tbuckley/cabot-search huggingface dataset:
SP0147 How the gut microbiota and its metabolites impact on bone homeostasis
Authors: M.M. Zaiss
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibres in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass <i>in vivo</i>. Treatment of mice with SCFA as well as feeding with a high-fibre diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption <i>in vitro</i> and <i>in vivo</i>, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis. <h3>Disclosure of Interest</h3> None declared
Plinabulin, a Novel Small Molecule in Development for Chemotherapy-Induced-Neutropenia (CIN) Prevention, Mobilizes CD34+ Cells through a Mechanism of Action (MoA) Different from G-CSF and from CXCR4 Inhibition
Authors: Douglas W. Blayney, Ene Ette, Stephan Ogenstad, Yuankai Shi, Lihua Du, Kenneth Lloyd, Lan Huang, Ramon Mohanlal
Journal: Blood (2018)
THU0574 Long term pharmacovigilance of biologics for juvenile idiopathic arthritis: the biker-registry
Authors: G. Horneff, G. Ganser, I. Foeldvari, F. Weller-Heinemann, A. Hospach, K. Minden, A. Klein
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Long-term surveillance of biologics drugs is particularly important in paediatric patients (pts) <h3>Objectives</h3> To evaluate long-term rates of serious adverse events (AE) and AEs of special interest (AESI) in clinical practice in pts with juvenile idiopathic arthritis (JIA) <h3>Methods</h3> Safety data from pts registered in the BIKER registry were analysed. Rates of 25 AESI were analysed from first dose through 70 days after last dose and compared by Wald test <h3>Results</h3> A total of 3975 courses of biologics with a total exposure of 7592 PY were identified with Etanercept (5376PY) followed by Adalimumab (1334PY), Tocilizumab (435PY), Abatacept (109PY), Infliximab (99PY), Anakinra (96 PY), Canakinumab (71PY) and Golimumab (67PY). Differences in JIA category distribution and concomitant treatment were noted. A total of 3586 AE (47.2/100PY), 461 (6.1) SAE and 629 (8.3) AESI were reported. The most common AESI were uveitis (194 (2.6)) followed by medically important infections (155 (2.0)), cytopenias (62 (0.8)), hepatic events 39 (0.5), anaphylaxis (28 (0.4))), other autoimmunopathies (25 (0.3)), chronic inflammatory bowel disease (23 (0.3)), depression (17 (0.2)), macrophage activation syndrome (12 (0.2)), malignancies (8 (0.1)) and pregnancies (8 (0.1)). There were marked differences in the rate of AESI with different biologics. Uveitis were most common in TNF-antibody treated cohorts, infections upon GOL, TOC, ANA, cytopenias upon TOC, CAN, hepatic events upon TOC, anaphylaxis upon INF, TOC, CED upon ETA, INF (table 1). One case of latent TB but no further opportunistic infections were reported. There was a single death due to sepsis. [KM1]Vorn 2481 [KM2]Vorn 67? <h3>Conclusions</h3> Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for long term treatment of children. Overall, tolerance is acceptable. Differences between several biologics were noted and should be considered in daily patient care <h3>Disclosure of Interest</h3> None declared
Guiding the first biopsy in glioma patients using estimated Ki-67 maps derived from MRI: conventional versus advanced imaging
Authors: Evan D H Gates, Jonathan S Lin, Jeffrey S Weinberg, Jackson Hamilton, Sujit S Prabhu, John D Hazle, Gregory N Fuller, Veera Baladandayuthapani, David Fuentes, Dawid Schellingerhout
Journal: Neuro-Oncology (2019)

Undersampling of gliomas at first biopsy is a major clinical problem, as accurate grading determines all subsequent treatment. We submit a technological solution to reduce the problem of undersampling by estimating a marker of tumor proliferation (Ki-67) using MR imaging data as inputs, against a stereotactic histopathology gold standard. MR imaging was performed with anatomic, diffusion, permeability, and perfusion sequences, in untreated glioma patients in a prospective clinical trial. Stereotactic biopsies were harvested from each patient immediately prior to surgical resection. For each biopsy, an imaging description (23 parameters) was developed, and the Ki-67 index was recorded. Machine learning models were built to estimate Ki-67 from imaging inputs, and cross validation was undertaken to determine the error in estimates. The best model was used to generate graphical maps of Ki-67 estimates across the whole brain. Fifty-two image-guided biopsies were collected from 23 evaluable patients. The random forest algorithm best modeled Ki-67 with 4 imaging inputs (T2-weighted, fractional anisotropy, cerebral blood flow, Ktrans). It predicted the Ki-67 expression levels with a root mean square (RMS) error of 3.5% (R2 = 0.75). A less accurate predictive result (RMS error 5.4%, R2 = 0.50) was found using conventional imaging only. Ki-67 can be predicted to clinically useful accuracies using clinical imaging data. Advanced imaging (diffusion, perfusion, and permeability) improves predictive accuracy over conventional imaging alone. Ki-67 predictions, displayed as graphical maps, could be used to guide biopsy, resection, and/or radiation in the care of glioma patients.
Alveolar Macrophage Apoptosis–associated Bacterial Killing Helps Prevent Murine Pneumonia
Authors: Julie A. Preston, Martin A. Bewley, Helen M. Marriott, A. McGarry Houghton, Mohammed Mohasin, Jamil Jubrail, Lucy Morris, Yvonne L. Stephenson, Simon Cross, David R. Greaves, Ruth W. Craig, Nico van Rooijen, Colin D. Bingle, Robert C. Read, Timothy J. Mitchell, Moira K. B. Whyte, Steven D. Shapiro, David H. Dockrell
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AMs) kill bacteria.Objectives: To define the role and mechanism of AM apoptosis–associated bacterial killing in the lung.Methods: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing.Measurements and Main Results: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for ≥12 h) overwhelmed initial killing, and a second, late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection.Conclusions: Mcl-1 upregulation prevents macrophage apoptosis–associated killing and establishes that apoptosis-associated killing is required to allow AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.
Abstract MP050: Changes in Dietary Fat Intake and Long-term Weight Change in US Women and Men
Authors: Xiaoran Liu, Yanping Li, Deirdre K Tobias, Dong D Wang, JoAnn E Manson, Walter C Willett, Frank B Hu
Journal: Circulation (2017)

Introduction: The role of dietary fat intake in body weight regulation remains controversial and few studies have examined long-term changes in types of dietary fat and weight change in longitudinal studies. Methods: We examined the association between changes in energy from dietary fat and weight change in three large, prospective cohorts including 102, 123 U.S. women and men who were free of diabetes, cardiovascular disease and cancer at baseline. Linear mixed model was used to assess the association between changes in energy from specific dietary fat and weight changes at 4-year intervals with multivariable adjustment for age, baseline body-mass index at each period, and simultaneous changes in dietary factors (total energy, energy from protein, cereal fiber) and lifestyle factors (smoking, physical activity, television watching, sleep duration). Results: Increased intake of polyunsaturated fatty acid (PUFA) was inversely associated with weight gain. A 5% increment in energy from total PUFA was associated with less weight gain (-1.8 lb, 95% CI: -1.95 to -1.65, p&lt;0.0001) and a 5% increment in energy from n-6 PUFA was associated with 0.90 lb (95% CI: -1.07 to -0.73, p &lt;0.0001) less weight gain over 4-yr period. For marine n-3 PUFA, a 0.3% increase in intake was associated with 2.28 lb (95% CI: -2.50 to -2.10, p&lt;0.0001) less weight gain; a 0.3% increase in intake of vegetable n-3 PUFA (ALA) was also associated with less weight gain (-0.77 lb, 95% CI: -0.86 to -0.68, p&lt;0.0001) at a 4-year interval. The effect of monounsaturated fatty acid (MUFA) intake on weight changes varied across time as the major food contributors to MUFA shifted from animal sources since 1986 to plant sources after 1994 in these cohorts. Prior to 1994, increasing intake of MUFA was positively associated with weight gain (0.50 lb, 95% CI: 0.36 to 0.65), whereas after 1994, increasing intake of MUFA was inversely associated with weight gain (-0.56 lb, 95% CI: -0.56 to 0.07, p&lt;0.0001 for interaction). In addition, a 5% increase in energy from SFA was associated with 1.71 lb (95% CI: 1.59 to 1.83) greater weight and a 1% increase in energy from trans -fat was associated with 1.97 lb (95% CI: 1.86 to 2.08) greater weight gain within each 4-year period. Conclusion: Different types of dietary fats have divergent associations with long-term weight change: higher intakes of PUFA (both n-6 and n-3 PUFA) and plant-based MUFA were associated with less weight gain, whereas increasing saturated and trans -fat intakes were associated with greater weight gain. Our results support the current dietary guidelines that recommend unsaturated fats as replacements for saturated and trans -fats.
Open or Endoscopic Vein Harvesting for Coronary-Artery Bypass Grafting
Authors: Subodh Verma, C. David Mazer
Journal: New England Journal of Medicine (2019)

Coronary-artery bypass grafting (CABG) is the most common cardiac surgical procedure performed worldwide, with more than 200,000 of the procedures performed annually in the United States alone.1 Amidst several advances, the use of saphenous-vein grafts for bypass grafting remains common2,3: more than 90% of CABG procedures are performed with saphenous-vein grafts. However, two recalcitrant issues with saphenous-vein grafts persist — early graft failure and harvest-site complications. Traditionally, harvesting of the greater saphenous vein involves a long incision along the medial part of the lower leg or thigh. This approach is associated with significant wound complications, including infection, delayed healing, and . . .
Abstract 19444: Feasibility of MRI-RHC Based Pressure Volume Loops in Control and PAH Patients
Authors: Jose A Rosado-Toro, Ryan J Avery, Maria I Altbach, Franz Rischard, Rebecca Vanderpool
Journal: Circulation (2017)

Introduction: Right ventricular (RV) function is a major determinate of mortality in patients with pulmonary arterial hypertension (PAH). RV coupling obtained from full conductance derived pressure-volume (PV) loops are difficult to obtain in clinical settings. Thus, simplified methods have been introduced but are limited as they rely on end-diastolic (ED) and end-systolic (ES) volumes. Presented is a novel method to measure full PV loops using cardiac magnetic resonance (CMR) images to generate volumetric data. We hypothesize that it is feasible to generate full clinical PV loops from CMR images to more accurately measure RV coupling than simplified methods. Methods: PV loops were generated in 9 subjects (5 control, 4 PAH) who had a CMR exam and right heart catheterization (RHC) within 48 hours. RV volumes were derived by propagating manually traced RV endocardium in the ED and ES frames throughout the cardiac cycle using an automated dynamic programming technique (Fig. 1A). RV volumes were matched with ...
N-Myc promotes therapeutic resistance development of neuroendocrine prostate cancer by differentially regulating miR-421/ATM pathway
Authors: Yu Yin, Lingfan Xu, Yan Chang, Tao Zeng, Xufeng Chen, Aifeng Wang, Jeff Groth, Wen-Chi Foo, Chaozhao Liang, Hailiang Hu, Jiaoti Huang
Journal: Molecular Cancer (2019)

MYCN amplification or N-Myc overexpression is found in approximately 40% NEPC and up to 20% CRPC patients. N-Myc has been demonstrated to drive disease progression and hormonal therapeutic resistance of NEPC/CRPC. Here, we aim to identify the molecular mechanisms underlying the N-Myc-driven therapeutic resistance and provide new therapeutic targets for those N-Myc overexpressed NEPC/CRPC. N-Myc overexpressing stable cell lines for LNCaP and C4–2 were generated by lentivirus infection. ADT-induced senescence was measured by SA-β-gal staining in LNCaP cells in vitro and in LNCaP xenograft tumors in vivo. Migration, cell proliferation and colony formation assays were used to measure the cellular response after overexpressing N-Myc or perturbing the miR-421/ATM pathway. CRISPR-Cas9 was used to knock out ATM in C4–2 cells and MTS cell viability assay was used to evaluate the drug sensitivity of N-Myc overexpressing C4–2 cells in response to Enzalutamide and ATM inhibitor Ku60019 respectively or in combination. N-Myc overexpression suppressed ATM expression through upregulating miR-421 in LNCaP cells. This suppression alleviated the ADT-induced senescence in vitro and in vivo. Surprisingly, N-Myc overexpression upregulated ATM expression in C4–2 cells and this upregulation promoted migration and invasion of prostate cancer cells. Further, the N-Myc-induced ATM upregulation in C4–2 cells rendered the cells resistance to Enzalutamide, and inhibition of ATM by CRISPR-Cas9 knockout or ATM inhibitor Ku60019 re-sensitized them to Enzalutamide. N-Myc differentially regulating miR-421/ATM pathway contributes to ADT resistance and Enzalutamide resistance development respectively. Combination treatment with ATM inhibitor re-sensitizes N-Myc overexpressed CRPC cells to Enzalutamide. Our findings would offer a potential combination therapeutic strategy using ATM kinase inhibitor and Enzalutamide for the treatment of a subset of mCRPC with N-Myc overexpression that accounts for up to 20% CRPC patients.
THU0423 Epidemiology and survival of systemic sclerosis-systemic lupus erythematosus overlap syndrome
Authors: S. Alharbi, Z. Ahmad, A. Bookman, Z. Touma, J. Sanchez-Guerrero, N. Mitsakakis, S.R. Johnson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic sclerosis (SSc) is an immune disorder characterised by vasculopathy and fibrosis that may overlap with another disease such as systemic lupus erythematous (SLE). Little is known about the epidemiology, clinical characteristics, and survival of SSc-SLE overlap (also called lupoderma). We evaluated the prevalence of SSc-SLE overlap syndrome, differences in SSc clinical characteristics and survival compared with SSc without SLE. <h3>Methods</h3> A cohort study was conducted including subjects who fulfilled the ACR-EULAR classification criteria for SSc and/or the ACR criteria for SLE. The primary outcome was the time from diagnosis to death from all causes. Survival was evaluated using Kaplan Meier curves and Cox Proportional Hazard models. <h3>Results</h3> We identified 1252 subjects (SSc n=1166, SSc-SLE n=86) with a SSc-SLE prevalence of 6.8%. SSc-SLE were younger at diagnosis (37.9 years versus 47.9 years, p&lt;0.001), more frequently had lupus anticoagulant (6% versus 0.3%, p&lt;0.001), anticardiolipin antibody (6% versus 0.9%, p&lt;0.001), and pulmonary arterial hypertension (PAH) (52% versus 31%, p&lt;0.001). SSc-SLE less frequently had calcinosis (13% versus 27%, p=0.007), telangiectasia (49% versus 75%, p&lt;0.001) and diffuse subtype (12% versus 35%, p&lt;0.001). There were no significant differences in the occurrence of renal crisis (7% versus 7%), interstitial lung disease (40% versus 34%), and digital ulcers (38% versus 32%). SSc-SLE had better survival (median 26.1 versus 22.4 years), but this was not statistically significant (log rank p=0.06). Female sex and diffuse subtype attenuated survival differences between groups (Hazard Ratio 0.70, 95% CI 0.45, 1.11). <h3>Conclusions</h3> SSc-SLE are younger at diagnosis, more frequently have PAH, and less frequently have cutaneous manifestations of SSc. SSc-SLE patients should be monitored for pulmonary hypertension, interstitial lung disease, renal crisis and digital ulcers. <h3>Disclosure of Interest</h3> None declared
Etiology and Risk Factors for Mortality in an Adult Community-acquired Pneumonia Cohort in Malawi
Authors: Stephen J. Aston, Antonia Ho, Hannah Jary, Jacqueline Huwa, Tamara Mitchell, Sarah Ibitoye, Simon Greenwood, Elizabeth Joekes, Arthur Daire, Jane Mallewa, Dean Everett, Mulinda Nyirenda, Brian Faragher, Henry C. Mwandumba, Robert S. Heyderman, Stephen B. Gordon
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa.
Oil Core–PEG Shell Nanocarriers for In Vivo MRI Imaging
Authors: Vincenzo Calcagno, Raffaele Vecchione, Vincenzo Quagliariello, Pasquina Marzola, Alice Busato, Pierangela Giustetto, Martina Profeta, Sara Gargiulo, Chiara Di Cicco, Hui Yu, Marco Cassani, Nicola Maurea, Marcello Mancini, Teresa Pellegrino, Paolo A. Netti
Journal: Advanced Healthcare Materials (2019)

Abstract Oil‐in‐water emulsions represent a promising carrier for in vivo imaging because of the possibility to convey poorly water‐soluble species. To promote accumulation at the tumor site and prolong circulation time, reduction of carrier size and surface PEGylation plays a fundamental role. In this work a novel, simple method to design an oil‐core/PEG‐shell nanocarrier is reported. A PEG‐shell is grown around a monodisperse oil‐in‐water nanoemulsion with a one‐pot method, using the radical polymerization of poly(ethylene glycol)diacrylate. PEG polymerization is triggered by UV, obtaining a PEG‐shell with tunable thickness. This core–shell nanosystem combines the eluding feature of the PEG with the ability to confine high payloads of lipophilic species. Indeed, the core is successfully loaded with a lipophilic contrast agent, namely super paramagnetic iron oxide nanocubes. Interestingly, it is demonstrated an in vitro and an in vivo MRI response of the nanocapsules. Additionally, when the nanosystem loaded with nanocubes is mixed with a fluorescent contrast agent, indo‐cyanine green, a relevant in vitro photoacoustic effect is observed. Moreover, viability and cellular uptake studies show no significant cell cytotoxicity. These results, together with the choice of low cost materials and the scale up production, make this nanocarrier a potential platform for in vivo imaging.
The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease
Authors: Birgit Liss, Jörg Striessnig
Journal: The Annual Review of Pharmacology and Toxicology (2019)

The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.
Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes
Authors: Andrew Wei, Stephen A. Strickland, Gail J. Roboz, Jing-Zhou Hou, Walter Fiedler, Tara L. Lin, Roland B. Walter, Anoop Enjeti, Brenda Chyla, Relja Popovic, Kaffa Fakouhi, Pooja Shah, Martin Dunbar, Tu Xu, Mack Mabry, John Hayslip
Journal: Blood (2017)