tbuckley/cabot-search huggingface dataset:
Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes
Authors: Sarah H. Shahmoradian, Amanda J. Lewis, Christel Genoud, Jürgen Hench, Tim E. Moors, Paula P. Navarro, Daniel Castaño-Díez, Gabriel Schweighauser, Alexandra Graff-Meyer, Kenneth N. Goldie, Rosmarie Sütterlin, Evelien Huisman, Angela Ingrassia, Yvonne de Gier, Annemieke J. M. Rozemuller, Jing Wang, Anne De Paepe, Johannes Erny, Andreas Staempfli, Joerg Hoernschemeyer, Frederik Großerüschkamp, Daniel Niedieker, Samir F. El-Mashtoly, Marialuisa Quadri, Wilfred F. J. Van IJcken, Vincenzo Bonifati, Klaus Gerwert, Bernd Bohrmann, Stephan Frank, Markus Britschgi, Henning Stahlberg, Wilma D. J. Van de Berg, Matthias E. Lauer
Journal: Nature Neuroscience (2019)
Neurturin-containing laminin matrices support innervated branching epithelium from adult epithelial salispheres
Authors: K.H. Vining, I.M.A. Lombaert, V.N. Patel, S.E. Kibbey, S. Pradhan-Bhatt, R.L. Witt, M.P. Hoffman
Journal: Biomaterials (2019)

Cell transplantation of autologous adult biopsies, grown ex vivo as epithelial organoids or expanded as spheroids, are proposed treatments to regenerate damaged branching organs. However, it is not clear whether transplantation of adult organoids or spheroids alone is sufficient to initiate a fetal-like program of branching morphogenesis in which coordinated branching of multiple cell types including nerves, mesenchyme and blood vessels occurs. Yet this is an essential concept for the regeneration of branching organs such as lung, pancreas, and lacrimal and salivary glands. Here, we used factors identified from fetal organogenesis to maintain and expand adult murine and human epithelial salivary gland progenitors in non-adherent spheroid cultures, called salispheres. These factors stimulated critical developmental pathways, and increased expression of epithelial progenitor markers such as Keratin5, Keratin14, FGFR2b and KIT. Moreover, physical recombination of adult salispheres in a laminin-111 extracellular matrix with fetal salivary mesenchyme, containing endothelial and neuronal cells, only induced branching morphogenesis when neurturin, a neurotrophic factor, was added to the matrix. Neurturin was essential to improve neuronal survival, axon outgrowth, innervation of the salispheres, and resulted in the formation of branching structures with a proximal-distal axis that mimicked fetal branching morphogenesis, thus recapitulating organogenesis. Epithelial progenitors were also maintained, and developmental differentiation programs were initiated, showing that the fetal microenvironment provides a template for adult epithelial progenitors to initiate branching and differentiation. Further delineation of secreted and physical cues from the fetal niche will be useful to develop novel regenerative therapies that instruct adult salispheres to resume a developmental-like program in vitro and to regenerate branching organs in vivo.
AB0821 APPRECIATION OF OSTEOPOROTIC TREATMENT COMPLIANCE WITH ALENDRONATE 70MG ORALLY
Authors: Bilal Bengana, Abdenour Boukabous, Naima Bahaz, Salima Lefkir
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Patients suffering from osteoporosis (OP) dont have the opportunity to enjoy from an accurate and concrete parameters response to OP treatment. They therefore have no palpable evidence of the favorable effect generated by anti- osteoporotic treatment (AOT), given the silent nature of the pathology. That is way we see the non-compliance with treatment in some patients. <h3>Objectives</h3> It was essential to estimate the extent of the lack of compliance with AOT in order to deduce the factors related to this deficiency in order to reduce the size of the problem. <h3>Methods</h3> Its a Descriptive cross study performed in all patients over 38 years for both sexes and that exhibit post menopausal or corticosteroid-induced OP justifying AOT orally ( alendronate 70mg oraly per week) observed over a period of at least 6months. <h3>Results</h3> We collected data of 153 patients, in 9 out of 10 cases this was a woman, the mean age was 59.3 ± 8.1 years, the average duration of gain of treatment was 32.2 ± 18.2 months, 3 of 5 patients believe that treatment is for musculoskeletal pains, 1/3 of respondents confess not to take their weekly treatment regularly, regular physical activity was performed by only 21% of patients, the factors related to non-compliance were : lack of education (p = 0, 032) and sedentary lifestyle (p = 0, 044). <h3>Conclusion</h3> OP is unfortunately underestimated by both patients and physicians, and its short- and long- term repercussions are often minimized. Our study has shown that the various measures required in its management are poorly followed by patients despite their proven effectiveness in reducing fractures.One in three patients in ours ample do not follow their treatment properly.Therapeutic education seems to be the answer to overcome this lack of adhesion. <h3>Disclosure of Interests</h3> None declared
Translational contributions to tissue specificity in rhythmic and constitutive gene expression
Authors: Violeta Castelo-Szekely, Alaaddin Bulak Arpat, Peggy Janich, David Gatfield
Journal: Genome biology (2017)

The daily gene expression oscillations that underlie mammalian circadian rhythms show striking differences between tissues and involve post-transcriptional regulation. Both aspects remain poorly understood. We have used ribosome profiling to explore the contribution of translation efficiency to temporal gene expression in kidney and contrasted our findings with liver data available from the same mice.Rhythmic translation of constantly abundant messenger RNAs (mRNAs) affects largely non-overlapping transcript sets with distinct phase clustering in the two organs. Moreover, tissue differences in translation efficiency modulate the timing and amount of protein biosynthesis from rhythmic mRNAs, consistent with organ specificity in clock output gene repertoires and rhythmicity parameters. Our comprehensive datasets provided insights into translational control beyond temporal regulation. Between tissues, many transcripts show differences in translation efficiency, which are, however, of markedly smaller scale than mRNA abundance differences. Tissue-specific changes in translation efficiency are associated with specific transcript features and, intriguingly, globally counteracted and compensated transcript abundance variations, leading to higher similarity at the level of protein biosynthesis between both tissues.We show that tissue specificity in rhythmic gene expression extends to the translatome and contributes to define the identities, the phases and the expression levels of rhythmic protein biosynthesis. Moreover, translational compensation of transcript abundance divergence leads to overall higher similarity at the level of protein production across organs. The unique resources provided through our study will serve to address fundamental questions of post-transcriptional control and differential gene expression in vivo.
Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis
Authors: Michael R. Wilson, Hannah A. Sample, Kelsey C. Zorn, Shaun Arevalo, Guixia Yu, John Neuhaus, Scot Federman, Doug Stryke, Benjamin Briggs, Charles Langelier, Amy Berger, Vanja Douglas, S. Andrew Josephson, Felicia C. Chow, Brent D. Fulton, Joseph L. DeRisi, Jeffrey M. Gelfand, Samia N. Naccache, Jeffrey Bender, Jennifer Dien Bard, Jamie Murkey, Magrit Carlson, Paul M. Vespa, Tara Vijayan, Paul R. Allyn, Shelley Campeau, Romney M. Humphries, Jeffrey D. Klausner, Czarina D. Ganzon, Fatemeh Memar, Nicolle A. Ocampo, Lara L. Zimmermann, Stuart H. Cohen, Christopher R. Polage, Roberta L. DeBiasi, Barbara Haller, Ronald Dallas, Gabriela Maron, Randall Hayden, Kevin Messacar, Samuel R. Dominguez, Steve Miller, Charles Y. Chiu
Journal: New England Journal of Medicine (2019)

Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test.In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review.We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment.Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).
Recent achievements in developing selective G<sub>q</sub> inhibitors
Authors: Hang Zhang, Alexander L. Nielsen, Kristian Strømgaard
Journal: Medicinal Research Reviews (2019)

G proteins are key mediators of G protein-coupled receptor (GPCR) signaling, facilitating a plethora of important physiological processes. The role of G proteins is much less understood than other aspects of GPCR function, which is largely due to the shortage of potent and selective G protein inhibitors. The natural cyclic depsipeptides YM-254890 and FR900359 are two of the very few known selective inhibitors of the Gq subfamily, and are used as unique pharmacological tools in the study of G q -mediated signaling. Moreover, a peptide-based G protein antagonist-2A (GP-2A), a 27-residue peptide (27mer(I860A)) derived from phospholipase C-β3 (PLC-β3), and the small molecule BIM-46187 have also been characterized as selective G q inhibitors within the past 5 years. In this review, we highlight the recent development in chemical syntheses, characterization, and mechanism of action of these selective G q inhibitors. The development and application of G q -selective inhibitors will expand our knowledge of the structure and function of G protein-mediated signaling, shed light on the development of inhibitors for other G protein classes, and feed in to drug discovery for diseases where G proteins are implicated, including various forms of cancer.
Abstract 20185: Maintained Coronary Perfusion Pressure by Extracorporeal Membrane Oxygenation Preserves Cardiac Mitochondrial Function in a Swine Model of Cardiac Arrest Independent of Ischemic Postconditioning
Authors: Timothy R Matsuura, Pierre S Sebastian, Scott H McKnite, Kadambari C Shekar, Madhusudana R Vuda, Jason A Bartos, Matthew D Olson, Jennifer N Rees, Matthias L Riess, Robert W Neumar, Tom P Aufderheide, Demetri Yannopoulos
Journal: Circulation (2017)

Introduction: Ischemic postconditioning (IPC) at the onset of cardiopulmonary resuscitation (CPR) has been shown to increase coronary perfusion pressure (CPP) and cardiac mitochondrial function aft...
Pharmacokinetics (PK) of split-dose flavopiridol (F) administered with CPT-11 (CPT) and cisplatin (Cis)
Authors: R. D. Carvajal, A. Tse, N. Wu, M. Gonen, R. Lefkowitz, H. Dials, A. Barbi, J. Mui, G. K. Schwartz, M. Shah
Journal: Journal of Clinical Oncology (2007)

2578 Background: F, a cyclin-dependent kinase inhibitor, induces tumor lysis in CLL when administered as a 30 mg/m 2 loading dose over 0.5h followed by a 30 mg/m 2 maintenance dose over 4h (hybrid F; Byrd et al, Blood 2006). F given as a 1h bolus (bolus F) demonstrates promising clinical activity when combined with CPT in solid tumors (Shah et al, CCR 2005). Data suggest that F concentrations of 2–3 μM are required to enhance the effects of CPT in solid tumors (Motwani et al, CCR 2001), but controversy exists over the optimal F schedule for chemotherapy potentiation. Methods: We are conducting a phase I trial of CPT/Cis→F, with F administered on both a bolus F and hybrid F schedule. After identifying the maximum tolerated dose (MTD) of bolus F (CPT/Cis→F 50mg/m 2 ), the hybrid F schedule was examined. The F loading dose was escalated from 20→30mg/m 2 and the F maintenance dose escalated from 20→50mg/m 2 . Plasma samples were obtained from patients (pts) treated with bolus F at the MTD and with hybrid F at all dose levels. To better assess F PK interaction with CPT/Cis, F was given before CPT/Cis on cycle 2 only. Results: Complete PK data are available from 6 pts treated at the bolus F MTD (50 mg/m 2 ) and on 20 pts treated with hybrid F (20→20 mg/m 2 , 25→25 mg/m 2 and 30→30 mg/m 2 ) for cycles 1 and 2. Both bolus F and hybrid F PK are consistent with data previously reported. Although cycle 1 AUCs are similar for bolus F 50 mg/m 2 and hybrid F 30→30 mg/m 2 (10.47±4.97 vs 10.75±15.14 μM/h, p=NS), the Cmax achieved with bolus F 50 mg/m 2 is significantly greater than that achieved with hybrid F 30→30 mg/m 2 (2.31±0.65 vs 1.21±0.35 μM, p&lt;0.02). No significant PK differences occurred between cycles 1 and 2. Toxicity was not associated with F Cmax. With CPT/Cis→bolus F, the PR rate was 10/29 (35%) vs 3/33 (9%) with CPT/Cis→hybrid F. Conclusions: The Cmax achieved with bolus F is greater than that achieved with hybrid F, with no increase in toxicity. Additionally, the Cmax achieved with hybrid F does not exceed the 2 μM plasma concentration required for potentiation of chemotherapy-induced apoptosis. The greater number of responses achieved with bolus F suggests that bolus F may be more efficacious than hybrid F when used in combination with CPT for the treatment of solid tumors. (Supported by R01-CA67819) No significant financial relationships to disclose.
Abstract 12693: Influence of Resting Heart Rate and Changes in Resting Heart Rate on Cardiovascular Outcomes From the Atherosclerosis Risk in Communities Study
Authors: Ali Vazir, Brian Claggett, Amil Shah, Hicham Skali, Susan Cheng, Christie M Ballantyne, David Aguilar, Orly Vardeny, Scott D Solomon
Journal: Circulation (2014)

Background: Resting heart rate (HR) and change in resting heart rate (ΔHR) over time are associated with increased risk of adverse outcome in patients with established heart failure (HF). We assessed whether the most recent HR and ΔHR are associated with cardiovascular (CV) outcomes in participants enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Methods: We studied 15,680 participants with HR recorded at baseline (age 54±6 years, women 55%, African American 27%) and over 3 follow-up visits with a median time interval between visits of 3.0 (IQR 2.9-4.0) years. ΔHR from the preceding visit was calculated. Participants were followed up for a median of 22.7 (19.8-23.7) years. We related baseline and most recent resting HR and ΔHR to all cause mortality and CV outcomes adjusting for established baseline and time-updated risk factors and medications. Results: Baseline and most recent HR and ΔHR were associated with all-cause mortality and CV outcomes (table), however most recent HR and ΔHR were more strongly associated with outcomes compared to baseline HR. Every 10bpm increase in HR from the preceding visit was associated with a 29%, 30% 22% and 15% increase risk of all-cause mortality, incident HF, incident MI and stroke respectively. Every 10 bpm higher most recent HR was associated with a 34%, 41% 23% and 14% increase risk of all-cause mortality, incident HF, incident MI and stroke respectively. Conclusion: In a community-based cohort, the most recent resting HR and ΔHR are strongly associated with outcomes; higher resting HR and increases in HR over time are associated with the greatest magnitude of risk.
Aspirin for Primary Prevention of Cardiovascular Events
Authors: Hesham K. Abdelaziz, Marwan Saad, Naga Venkata K. Pothineni, Michael Megaly, Rahul Potluri, Mohammed Saleh, David Lai Chin Kon, David H. Roberts, Deepak L. Bhatt, Herbert D. Aronow, J. Dawn Abbott, Jawahar L. Mehta
Journal: Journal of the American College of Cardiology (2019)
Helen Salisbury: Small is beautiful
Authors: Helen Salisbury
Journal: BMJ (2019)

This week I learnt that 138 GP surgeries closed their doors for the last time in 2018.1 Some of the practices merged, some doctors were employed or became partners elsewhere, and some GPs, wearied and defeated, took early retirement.

Most of the practices affected were small, with lists of fewer than 5000 patients. It’s easy to see why smaller practices are vulnerable. A single retirement or episode of ill health can be enough to close a practice if it can’t recruit new staff. The ever increasing regulatory burden on primary care is …
FRI0600 FIRST SINGLE-CENTERED COHORT OF CHINESE PATIENTS WITH PEDIATRIC SAPHO
Authors: Yuming Shao, Chen Li, Shuang Liu, Wen Zhang
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) is an disease entity with chronic inflammatory osteoarticular symptoms and typical dermatological lesions. Pediatric SAPHO is regarded as equivalent of Chronic Recurrent Multifocal Osteomyelitis (CRMO) or Chronic Non-bacterial Osteomyelitis (CNO). There have already been several pediatric SAPHO cohorts about Caucasian populations. No Chinese cohorts have been reported. <h3>Objectives</h3> The aim of this study was to evaluate clinical features and treatment for all pediatric SAPHO patients admitted to Peking Union Medical College Hospital (PUMCH, Beijing, China) <h3>Methods</h3> We conducted a single-centered non-intervention retrospective study of 24 pediatric SAPHO patients who were diagnosed with Khan's modified criteria in PUMCH from April 2014 to August 2018 [1]. The demographic (sex, age, onset age, follow-up years), clinical (bone and skin symptoms), laboratory (ESR, CRP, HLA-B27, ANA, IL-6, IL-8, TNF-α), imaging (CT, MRI, bone scintigraphy), histologic (lymphocytic, granulocytic) and treatment (medications and effect) data were collected. <h3>Results</h3> Detailed information of 15 male and 9 female was available. The mean ± SD age at onset of bone and skin symptoms was 11.7 ± 3.8 and 14.4 ± 2.7 years, respectively. The duration of follow-up was 19.2 ± 15.2 months. 17 (71%) patients had skin manifestations (46% Severe Acne, all male; 21% Palmoplantar Pustulosis, all female; 4% psoriasis). Involvement of bone lesions varied (42% anterior chest wall, 29% mandible, 50% peripheral bones, 21% spinal bones). ESR, CRP, IL-6, IL-8, IL-10 was elevated in 88%, 96%, 50%, 71%, 70% patients, respectively. 11 did bone biopsy (6 dominantly lymphocytic, 3 granulocytic, 2 both). CT, MRI and bone scintigraphy were performed in 79%, 96%, 96% patients, respectively. A total of 6 patients have been treated with NSAIDs, 10 with bisphosphonate, 10 with TNF-α antagonist, 1 with Glucocorticoids, with a variable response. 70% patients showed complete remission after bisphosphonate or TNF-α antagonist therapy. <h3>Conclusion</h3> This is the first Chinese cohort of pediatric SAPHO patients. Their bone lesions could be divided into 4 types, anterior chest wall, mandible, peripheral bones and spinal bones. We also provide evidence that bisphosphonate and TNF-α antagonist are useful for pediatric SAPHO treatment. <h3>References</h3> [1] Hayem G. SAPHO syndrome. Rev Prat. 2004;54(15):1635–6. <h3>Disclosure of Interests</h3> None declared
Reply to Xueliang Zhou and Xinwei Han's Letter to the Editor re: Thomas Van den Broeck, Roderick C.N. van den Bergh, Nicolas Arfi, et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. Eur Urol 2019;75:967–87
Authors: Thomas Van den Broeck, Nicolas Mottet, Thomas Lam
Journal: European Urology (2019)
Becoming a Statistic in the Middle of an Epidemic—A Call to Consider Alternate Risk Factors for Early-Onset Colorectal Cancer
Authors: Briana Mezuk
Journal: JAMA Oncology (2019)

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Abstract 1258: Changes in Atrial Connexin40 and 43 are Apparent after 2 Months of Atrial Fibrillation in a Goat Model
Authors: Rasheda A Chowdhury, Yasmina Aguiar-Martins, Pravina M Patel, Linda Inuabasi, Paramdeep S Dhillon, Mark C Hall, Senthil Kirubakaran, Clifford J Garratt, Nicholas S Peters
Journal: Circulation (2006)

Introduction: Atrial fibrillation (AF) has a tendency to persist. The predisposition for persistent AF occurs over a longer timescale than electrical remodelling. A “second factor” may influence the persistency of AF and it has been suggested that gap junction remodelling via altered connexin (Cx) expression may be involved in this process. We have previously shown that the relative ratio of connexins, expressed as Cx40/(Cx40+Cx43), in the human right atrial free wall correlates with atrial conduction velocity. We used a goat model of AF to investigate the time course of these changes in Cxs.  Methods and Results: Control goats in sinus rhythm (SR) were compared to goats maintained in AF for periods of 1 month by programmed right atrial burst pacing. Between periods of AF goats were DC cardioverted to SR and their atrial effective refractory period was allowed to return to baseline before induction of a further month of AF. Tissue was taken from the right and left atria and snap frozen in liquid nitrogen. Western blotting analysis was carried out for Cx40 and Cx43 and a relative ratio of Cx40/(Cx40+Cx43) was calculated. In the right atrium there was no significant difference between control (0.69±0.08, n=4) and goats with 1 month AF (0.72±0.09, n=4). However, in the right atrium there was a significant decrease in the relative ratio for goats with 2 months AF (0.42±0.09, p=0.016, n=3) and with 3 months AF (0.54±0.065, p=0.023, n=4) compared to control. Differences in the left atrium did not achieve significance between control and any time point of AF.  Conclusion: AF is associated with changes in the relative ratio of connexins in the right atrium in a goat model. The timescale of these changes suggest that gap junction remodelling remains a candidate for the “second factor”.