tbuckley/cabot-search huggingface dataset:
Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions
Authors: Rucha Pandit, Gerhard Leinenga, Jürgen Götz
Journal: Theranostics (2019)

Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model. Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments. Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes. Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.
Abstract 16488: Genome-Wide Multi-Ancestry Meta-Analyses Identifies Novel Loci for Blood Pressure Through Gene-Social Support Interaction
Authors: Melissa A Richard, Solomon K Musani, Alanna C Morrison, Xiuqing Guo, Walter R Palmas, Bruce M Psaty, Nora Franceschini, Mario Sims, Myriam Fornage
Journal: Circulation (2017)

Social support is the availability of individuals to turn to in times of need or stress and is associated with cardiovascular health. We hypothesized that social support may modify the biological r...
PB2356 IMPACT OF ABO BLOOD GROUP INCOMPATIBILITY ON THE OUTCOMES OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: R. Çiftçiler, H. Goker, Y. Buyukasık, S. Aksu, H. Demiroglu
Journal: HemaSphere (2019)

Background: Impact of ABO Blood Group Incompatibility on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation Aims: ABO and Rh compatibility are not required between the donor and recipient for alloHSCT. Although ABO incompatibility is not considered a contraindication in HSCT, its clinical outcomes are still a doubtful. In this study, we analyzed the neutrophil and platelet recovery, GVHD, relapse rate, mortality rate, non‐relapse mortality and survival in patients who underwent alloHSCT. Methods: Two hundred and sixty eight patients with hematopoietic malign diseases and inborn errors of metabolism or the immune system who received an alloHSCT in our HSC transplant center between the years of 2001 and 2018 were evaluated. Results: There were 264 (98.5%) matched sibling, and 4 (1.5%) haploidentic transplants. Indications for HSCT included both hematological malignancies (n = 261) and benign conditions (n = 7). Of these donor recipient pairs, there were 193 (72%) matches, 36 (13.4%) major, 29 (10.8%) minor and 10 (3.7%) bidirectional ABO mismatches. The median follow‐up of 120 months (range, 6‐213) for the entire group. The OS and DFS were not statistically significant different between two groups. The seventy one (41.1%) of the ABO match patients and 27 (35.5%) of the ABO mismatch patients developed GvHD. There was no significant difference between the two groups in terms of GvHD (p = 0.86). The median neutrophil engraftment day was 11 (7‐20) day in ABO match patients and 11 (7‐19) day in ABO mismatch patients (p = 0.44). The median platelet engraftment day was 12 (8‐38) day in ABO match patients and 12 (8‐40) day in ABO mismatch patients (p = 0.48). Summary/Conclusion: In conclusion, this study showed major ABO incompatibility does not lead mainly to delayed RBC recovery, platelet engraftment and neutrophil engraftment after alloHSCT. Major ABO mismatch does not seem to have a significant effect on other major outcomes after alloHSCT, such as GVHD, relapse rate, mortality rate, non‐relapse mortality rate, DFS and OS. image
Association of Opioid Overdose With Opioid Prescriptions to Family Members
Authors: Nazleen F. Khan, Brian T. Bateman, Joan E. Landon, Joshua J. Gagne
Journal: JAMA Internal Medicine (2019)

Prescription opioid misuse is a public health problem that leads to overdose. Although existing interventions focus on limiting prescribing to patients at high risk, individuals may still access prescription opioids dispensed to family members.To determine whether opioid prescriptions to family members were associated with overdose for individuals who themselves did not have an opioid prescription.We conducted a 1:4 matched case-control study using health care utilization data from 2004 through 2015 from a large US commercial insurance company. Eligible individuals were required to have at least 12 months of continuous enrollment and 1 or more family members in the database. Individuals who experienced overdose were identified by their first opioid overdose after the baseline period and matched to control participants by time in the database, calendar time, age, sex, and number of individuals in the family unit. Both groups were restricted to individuals with no prior opioid dispensing of their own. Data analysis was conducted from January 2018 to August 2018.Any prior opioid dispensing to a family member, total morphine milligram equivalents dispensed to family members, and the type of opioid product dispensed.Individual odds of opioid overdose resulting in an emergency department visit or hospitalization were the primary end point. The primary analysis evaluated the odds of overdose among individuals whose family members had been dispensed an opioid. Sensitivity analyses examined the odds stratified by age and timing relative to the dispensing of opioids to family members.A total of 2303 individuals who experienced opioid overdose and 9212 matched control individuals were identified. The mean (SD) age was 23.2 (18.1) years; 1158 affected individuals and 4632 control individuals (50.3%) were female. The mean (SD) time in the database before an overdose case was 3.2 (3.3) years. Prior opioid dispensing to family members was associated with individual overdose (odds ratio [OR], 2.89 [95% CI, 2.59-3.23]). There was a significant dose-response association between increasing amounts of opioids dispensed to family members and odds of overdose (>0-<50 morphine milligram equivalents per day: OR, 2.71 [95% CI, 2.42-3.03]; 50-<90 morphine milligram equivalents per day: OR, 7.80 [95% CI, 3.63-16.78]; ≥90 morphine milligram equivalents per day: OR, 15.08 [95% CI, 8.66-26.27]).In this analysis, opioid prescriptions to family members were associated with overdose among individuals who do not receive opioid prescriptions. Interventions may focus on expanding access to opioid antagonists, locking prescription opioids in the home, and providing greater patient education to limit fatal overdose among family members.
Tissue adaptation: Implications for gut immunity and tolerance
Authors: Ana M.C. Faria, Bernardo S. Reis, Daniel Mucida
Journal: The Journal of Experimental Medicine (2017)

Tissue adaptation is an intrinsic component of immune cell development, influencing both resistance to pathogens and tolerance. Chronically stimulated surfaces of the body, in particular the gut mucosa, are the major sites where immune cells traffic and reside. Their adaptation to these environments requires constant discrimination between natural stimulation coming from harmless microbiota and food, and pathogens that need to be cleared. This review will focus on the adaptation of lymphocytes to the gut mucosa, a highly specialized environment that can help us understand the plasticity of leukocytes arriving at various tissue sites and how tissue-related factors operate to shape immune cell fate and function.
Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts
Authors: Hung-Ming Lam, Holly M. Nguyen, Mark P. Labrecque, Lisha G. Brown, Ilsa M. Coleman, Roman Gulati, Bryce Lakely, Daniel Sondheim, Payel Chatterjee, Brett T. Marck, Alvin M. Matsumoto, Elahe A. Mostaghel, Michael T. Schweizer, Peter S. Nelson, Eva Corey
Journal: European Urology (2019)
AB1306 PILOT STUDY OF ADHERENCE IN PATIENTS WITH RHEUMATOLOGICAL DISEASES AUTOIMMUNE
Authors: E.C. Cervantes Pérez, Jose Ramón Maneiro Fernández, Begoña Moreira, José Antonio Mosquera Martínez, Natalia Bea, Susana Romero-Yuste
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Data on adherence in patients with autoimmune rheumatological diseases are limited. <h3>Objectives:</h3> To analyze the adherence to treatment in patients with autoimmune rheumatological diseases. <h3>Methods:</h3> A cross-sectional study was performed in patients from the Complexo Hospitalario Universitario de Pontevedra with diagnosis of systemic lupus erythematosus (SLE), Sjögren's Syndrome (SS) and Systemic Sclerosis (SE). The patients filled an anonymous survey that included data about demographic, diagnosis and treatment. Adherence to treatment was assessed using the Spanish Compliance Questionnaire in Rheumatology (sCQR). [1] Likewise, a linear regression analysis was carried out in order to identify factors related to adherence to treatment. A significant value was considered as p &lt; 0.05. Stata version 11.1 (Stata/IC 11.1 for Windows, StataCorp LP, College Station, TX) was used to perform all analyzes. <h3>Results:</h3> A total of 44 patients participated in the study, although 90.9% of the surveys carried out could be used for the analysis. A total of 25 (62.5%) SLE, 9 (22.5%) SS and 6 (15.0%) SE patients participated. There were 82.5% of women and the mean age was 48.9 ± 12.8 (See Table 1). According to the sCQR 82.5% were compliant patients. None of the studied variables was associated with the adherence rate: sex (p = 1.000), age (0.134), time of evolution (p = 1.000), level of education (p = 0.677), marital status (0.392), illness (p = 1.000), number of drugs ingested per day (p = 0.873), treatment with steroids (p = 0.679) or antimalarials (p = 1.000). <h3>Conclusion:</h3> The adherence rate in our cohort was 82.5% higher than previously reported in other studies. [2,3] The sCQR could be a useful and easy-to-apply tool for the study of adherence in these patients. <h3>References</h3> [1] Salgado E, Maneiro Fernandez JR, Souto Vilas A, Gomez-Reino JJ. Correction to: Spanish transcultural adaptation and validation of the English version of the compliance questionnaire in rheumatology. Rheumatol Int 2018. [2] Feldman CH, Yazdany J, Guan H, Solomon DH, Costenbader KH. Medication nonadherence is associated with increased subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus. Arthritis Care Res 2015;67:1712–21. [3] Alsowaida N, Alrasheed M, Mayet A, Alsuwaida A, Omair MA. Medication adherence, depression and disease activity among patients with systemic lupus erythematosus. Lupus. 2018 Feb;27(2):327-332. doi: 10.1177/0961203317725585. Epub 2017 Aug 21. PubMed PMID: 28825347. <h3>Disclosure of Interests:</h3> None declared
Fast Genome-Wide Functional Annotation through Orthology Assignment by eggNOG-Mapper
Authors: Jaime Huerta-Cepas, Kristoffer Forslund, Luis Pedro Coelho, Damian Szklarczyk, Lars Juhl Jensen, Christian von Mering, Peer Bork
Journal: Molecular Biology and Evolution (2017)

Orthology assignment is ideally suited for functional inference. However, because predicting orthology is computationally intensive at large scale, and most pipelines are relatively inaccessible (e.g., new assignments only available through database updates), less precise homology-based functional transfer is still the default for (meta-)genome annotation. We, therefore, developed eggNOG-mapper, a tool for functional annotation of large sets of sequences based on fast orthology assignments using precomputed clusters and phylogenies from the eggNOG database. To validate our method, we benchmarked Gene Ontology (GO) predictions against two widely used homology-based approaches: BLAST and InterProScan. Orthology filters applied to BLAST results reduced the rate of false positive assignments by 11%, and increased the ratio of experimentally validated terms recovered over all terms assigned per protein by 15%. Compared with InterProScan, eggNOG-mapper achieved similar proteome coverage and precision while predicting, on average, 41 more terms per protein and increasing the rate of experimentally validated terms recovered over total term assignments per protein by 35%. EggNOG-mapper predictions scored within the top-5 methods in the three GO categories using the CAFA2 NK-partial benchmark. Finally, we evaluated eggNOG-mapper for functional annotation of metagenomics data, yielding better performance than interProScan. eggNOG-mapper runs ∼15× faster than BLAST and at least 2.5× faster than InterProScan. The tool is available standalone and as an online service at http://eggnog-mapper.embl.de.
DNA Topoisomerase I differentially modulates R-loops across the human genome
Authors: Stefano G. Manzo, Stella R. Hartono, Lionel A. Sanz, Jessica Marinello, Sara De Biasi, Andrea Cossarizza, Giovanni Capranico, Frederic Chedin
Journal: Genome biology (2018)

Co-transcriptional R-loops are abundant non-B DNA structures in mammalian genomes. DNA Topoisomerase I (Top1) is often thought to regulate R-loop formation owing to its ability to resolve both positive and negative supercoils. How Top1 regulates R-loop structures at a global level is unknown. Here, we perform high-resolution strand-specific R-loop mapping in human cells depleted for Top1 and find that Top1 depletion results in both R-loop gains and losses at thousands of transcribed loci, delineating two distinct gene classes. R-loop gains are characteristic for long, highly transcribed, genes located in gene-poor regions anchored to Lamin B1 domains and in proximity to H3K9me3-marked heterochromatic patches. R-loop losses, by contrast, occur in gene-rich regions overlapping H3K27me3-marked active replication initiation regions. Interestingly, Top1 depletion coincides with a block of the cell cycle in G0/G1 phase and a trend towards replication delay. Our findings reveal new properties of Top1 in regulating R-loop homeostasis in a context-dependent manner and suggest a potential role for Top1 in modulating the replication process via R-loop formation.
Optimal timing of radioactive tracer for sentinel node biopsy in breast cancer patients
Authors: N. P. Reuter, M. R. Bower, C. R. Scoggins, R. C. Martin, K. M. McMasters, A. B. Chagpar
Journal: Journal of Clinical Oncology (2009)

611 Background: While sentinel node biopsy (SNB) is well established as a minimally invasive means of staging the axilla in breast cancer patients, the optimal timing of injection of technetium 99m sulfur colloid (Tm) for SNB remains unclear. Methods: In a prospective multicenter study of 4131 patients who had a SNB for breast cancer followed by axillary node dissection, 3305 patients had a SNB using Tm with the elapsed time from injection to SNB being recorded. These 3305 patients formed the cohort of interest for this study. The dose of Tm remaining at the time of SNB was calculated with the formula mCi remaining =mCi injected *0.5^(elapsed hours/6). Patients with injection of Tm ≤12h and &gt;12h were compared using SPSS. Results: The mean age of the 3305 patients in this study was 60 years, with a mean tumor size of 1.8 cm. A sentinel node (SN) was identified in 95% of patients. SN identification (ID) was not affected by mCi injected (p=0.88), mCi remaining at time of SNB (p=0.13), or type of Tm (filtered vs. unfiltered, p=0.37). There was a statistically non-significant trend of more SN's removed in the ≤12h group (3.2 vs. 2.5, p=0.06). False negative rate was not affected by mCi injected (p=0.39), mCi remaining at time of SNB (p=0.24), or type of Tm (filtered vs. unfiltered, p=1.00). The overall false negative (FN) rate was 8.0%. Of the 3305 patients in this study, 3221 were injected ≤12h prior to SNB and 84 were injected &gt;12h prior to SNB. For the patients injected ≤12h compared to &gt;12h, there was no difference in SN ID rate, FN rate, counts of the hottest node, or background counts despite more mCi injected and less mCi remaining at SNB in the &gt;12h cohort (see Table). Conclusions: Injecting Tm &gt;12h prior to SNB has an acceptable SN identification rate, and the FN rate was not significantly different than injecting Tm ≤12h prior to SNB. [Table: see text] No significant financial relationships to disclose.
The Evolving Modern Management of Brain Metastasis
Authors: Peter E. Fecci, Cosette D. Champion, Jacob Hoj, Courtney M. McKernan, C. Rory Goodwin, John P. Kirkpatrick, Carey K. Anders, Ann Marie Pendergast, John H. Sampson
Journal: Clinical Cancer Research (2019)

The incidence of brain metastases is increasing as cancer therapies improve and patients live longer, providing new challenges to the multidisciplinary teams that care for these patients. Brain metastatic cancer cells possess unique characteristics that allow them to penetrate the blood-brain barrier, colonize the brain parenchyma, and persist in the intracranial environment. In addition, brain metastases subvert the innate and adaptive immune system, permitting evasion of the antitumor immune response. Better understanding of the above mechanisms will allow for development and delivery of more effective therapies for brain metastases. In this review, we outline the molecular mechanisms underlying development, survival, and immunosuppression of brain metastases. We also discuss current and emerging treatment strategies, including surgery, radiation, disease-specific and mutation-targeted systemic therapy, and immunotherapy.
The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies
Authors: Iris Dotan, Matthieu Allez, Silvio Danese, Mary Keir, Swati Tole, Jacqueline McBride
Journal: Medicinal Research Reviews (2019)

Abstract Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.
CRISPR–Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity
Authors: Nicholas J. Kramer, Michael S. Haney, David W. Morgens, Ana Jovičić, Julien Couthouis, Amy Li, James Ousey, Rosanna Ma, Gregor Bieri, C. Kimberly Tsui, Yingxiao Shi, Nicholas T. Hertz, Marc Tessier-Lavigne, Justin K. Ichida, Michael C. Bassik, Aaron D. Gitler
Journal: Nature Genetics (2018)
Abstract 16144: Regional Variations in Mortality in Patients With Heart Failure Across Asia: Outcomes in the ASIAN-HF Registry
Authors: Michael R Macdonald, Wan Ting Tay, Tiew-Hwa Katherine Teng, Jasper Tromp, Jonathan Yap, Inder Anand, Carolyn Lam
Journal: Circulation (2017)

Introduction: Heart failure(HF) is a global epidemic. Despite Asia holding 60% of the world’s population, there is a paucity of comparative outcome data in patients with HF across Asia. Methods: AS...
AB0310 THE INCIDENCE OF EXTRA-ARTICULAR MANIFESTATIONS IN SOUTHERN CHINESE PATIENTS WITH INFLAMMATORY JOINT DISEASES
Authors: Siyu Yan, Yang Cui, Xiao Zhang
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Inflammatory joint diseases (IJDs) are chronic arthritis, but frequently present with co-morbidities of other organs and systems, which is known as extra-articular manifestations (EAMs) <sup>1</sup>. It is still unclear which clinical characteristics or bio-markers can predict the development of EAMs<sup>2</sup>. <h3>Objectives</h3> The aim of this study was to estimate the proportion of EAMs in southern Chinese patients with IJDs and to explore the risk factors. <h3>Methods</h3> This was a retrospective cohort study of a total 1135 IJDs patients, including 788 rheumatoid arthritis (RA) patients, 307 ankylosing spondylitis (AS) patients and 40 psoriatic arthritis (PsA) patients. Demographic data, disease characteristics, laboratory blood tests, medical imaging, and the presence of EAMs were recorded. <h3>Results</h3> We found 459 (40.44%) of them presented with EAMs: 30.84% had cardiovascular; 7.67% had pulmonary, 5.29% had osteoporosis/low bone mineral density, 2.29% had ocular, 0.79% had gastrointestinal and 0.26% had renal involvements. Multivariate logistic regression showed older age (OR: 1.05, P&lt;0.001) and higher anti-cyclic citrullinated peptide antibody (anti-CCP) levels (OR: 1.003, P=0.011) were independent risks of EAMs in RA patients. In AS group, older age (OR: 1.07, P&lt;0.001) and higher disease activity (OR: 2.06, P&lt;0.001), were independent risks of EAMs. As in PsA group, longer disease duration (OR: 1.01, P=0.046) and higher disease activity (OR: 1.15, P=0.011) were independent risks. <h3>Conclusion</h3> These results suggested the high prevalence of EAMs, and it is important to regularly screen on EAMs, as it influences treatment decision and impacts on patients' quality of life. <h3>References</h3> [1] Agca R, Heslinga SC, van Halm VP, Nurmohamed MT. Atherosclerotic cardiovascular disease in patients with chronic inflammatory joint disorders. Heart2016;102:790-5. [2] Carmen Stolwijk AvT, José Dionisio Castillo-Ortiz AB. revalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis. Ann Rheum Dis2015;74:65–73. <h3>Disclosure of Interests</h3> None declared