tbuckley/cabot-search huggingface dataset:
Functional variants in the <i>LRRK2</i> gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease
Authors: Ken Y. Hui, Heriberto Fernandez-Hernandez, Jianzhong Hu, Adam Schaffner, Nathan Pankratz, Nai-Yun Hsu, Ling-Shiang Chuang, Shai Carmi, Nicole Villaverde, Xianting Li, Manual Rivas, Adam P. Levine, Xiuliang Bao, Philippe R. Labrias, Talin Haritunians, Darren Ruane, Kyle Gettler, Ernie Chen, Dalin Li, Elena R. Schiff, Nikolas Pontikos, Nir Barzilai, Steven R. Brant, Susan Bressman, Adam S. Cheifetz, Lorraine N. Clark, Mark J. Daly, Robert J. Desnick, Richard H. Duerr, Seymour Katz, Todd Lencz, Richard H. Myers, Harry Ostrer, Laurie Ozelius, Haydeh Payami, Yakov Peter, John D. Rioux, Anthony W. Segal, William K. Scott, Mark S. Silverberg, Jeffery M. Vance, Iban Ubarretxena-Belandia, Tatiana Foroud, Gil Atzmon, Itsik Pe’er, Yiannis Ioannou, Dermot P. B. McGovern, Zhenyu Yue, Eric E. Schadt, Judy H. Cho, Inga Peter
Journal: Science Translational Medicine (2018)

Crohn’s disease (CD)–associated variants in the LRRK2 gene for risk (N2081D) and for protection (N551K) mediate shared effects in CD and Parkinson’s disease.
GP out-of-hours services struggle to fill shifts amid “intense” winter pressure
Authors: Gareth Iacobucci
Journal: BMJ (2018)

Providers of out-of-hours GP services are struggling to fill gaps in their rotas in the face of “intense” pressure this winter, despite a £10m (€11.2m; $13.6m) cash injection to help cover indemnity fees that was intended to ensure full coverage.1

Simon Abrams, chair of Urgent Health UK, a federation of social enterprises that provide out-of-hours GP services, told The BMJ , “My colleagues generally have found it more difficult this year to recruit doctors to shifts. Pressure on health services has been intense this winter, especially over the bank holidays.”

Abrams believed that previous extra funding from government for winter pressure, such as the £335m announced in November,2 had been too focused on hospitals. “In the wider strategy, there hasn’t been that recognition of …
Cabozantinib, a New Standard of Care for Patients With Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial
Authors: Bernard Escudier, Thomas Powles, Robert J. Motzer, Thomas Olencki, Osvaldo Arén Frontera, Stephane Oudard, Frederic Rolland, Piotr Tomczak, Daniel Castellano, Leonard J. Appleman, Harry Drabkin, Daniel Vaena, Steven Milwee, Jillian Youkstetter, Julie C. Lougheed, Sergio Bracarda, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2018)

Purpose Cabozantinib, an inhibitor of tyrosine kinases including MET, vascular endothelial growth factor receptors, and AXL, increased progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients with advanced renal cell carcinoma (RCC) after previous vascular endothelial growth factor receptor-targeted therapy in the phase III METEOR trial. Because bone metastases are associated with increased morbidity in patients with RCC, bone-related outcomes were analyzed in METEOR. Patients and Methods Six hundred fifty-eight patients were randomly assigned 1:1 to receive 60 mg cabozantinib or 10 mg everolimus. Prespecified subgroup analyses of PFS, OS, and ORR were conducted in patients grouped by baseline bone metastases status per independent radiology committee (IRC). Additional end points included bone scan response per IRC, skeletal-related events, and changes in bone biomarkers. Results For patients with bone metastases at baseline (cabozantinib [n = 77]; everolimus [n = 65]), median PFS was 7.4 months for cabozantinib versus 2.7 months for everolimus (hazard ratio, 0.33 [95% CI, 0.21 to 0.51]). Median OS was also longer with cabozantinib (20.1 months v 12.1 months; hazard ratio, 0.54 [95% CI, 0.34 to 0.84]), and ORR per IRC was higher (17% v 0%). The rate of skeletal-related events was 23% with cabozantinib and 29% with everolimus, and bone scan response per IRC was 20% versus 10%, respectively. PFS, OS, and ORR were also improved with cabozantinib in patients without bone metastases. Changes in bone biomarkers were greater with cabozantinib than with everolimus. The overall safety profiles of cabozantinib and everolimus in patients with bone metastases were consistent with those observed in patients without bone metastases. Conclusion Cabozantinib treatment was associated with improved PFS, OS, and ORR when compared with everolimus treatment in patients with advanced RCC and bone metastases and represents a good treatment option for these patients.
Achieving Mental Health and Substance Use Disorder Treatment Parity: A Quarter Century of Policy Making and Research
Authors: Emma Peterson, Susan Busch
Journal: Annual Review of Public Health (2018)

The Mental Health Parity and Addiction Equity Act (MHPAEA) of 2008 changed the landscape of mental health and substance use disorder coverage in the United States. The MHPAEA's comprehensiveness compared with past parity laws, including its extension of parity to plan management strategies, the so-called nonquantitative treatment limitations (NQTL), led to significant improvements in mental health care coverage. In this article, we review the history of this landmark legislation and its recent expansions to new populations, describe past research on the effects of this and other mental health/substance use disorder parity laws, and describe some directions for future research, including NQTL compliance issues, effects of parity on individuals with severe mental illness, and measurement of benefits other than mental health care use.
Abstract #1793: Comparison of gene expression and reverse-phase protein microarray profiling for prediction of chemosensitivity to lapatinib in human bladder cancer
Authors: Dmytro Havaleshko, Steven Smith, HyungJun Cho, Sooyoung Cheon, Charles Owens, Jae Lee, Emanuel Petricoin, Dan Theodorescu
Journal: Cancer Research (2009)

Effective treatment of metastatic bladder cancer remains difficult with current therapy. Given prior results suggesting a key role for EGFR signaling in the progression of bladder cancer, the dual EGFR/HER2 tyrosine kinase inhibitor, lapatinib, might offer improved therapy for this disease, especially when coupled with biomarker-guided patient selection. Here we develop biomarker models for prediction of response to lapatinib treatment based on both gene expression and phosphoproteomic profiling of forty bladder cancer cell lines by using the misclassification-penalized posterior (MiPP) algorithm. After empirically determining susceptibility or resistance to lapatinib treatment for these forty cells, we used the MiPP methodology to develop parsimonious prediction models for response, independently based on either oligonucleotide microarray based gene expression or reverse-phase protein microarray based phosphoproteomic profiles for EGFR pathway proteins. In cross-validation studies, we found that two prediction models, both derived from microarray gene expression data, showed better predictive power, (93.22% - 98.22%, mean sMiPP 0.8434 - 0.956); compared to models derived from either phosphoproteomic profiling of the EGFR pathway alone (54.8% - 61.2%, mean sMiPP between 0.0864 - 0.1901) or from a subset of the microarray data for genes related to the EGFR pathway: (86.2%, mean sMiPP between 0.0864 - 0.1901). A final model, based on combining data from both array and phosphoproteomic profiles, did not improve prediction. Our findings suggest that while developing biomarker models based on EGFR pathway related genes and phosphoproteins has the advantage of selecting well characterized targets with known biologic roles, such a selected strategy, as opposed to a proteomic approach, may not provide optimal predictive biomarker signatures. In contrast, the unbiased use of high resolution oligonucleotide microarray gene expression profiles provides superior and hitherto uncharacterized high fidelity biomarkers of treatment response. Such signatures are adaptable for evaluation in patient treatment cohorts.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1793.
Abstract 18410: The Role of CD40 in Endothelial and Smooth Muscle Cells in Atherosclerosis
Authors: Mark C Gissler, Florian Willecke, Nathaly Anto Michel, Carmen Härtner, Ingo Hilgendorf, Dennis Wolf, Peter Stachon, Norbert Gerdes, Andreas Zirlik
Journal: Circulation (2016)

Objective:  The interaction of CD40-CD40 ligand (CD40L; CD154) plays a central role in inflammatory disease. However, there are conflicting reports about its contribution to atherogenesis. Some of this controversy may arise from cell type-specific signaling initiated by CD40 ligation. To further clarify the cell-specific roles of CD40-associated inflammation in the context of atherosclerosis, we generated tamoxifen-inducible smooth muscle cell (SMC)-specific CD40 (Smmc-Cre + CD40 fl/fl ) and endothelial cell (EC)-specific CD40 deficient mice (Bmx-Cre + CD40 fl/fl ) on an ApoE-deficient background (iSMC-CD40 -/- /Apoe -/-  and iEC-CD40 -/- /Apoe -/- , respectively).   Methods & Results:  All mice (including CD40 fl/fl /Apoe -/-  controls) received tamoxifen at 9 weeks and consumed chow diet for additional 20 weeks to induce slow progression of atherosclerosis. Although less leukocytes adhered to the endothelium in iEC-CD40 -/- /ApoE -/-  mice as assessed by intravital microscopy, the size of atherosclerotic plaques did not differ compared with respective controls. In contrast, iSMC-CD40 -/- /ApoE -/-  mice exhibited decreased atherosclerotic plaque size in the aortic root. iSMC-CD40 -/- /ApoE -/-  mice showed a significant increase of circulating granulocytes and monocytes and a shift to more Ly6C low  monocytes and regulatory T cells. Notably, iSMC-CD40 -/- /ApoE -/-  mice displayed substantial splenomegaly. CD11b +  leukocytes in the peritoneum were decreased suggesting impaired capacity of monocytes and granulocytes to migrate.   Conclusion:  We studied the role of CD40 in non-hematopoietic vascular cells on atherosclerosis: Whereas EC-specific CD40 deficiency does not affect atherogenesis, SMC-specific deletion of CD40 attenuates atherogenesis, likely by impaired infiltration into the arterial wall. However, further mechanistic studies are ongoing to elucidate the SMC-specific role of CD40 on inflammation and atherosclerosis.
Specific IgE for Staphyloccocus Aureus In Patients With Allergic Rhinitis
Authors: Katia Guzman Avilan, Sandra Nora Gonzalez-Diaz, Alfredo Arias Cruz, Alejandra Macias-Weinmann, Rosa Ivett Guzman-Avilan, Barbara Elizondo Villarreal, Cindy Elizabeth de Lira-Quezada, Rosalaura Virginia Villarreal-Gonzalez, Carlos de la Cruz
Journal: Journal of Allergy and Clinical Immunology (2018)
Left Atrial Appendage Closure and Systemic Homeostasis
Authors: Dhanunjaya Lakkireddy, Mohit Turagam, Muhammad Rizwan Afzal, Johnson Rajasingh, Donita Atkins, Buddhadeb Dawn, Luigi Di Biase, Krzysztof Bartus, Saibal Kar, Andrea Natale, David J. Holmes
Journal: Journal of the American College of Cardiology (2018)
Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update
Authors: Kenneth Anderson, Nofisat Ismaila, Patrick J. Flynn, Susan Halabi, Sundar Jagannath, Mohammed S. Ogaily, Jim Omel, Noopur Raje, G. David Roodman, Gary C. Yee, Robert A. Kyle
Journal: Journal of Clinical Oncology (2018)

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .
Urgent action is needed to manage doctors’ fatigue, says BMA
Authors: Abi Rimmer
Journal: BMJ (2018)

The government and employers must act urgently to tackle the risk of fatigue in doctors, the BMA has said.

In a report published on 9 January the association warns that fatigue and sleep deprivation are a danger to patients and doctors because of increased clinical error, occupational incidents, road traffic crashes, and needlestick injuries.

The BMA’s report urges the government and other national bodies to develop a comprehensive …
Short Course of Lolium Perenne Peptides (LPP) Immunotherapy Deletes Circulating IL-4 + IL-21 + T follicular helper cells and Induces FoxP3 + T follicular regulatory cells: A Randomized Controlled Trial
Authors: Hanisah Sharif, Angeliki Karamani, Rebecca Parkin, Lubna Kouser, Iesha Singh, Abigail Robb, Gabriële Holtappels, Lara Derycke, Rémy von Frenckell, Nathalie Wathelet, Jean Duchateau, Thierry Legon, Sabine Pirotton, Ralph Mosges, Stephen R. Durham, Claus Bachert, Mohamed H. Shamji
Journal: Journal of Allergy and Clinical Immunology (2018)
Can urinary tetranor-PGDM, a metabolite from prostaglandin D 2 , be used as a reliable marker for evaluating the effectiveness of oral immunotherapies for children with food allergies?
Authors: Shinichiro Inagaki, Masami Narita, Tatsuro Nakamura, Takahisa Murata, Yukihiro Ohya
Journal: Journal of Allergy and Clinical Immunology (2018)
The host protecting the tumor from the host — targeting PD‑L1 expressed by host cells
Authors: David H. Munn
Journal: Journal of Clinical Investigation (2018)

Tumors frequently escape from immune surveillance by hijacking the natural control mechanisms that regulate normal immune responses. The programmed death-1 receptor (PD‑1) on T cells normally helps limit excessive immune activation, but it can also suppress beneficial antitumor immunity. In the clinic, blocking either PD‑1 or one of its principal counterligands, programmed death-ligand 1 (PD‑L1), can lead to dramatic responses in certain patients. Because PD‑L1 can be expressed by both the tumor cells themselves and also the host cells, including host immune cells, the actual mechanistic target of therapy has remained unclear. In the current issue of the JCI, two papers, one by Tang and colleagues and the other by Lin and colleagues, used a variety of mouse tumor models to demonstrate that the relevant target for therapy in each case was the PD‑L1 molecules expressed by host cells and not by tumor cells. If this finding is generalized to humans, then it would suggest that the tumor persuades the host to actively suppress its own attempted immune response against the tumor cells.
The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) – what is the evidence for causation?
Authors: Amalie Dyda, Sacha Stelzer-Braid, Dillon Adam, Abrar A Chughtai, C Raina MacIntyre
Journal: Eurosurveillance (2018)

Background Enterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. In recent years, there has been evidence of an increase in EV-D68 infections globally. Large outbreaks of EV-D68, with thousands of cases, occurred in the United States, Canada and Europe in 2014. The outbreaks were associated temporally and geographically with an increase in clusters of acute flaccid myelitis (AFM). Aims: We aimed to evaluate a causal association between EV-D68 and AFM. Methods: Using data from the published and grey literature, we applied the Bradford Hill criteria, a set of nine principles applied to examine causality, to evaluate the relationship between EV-D68 and AFM. Based on available evidence, we defined the Bradford Hill Criteria as being not met, or met minimally, partially or fully. Results: Available evidence applied to EV-D68 and AFM showed that six of the Bradford Hill criteria were fully met and two were partially met. The criterion of biological gradient was minimally met. The incidence of EV-D68 infections is increasing world-wide. Phylogenetic epidemiology showed diversification from the original Fermon and Rhyne strains since the year 2000, with evolution of a genetically distinct outbreak strain, clade B1. Clade B1, but not older strains, is associated with AFM and is neuropathic in animal models. Conclusion: While more research is needed on dose–response relationship, application of the Bradford Hill criteria supported a causal relationship between EV-D68 and AFM.
Abstract MP85: Fitbit Provides Valid Measures of Sedentary and Physical Activity in Preschool Children
Authors: Wonwoo Byun, Allison Barry, Jung-Min Lee, Youngdoek Kim
Journal: Circulation (2016)

Introduction: Both monitoring and promoting PA in children, two important areas in epidemiologic research, require the use of accurate and feasible measurement tools. The Fitbit activity monitor is one of the most widely commercialized, consumer-based activity monitors and its validity and reliability has been determined in adults; however, little research has determined the validity of Fitbit activity monitor in measuring sedentary behavior and PA in preschool-age children. Hypothesis: We hypothesized that, when comparing to the direct observation (DO), the Fitbit Flex (FF) activity monitor would accurately measure the time spent in sedentary, moderate-to-vigorous PA (MVPA), and Total (light-to-vigorous) PA in preschool-age children. Methods: A total of 28 preschool age children (Female: 46%, Age: 4.6 ± 1.0 yrs, BMI: 16.4 ± 1.5 kg·m2) wore the FF (on the wrist) and were directly observed while performing a set of unstructured and structured activities with varying intensity levels such as watching TV, drawing, playing with toys, playing soccer, and shooting basket. Breath-by-breath oxygen consumption were also measured using Oxycon Mobile indirect calorimetry (OM). Data from the FF (PA counts) and the OM (VO2 ml·kg·min-1) were summarized in terms of minute-by-minute basis. The validity of FF for measuring the time spent in sedentary behavior, MVPA, and Total PA against DO was examined using three ways: (1) Pearson correlation examining the relatively agreement between FF and DO; (2) Mean absolute percent error (MAPE) examining the measurement errors of FF; and (3) One-sided equivalence test examining the absolute agreement between FF and DO by comparing the 90% confidence intervals (CI) of the estimates from the FF with the respective equivalence zone (EZ; ± 10% of the mean estimates from the DO). Results: On average, oxygen consumptions for sedentary, light, MVPA were 9.0 ± 1.6, 14.9 ± 3.9, 23.5 ± 5.5, and 33.8 ± 5.6 ml·kg·min-1, respectively. Correlations between FF and DO were consistently high for sedentary (r = 0.81, P &lt;.001), MVPA (r = 0.62, P &lt;.001), and Total PA (r = 0.81, P &lt;.001). MAPEs were 8.2%, 21.1%, and 8.2% for sedentary, MVPA, and Total PA, respectively. The estimates from the FF were not significantly equivalent to those from the DO; sedentary (FF: Mean (M) = 7.8 min, 90% CI: 7.3 - 8.3 min vs. DO: M = 6 min, EZ: 5.4 - 6.6 min), MVPA (FF: M = 7.2 min, 90% CI: 6.2 - 8.2 min vs. DO: M = 12 min, EZ: 10.8 - 13.2 min), and Total PA (FF: M = 14.0 min, 90% CI: 13.6 - 14.4 min vs. DO: M = 16 min, EZ: 14.4 - 17.6 min). Conclusions: The validity of the FF was supported by the consistently high correlations with the criterion measure. However, inconsistent results from equivalence testing warrants subsequent assessment of the validity of the FF as it has a high potential for replacing research-based PA monitors in preschool-age children.
Particle Targeting: Particle Targeting in Complex Biological Media (Adv. Healthcare Mater. 1/2018)
Authors: Qiong Dai, Nadja Bertleff‐Zieschang, Julia A. Braunger, Mattias Björnmalm, Christina Cortez‐Jugo, Frank Caruso
Journal: Advanced Healthcare Materials (2018)

Nanoengineered particles are gaining increasing interest for applications in the biomedical realm. However, the behavior of targeted particles in complex biological environments is still poorly understood. In article number 1700575, Frank Caruso and co-workers discuss the parameters that influence the biological performance of particles and highlight the strategies for improving the targeting ability of particles.
Octopod PtCu Nanoframe for Dual-Modal Imaging-Guided Synergistic Photothermal Radiotherapy
Authors: Jinghua Li, Xiangyang Zu, Gaofeng Liang, KeKe Zhang, Yuliang Liu, Ke Li, Zhong Luo, Kaiyong Cai
Journal: Theranostics (2018)

Heavy atom nanoparticles have high X-ray absorption capacity and near infrared (NIR) photothermal conversion efficiency, which could be used as radio-sensitizers.We hypothesized that concave PtCu octopod nanoframes (OPCNs) would be an efficient nanoplatform for synergistic radio-photothermal tumor ablation.Methods: In this study, we newly exploited a folic acid-receptor (FR) mediated photothermal radiotherapy nanoagent base on OPCNs.OPCNs were synthesized with a hydrothermal method and then modified with polyethylene glycol (PEG) and folic acid (FA).A series of physical and chemical characterizations, cytotoxicity, targeting potential, endocytosis mechanism, biodistribution, systematic toxicological evaluation, pharmacokinetics, applications of OPCNs-PEG-FA for in vitro and in vivo infrared thermal imaging (ITI)/photoacoustic imaging (PAI) dual-modal imaging and synergistic photothermal radiotherapy against tumor were carried out.Results: The OPCNs-PEG-FA demonstrated good biocompatibility, strong NIR absorption and X-ray radio-sensitization, which enabling it to track and visualize tumor in vivo via ITI/PAI dual-modal imaging.Moreover, the as-synthesized OPCNs-PEG-FA exhibited remarkable photothermal therapy (PTT) and radiotherapy (RT) synergistic tumor inhibition when treated with NIR laser and X-ray.Conclusion: A novel multifunctional theranostic nanoplatform based on OPCNs was designed and developed for dual-modal image-guided synergistic tumor photothermal radiotherapy.
Clonal Hematopoiesis in Erdheim-Chester Disease
Authors: Julien Haroche, Stéphanie Poulain, Alice Marceau-Renaut, Aline Renneville, Catherine Settegrana, Karim Maloum, Damien Roos-Weil, Florence Nguyen-Khac, Jean Donadieu, Jean-François Emile, Zahir Amoura, Fleur Cohen-Aubart
Journal: Blood (2017)