tbuckley/cabot-search huggingface dataset:
Organic Cation Transporters in Health and Disease
Authors: Hermann Koepsell
Journal: Pharmacological Reviews (2019)

The organic cation transporters (OCTs) OCT1, OCT2, OCT3, novel OCT (OCTN)1, OCTN2, multidrug and toxin exclusion (MATE)1, and MATE kidney-specific 2 are polyspecific transporters exhibiting broadly overlapping substrate selectivities. They transport organic cations, zwitterions, and some uncharged compounds and operate as facilitated diffusion systems and/or antiporters. OCTs are critically involved in intestinal absorption, hepatic uptake, and renal excretion of hydrophilic drugs. They modulate the distribution of endogenous compounds such as thiamine, L-carnitine, and neurotransmitters. Sites of expression and functions of OCTs have important impact on energy metabolism, pharmacokinetics, and toxicity of drugs, and on drug–drug interactions. In this work, an overview about the human OCTs is presented. Functional properties of human OCTs, including identified substrates and inhibitors of the individual transporters, are described. Sites of expression are compiled, and data on regulation of OCTs are presented. In addition, genetic variations of OCTs are listed, and data on their impact on transport, drug treatment, and diseases are reported. Moreover, recent data are summarized that indicate complex drug–drug interaction at OCTs, such as allosteric high-affinity inhibition of transport and substrate dependence of inhibitor efficacies. A hypothesis about the molecular mechanism of polyspecific substrate recognition by OCTs is presented that is based on functional studies and mutagenesis experiments in OCT1 and OCT2. This hypothesis provides a framework to imagine how observed complex drug–drug interactions at OCTs arise. Finally, preclinical in vitro tests that are performed by pharmaceutical companies to identify interaction of novel drugs with OCTs are discussed. Optimized experimental procedures are proposed that allow a gapless detection of inhibitory and transported drugs.
Development of a ternary hybrid fNIRS-EEG brain–computer interface based on imagined speech
Authors: Alborz Rezazadeh Sereshkeh, Rozhin Yousefi, Andrew T Wong, Frank Rudzicz, Tom Chau
Journal: Brain-Computer Interfaces (2019)

There is increasing interest in developing intuitive brain-computer interfaces (BCIs) to differentiate intuitive mental tasks such as imagined speech. Both electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) have been used for this purpose. However, the classification accuracy and number of commands in such BCIs have been limited. The use of multi-modal BCIs to address these issues has been proposed for some common BCI tasks, but not for imagined speech. Here, we propose a multi-class hybrid fNIRS-EEG BCI based on imagined speech. Eleven participants performed multiple iterations of three tasks: mentally repeating 'yes' or 'no' for 15 s or an equivalent duration of unconstrained rest. We achieved an average ternary classification accuracy of 70.45 ± 19.19% which is significantly better than that attained with each modality alone (p < 0.05). Our findings suggest that concurrent measurements of EEG and fNIRS can improve classification accuracy of BCIs based on imagined speech.
Ancestral Hybridization Facilitated Species Diversification in the Lake Malawi Cichlid Fish Adaptive Radiation
Authors: Hannes Svardal, Fu Xiang Quah, Milan Malinsky, Benjamin P Ngatunga, Eric A Miska, Walter Salzburger, Martin J Genner, George F Turner, Richard Durbin
Journal: Molecular Biology and Evolution (2019)

The adaptive radiation of cichlid fishes in East African Lake Malawi encompasses over 500 species that are believed to have evolved within the last 800,000 years from a common founder population. It has been proposed that hybridization between ancestral lineages can provide the genetic raw material to fuel such exceptionally high diversification rates, and evidence for this has recently been presented for the Lake Victoria region cichlid superflock. Here, we report that Lake Malawi cichlid genomes also show evidence of hybridization between two lineages that split 3-4 Ma, today represented by Lake Victoria cichlids and the riverine Astatotilapia sp. "ruaha blue." The two ancestries in Malawi cichlid genomes are present in large blocks of several kilobases, but there is little variation in this pattern between Malawi cichlid species, suggesting that the large-scale mosaic structure of the genomes was largely established prior to the radiation. Nevertheless, tens of thousands of polymorphic variants apparently derived from the hybridization are interspersed in the genomes. These loci show a striking excess of differentiation across ecological subgroups in the Lake Malawi cichlid assemblage, and parental alleles sort differentially into benthic and pelagic Malawi cichlid lineages, consistent with strong differential selection on these loci during species divergence. Furthermore, these loci are enriched for genes involved in immune response and vision, including opsin genes previously identified as important for speciation. Our results reinforce the role of ancestral hybridization in explosive diversification by demonstrating its significance in one of the largest recent vertebrate adaptive radiations.
Author Correction: A consensus-based transparency checklist
Authors: Balazs Aczel, Barnabas Szaszi, Alexandra Sarafoglou, Zoltan Kekecs, Šimon Kucharský, Daniel Benjamin, Christopher D. Chambers, Agneta Fisher, Andrew Gelman, Morton A. Gernsbacher, John P. Ioannidis, Eric Johnson, Kai Jonas, Stavroula Kousta, Scott O. Lilienfeld, D. Stephen Lindsay, Candice C. Morey, Marcus Munafò, Benjamin R. Newell, Harold Pashler, David R. Shanks, Daniel J. Simons, Jelte M. Wicherts, Dolores Albarracin, Nicole D. Anderson, John Antonakis, Hal R. Arkes, Mitja D. Back, George C. Banks, Christopher Beevers, Andrew A. Bennett, Wiebke Bleidorn, Ty W. Boyer, Cristina Cacciari, Alice S. Carter, Joseph Cesario, Charles Clifton, Ronán M. Conroy, Mike Cortese, Fiammetta Cosci, Nelson Cowan, Jarret Crawford, Eveline A. Crone, John Curtin, Randall Engle, Simon Farrell, Pasco Fearon, Mark Fichman, Willem Frankenhuis, Alexandra M. Freund, M. Gareth Gaskell, Roger Giner-Sorolla, Don P. Green, Robert L. Greene, Lisa L. Harlow, Fernando Hoces de la Guardia, Derek Isaacowitz, Janet Kolodner, Debra Lieberman, Gordon D. Logan, Wendy B. Mendes, Lea Moersdorf, Brendan Nyhan, Jeffrey Pollack, Christopher Sullivan, Simine Vazire, Eric-Jan Wagenmakers
Journal: Nature Human Behaviour (2019)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Investigation of Hepatitis E Outbreak Among Refugees — Upper Nile, South Sudan, 2012–2013
Authors: Kerry Thomson, Dvorzak José Luis, John Lagu, Richard Laku, Brendan Dineen, Marian Schilperoord, Martin Muita, Stella Gikunju, Lilian Waiboci, Barry Fields, Eyasu Teshale, Gemechu Gerbi, Susan Cookson, Tom Handzel, Miriam Shiferaw, Kevin Clarke
Journal: MMWR Morbidity and Mortality Weekly Report (2013)
Hospitalizations for Inflammatory Bowel Disease Among Medicare Fee-for-Service Beneficiaries — United States, 1999–2017
Authors: Fang Xu, Anne G. Wheaton, Yong Liu, Hua Lu, Kurt J. Greenlund
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel disease (IBD), are conditions characterized by chronic inflammation of the gastrointestinal tract. The incidence and prevalence of IBD is increasing globally, and although the disease has little impact on mortality, the number of older adults with IBD is expected to increase as the U.S. population ages (1). Older adults with IBD have worse hospitalization outcomes than do their younger counterparts (2). CDC analyzed Medicare Provider Analysis and Review (MedPAR) data to estimate IBD-related hospitalization rates and hospitalization outcomes in 2017 among Medicare fee-for-service beneficiaries aged ≥65 years, by selected demographics and trends in hospitalization rates and by race/ethnicity during 1999-2017. In 2017, the age-adjusted hospitalization rate for Crohn's disease was 15.5 per 100,000 Medicare enrollees, and the IBD-associated surgery rate was 17.4 per 100 hospital stays. The age-adjusted hospitalization rate for ulcerative colitis was 16.2 per 100,000 Medicare enrollees, and the surgery rate was 11.2 per 100 stays. During 1999-2017, the hospitalization rate for both Crohn's disease and ulcerative colitis decreased among non-Hispanic white (white) beneficiaries, but not among non-Hispanic black (black) beneficiaries. Health care utilization assessment is needed among black beneficiaries with IBD. Disease management for older adults with IBD could focus on increasing preventive care and preventing emergency surgeries that might result in further complications.
PD-L1 profiling of circulating tumour cells is a viable companion diagnostic for checkpoint inhibitor therapy in lung cancer
Authors: R. Patil, S. Limaye, D. Akolkar, D. Patil, V. Datta, P. Devhare, S. Patel, A. Srinivasan, R. Datar
Journal: Annals of Oncology (2019)
Fever, Abdominal Pain, and Jaundice in a Pacific Islander Woman
Authors: Zao Zhang, Heath Chung, Ting Gong
Journal: JAMA (2019)

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A New CDK9 Inhibitor on the Block to Treat Hematologic Malignancies
Authors: Clara Alcon, Albert Manzano-Muñoz, Joan Montero
Journal: Clinical Cancer Research (2019)

CDK9-specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematologic malignancies preclinical models. This new clinical candidate should be further explored in the clinic not only as a monotherapy but also in combination with BH3 mimetics to prevent treatment resistance.See related article by Cidado et al., p. 922.
Withdrawal of low-dose prednisone in SLE patients with a clinically quiescent disease for more than 1 year: a randomised clinical trial
Authors: Alexis Mathian, Micheline Pha, Julien Haroche, Fleur Cohen-Aubart, Miguel Hié, Marc Pineton de Chambrun, Thi Huong Du Boutin, Makoto Miyara, Guy Gorochov, Hans Yssel, Patrick Cherin, Hervé Devilliers, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2019)

To compare the efficacy to prevent flares of maintenance versus withdrawal of 5 mg/day prednisone in systemic lupus erythematosus (SLE) patients with clinically quiescent disease. A monocentric, 12-month, superiority, open-label, randomised (1:1) controlled trial was conducted with 61 patients continuing 5 mg/day prednisone and 63 stopping it. Eligibility criteria were SLE patients who, during the year preceding the inclusion, had a clinically inactive disease and a stable SLE treatment including 5 mg/day prednisone. The primary endpoint was the proportion of patient experiencing a flare defined with the SELENA-SLEDAI flare index (SFI) at 52 weeks. Secondary endpoints included time to flare, flare severity according to SFI and British Isles Lupus Assessment Group (BILAG) index and increase in the Systemic Lupus International Collaborating Clinics (SLICC) damage index (SDI). Proportion of patients experiencing a flare was significantly lower in the maintenance group as compared with the withdrawal group (4 patients vs 17; RR 0.2 (95% CI 0.1 to 0.7), p=0.003). Maintenance of 5 mg prednisone was superior with respect to time to first flare (HR 0.2; 95% CI 0.1 to 0.6, p=0.002), occurrence of mild/moderate flares using the SFI (3 patients vs 12; RR 0.2 (95% CI 0.1 to 0.8), p=0.012) and occurrence of moderate/severe flares using the BILAG index (1 patient vs 8; RR 0.1 (95% CI 0.1 to 0.9), p=0.013). SDI increase and adverse events were similar in the two treatment groups. Subgroup analyses of the primary endpoint by predefined baseline characteristics did not show evidence of a different clinical response. Maintenance of long term 5 mg prednisone in SLE patients with inactive disease prevents relapse. NCT02558517; Results.
Nivolumab Plus Low-Dose IPILIMUMAB as First-Line Treatment of Advanced NSCLC: Overall Survival Analysis of Checkmate 817
Authors: F. Barlesi, C. Audigier-Valette, E. Felip, T.-E. Ciuleanu, K. Jao, E. Rijavec, L. Urban, J.-S. Aucoin, C. Zannori, K. Vermaelen, O. Arén Frontera, N. Ready, A. Curioni, H. Linardou, E. Poddubskaya, J.R. Fischer, R. Pillai, S. Li, A. Acevedo, L. Paz-Ares
Journal: Annals of Oncology (2019)
DC-HIL/Gpnmb Is a Negative Regulator of Tumor Response to Immune Checkpoint Inhibitors
Authors: Jin-Sung Chung, Vijay Ramani, Masato Kobayashi, Farjana Fattah, Vinita Popat, Song Zhang, Ponciano D. Cruz, David E. Gerber, Kiyoshi Ariizumi
Journal: Clinical Cancer Research (2019)

Immune checkpoint inhibitors (ICI) benefit only a minority of treated patients with cancer. Identification of biomarkers distinguishing responders and nonresponders will improve management of patients with cancer. Because the DC-HIL checkpoint differs from the PD1 pathway in expression and inhibitory mechanisms, we examined whether DC-HIL expression regulates ICI responsiveness.Plasma samples were collected from patients with advanced non-small cell lung carcinoma (NSCLC) (n = 76) at baseline and/or follow-up after ICI monotherapy. Blood-soluble DC-HIL (sDC-HIL) was determined and analyzed for correlation with the early tumor response. To study the mechanisms, we measured effect of anti-DC-HIL versus anti-PDL1 mAb on growth of mouse tumor cells in experimentally metastatic lung. Influence of DC-HIL to anti-PDL1 treatment was assessed by changes in tumor response after deletion of host-DC-HIL gene, injection of DC-HIL-expressing myeloid-derived suppressor cells (MDSC), or induction of sDC-HIL expression.Nonresponders expressed significantly higher levels of baseline sDC-HIL levels than responders. Among patients (n = 28) for fluctuation with time, nonresponders (14/15 cases) showed increasing or persistently elevated levels. Responders (12/13) had decreasing or persistently low levels. Among various tumors, B16 melanoma exhibited resistance to anti-PDL1 but responded to anti-DC-HIL mAb. Using B16 melanoma and LL2 lung cancer, we showed that deletion of host-derived DC-HIL expression converted the resistant tumor to one responsive to anti-PDL1 mAb. The responsive state was reversed by infusion of DC-HIL+MDSC or induction of sDC-HIL expression.sDC-HIL in the blood and probably DC-HIL receptor expressed by MDSC play an important role in regulating response to ICI in advanced NSCLC.
Probabilities of Unranked and Ranked Anomaly Zones under Birth–Death Models
Authors: Anastasiia Kim, Noah A Rosenberg, James H Degnan
Journal: Molecular Biology and Evolution (2019)

Abstract A labeled gene tree topology that is more probable than the labeled gene tree topology matching a species tree is called “anomalous.” Species trees that can generate such anomalous gene trees are said to be in the “anomaly zone.” Here, probabilities of “unranked” and “ranked” gene tree topologies under the multispecies coalescent are considered. A ranked tree depicts not only the topological relationship among gene lineages, as an unranked tree does, but also the sequence in which the lineages coalesce. In this article, we study how the parameters of a species tree simulated under a constant-rate birth–death process can affect the probability that the species tree lies in the anomaly zone. We find that with more than five taxa, it is possible for species trees to have both anomalous unranked and ranked gene trees. The probability of being in either type of anomaly zone increases with more taxa. The probability of anomalous gene trees also increases with higher speciation rates. We observe that the probabilities of unranked anomaly zones are higher and grow much faster than those of ranked anomaly zones as the speciation rate increases. Our simulation shows that the most probable ranked gene tree is likely to have the same unranked topology as the species tree. We design the software PRANC, which computes probabilities of ranked gene tree topologies given a species tree under the coalescent model.
Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis
Authors: Silvana P. Barros, Farahnaz Fahimipour, Robert Tarran, Steven Kim, Raquel Mantuaneli Scarel‐Caminaga, Anne Justice, Kari North
Journal: Periodontology 2000 (2019)

Periodontitis is a chronic multifactorial inﬂammatory disease associated with microbial dysbiosis and characterized by progressive destruction of the periodontal tissues. Such chronic infectious inflammatory disease is recognized as a major public health problem worldwide with measurable impact in systemic health. It has become evident that the periodontal disease phenotypes are not only determined by the microbiome effect, but the extent of the tissue response is also driven by the host genome and epigenome patterns responding to various environmental exposures. More recently there is mounting evidence indicating that epigenetic reprogramming in response to combined intrinsic and environmental exposures, might be particularly relevant due its plasticity and potential application towards precision health. The complex epigenetic crosstalk is reflected in the prognosis and progress of periodontal diseases and may also lead to a favorable landscape for cancer development. This review discusses epigenomics modifications focusing on the role of DNA methylation and pathways linking microbial infection and inflammatory pathways, which are also associated with carcinogenesis. There is a more clear vision whereas 'omics' technologies applied to unveil relevant epigenetic factors could play a significant role in the treatment of periodontal disease in a personalized mode, evidencing that public health approach should coexist with precision individualized treatment.
Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects
Authors: Theodosia A. Kalfa, Frans A Kuypers, Marilyn J. Telen, Punam Malik, Diamantis G. Konstantinidis, Jeremy H. Estepp, Hyon J. Kim, Santosh L. Saraf, Lindsey Wilson, Maria D Ribadeneira, Sanjeev Forsyth, Patricia Schroeder, Adam Drake, Olga Polyanskaya, Patrick Kelly, Lukasz Biernat
Journal: Blood (2019)
Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies
Authors: Gabrielle M. Siegers, Mahima Swamy, Edgar Fernández-Malavé, Susana Minguet, Sylvia Rathmann, Alberto C. Guardo, Verónica Pérez-Flores, Jose R. Regueiro, Balbino Alarcón, Paul Fisch, Wolfgang W.A. Schamel
Journal: The Journal of Experimental Medicine (2007)

The γδ T cell receptor for antigen (TCR) comprises the clonotypic TCRγδ, the CD3 (CD3γε and/or CD3δε), and the ζζ dimers. γδ T cells do not develop in CD3γ-deficient mice, whereas human patients lacking CD3γ have abundant peripheral blood γδ T cells expressing high γδ TCR levels. In an attempt to identify the molecular basis for these discordant phenotypes, we determined the stoichiometries of mouse and human γδ TCRs using blue native polyacrylamide gel electrophoresis and anti-TCR–specific antibodies. The γδ TCR isolated in digitonin from primary and cultured human γδ T cells includes CD3δ, with a TCRγδCD3ε2δγζ2 stoichiometry. In CD3γ-deficient patients, this may allow substitution of CD3γ by the CD3δ chain and thereby support γδ T cell development. In contrast, the mouse γδ TCR does not incorporate CD3δ and has a TCRγδCD3ε2γ2ζ2 stoichiometry. CD3γ-deficient mice exhibit a block in γδ T cell development. A human, but not a mouse, CD3δ transgene rescues γδ T cell development in mice lacking both mouse CD3δ and CD3γ chains. This suggests important structural and/or functional differences between human and mouse CD3δ chains during γδ T cell development. Collectively, our results indicate that the different γδ T cell phenotypes between CD3γ-deficient humans and mice can be explained by differences in their γδ TCR composition.
In bone and joint infection, oral antibiotic therapy was noninferior to IV therapy and reduced costs
Authors: Thomas Fekete
Journal: Annals of Internal Medicine (2019)

Source Citation Scarborough M, Li HK, Rombach I, et al. Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT. Health Technol Assess. 2019;23:1-92. 31373271
Abstract 11187: Atrial Fibrillation in Women With Acute Myocardial Infarction: Insights From a 20-Years Registry in Qatar (1991-2010)
Authors: Amar M Salam, Hajar AlBinali, Rajvir Singh, Awad Al-Qahtani, Nidal Asaad, Jassim Al-Suwaidi
Journal: Circulation (2014)

Objectives: There is very scarce data on women with atrial fibrillation (AF) in the setting of acute myocardial infarction (AMI). The aim of this study was to compare women and men with AF during hospitalization with AMI in a real-world population. Methods: Retrospective analysis of all patients hospitalized with AMI and AF in Qatar from 1991 through 2010 was made. Patients were divided into two groups according to gender. Clinical characteristics, management and outcomes were analyzed. Results: During the 20-years period, 12871 patients were hospitalized with AMI; 1611 women and 11260 men. Of these 227 patients developed AF during hospitalization; 69 women (4.3%) and 158 men (1.4%), p &lt;0.05. Women with AF were 6 years older and had significantly higher rates of hypertension (72.5% vs. 44.3%), diabetes mellitus (66.7% vs. 43%), dyslipidemia (18.8% vs. 7.6%) and chronic renal impairment (8.7% vs. 7%) compared to men [all P=0.001]. Non ST-elevation AMI was the commonest underlying type of AMI in both sexes and it was more common in women compared to men (81.2% vs. 67.7%, P= 0.04). Women with AF had significantly longer hospital stay compared to men (8.5 days versus 6 days, p=0.02) whereas in-hospital mortality and stroke rates were comparable between the two groups [table]. Conclusions: We report significant risk profiles differences and a higher prevalence of AF following AMI in women. Further studies are warranted to further explore and confirm this observation in larger registries.
Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia
Authors: Konstanze Döhner, Christian Thiede, Nikolaus Jahn, Ekaterina Panina, Agnes Gambietz, Richard A. Larson, Thomas W. Prior, Guido Marcucci, Dan Jones, Jürgen Krauter, Michael Heuser, Maria Teresa Voso, Tiziana Ottone, Josep F. Nomdedeu, Sumithra J. Mandrekar, Rebecca B. Klisovic, Andrew H. Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, Theo de Witte, Joop H. Jansen, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C. Medeiros, Martin S. Tallman, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori, Insa Gathmann, Axel Benner, Celine Pallaud, Richard M. Stone, Hartmut Döhner, Clara D. Bloomfield
Journal: Blood (2019)