging (largest lesion indicated by arrow), with negative malignancy, infection and autoimmune workups, developed two mobile subcutaneous nodules on the right thigh.(b, Video S1) Excision revealed a moving subcutaneous worm, histologically a sparganum (c, d), featuring loose stroma, smooth muscle, secretory tegument and calcareous bodies (arrow; confirmed by the Centers for Disease Control and Prevention).Imaging review supported cerebral sparganosis.Sparganosis, a parasitic zoonosis caused by Spirometra tapeworms, is most common in China and Korea. 1Humans acquire infection by ingesting contaminated water or undercooked frog or snake, or using raw flesh poultices.Spargana can migrate widely (brain, eyes, subcutis, viscera), generating variable presentations.The patient reported using poultices in Korea.Symptomatic and radiographic improvement occurred over six cycles of high-dose praziquantel. 2
Potassium abnormalities in patients with heart failure from 11 Asian regions: insights from the ASIAN‐HF registry
Authors: Joost C. Beusekamp, Tiew‐Hwa Katherine Teng, Wan Ting Tay, Wouter Ouwerkerk, A. Mark Richards, Inder S. Anand, Vijay K. Chopra, Gurpreet S. Wander, Peter van der Meer, Adriaan A. Voors, Carolyn S.P. Lam, Jasper Tromp
Journal: European Journal of Heart Failure (2019)
A systematic review and meta-analysis of trials assessing activity of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) for pre-treated advanced malignant mesothelioma (aMM)
Authors: M. Tagliamento, P. Bironzo, E. De Luca, D. Pignataro, S.G. Rapetti, M. Audisio, V. Bertaglia, C. Paratore, M. Bungaro, E. Olmetto, E. Artusio, M.L. Reale, C. Zichi, E. Capelletto, S. Carnio, L. Buffoni, F. Passiglia, S. Novello, M. Di Maio
Journal: Annals of Oncology (2019)
Challenging the assumption that interpregnancy interval causes stillbirth in low-income and middle-income countries
Authors: Gizachew Assefa Tessema, Gavin Pereira
Journal: The Lancet Global Health (2019)

Interpregnancy interval, which is the time between the end of one pregnancy and conception of the subsequent pregnancy, is a modifiable risk factor that has the potential to prevent a fraction of stillbirths—particularly in low-income and middle-income countries (LMICs) where 98% of global stillbirths occur.1 Most of these stillbirths are attributable to poor maternal health and inadequate antenatal and intrapartum care.2 Several studies have reported associations between stillbirth and interpregnancy interval.
Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity
Authors: Conor McClenaghan, Yan Huang, Zihan Yan, Theresa M. Harter, Carmen M. Halabi, Rod Chalk, Attila Kovacs, Gijs van Haaften, Maria S. Remedi, Colin G. Nichols
Journal: Journal of Clinical Investigation (2019)

Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of KATP channel activity specifically in VSM, and by chronic administration of the clinically used KATP channel inhibitor, glibenclamide. These findings demonstrate that VSM KATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.