tbuckley/cabot-search huggingface dataset:
Vitamin D levels during and after high-dose vitamin D supplementation in women with early-stage breast cancer
Authors: Q. J. Khan, B. F. Kimler, P. Sharma, P. S. Reddy, S. Baxa, J. R. Klemp, C. J. Fabian
Journal: Journal of Clinical Oncology (2009)

e20561 Background: Experts define vitamin D deficiency as a 25-hydroxyvitamin D (25OHD) level of &lt; 20 ng/ml; a level &lt; 32 ng/ml is considered insufficient for bone health and &gt; 40 ng/ml may be associated with optimum musculoskeletal function and reduced risk for breast cancer. We conducted a study to determine the effect of high dose vitamin D3 at 50,000 IU/wk (HD vitD) on musculoskeletal symptoms from adjuvant letrozole in breast cancer patients. We present here the effectiveness of HD vitD in achieving optimum 25OHD levels and the rate of decline of 25OHD levels after 12 weeks of HD vitD. Methods: The cohort included post-menopausal women with early stage hormone receptor positive breast cancer initiating letrozole treatment. Women with baseline 25OHD levels &lt; 40 ng/ml received 12 weeks of HD vitD. 25OHD levels were assessed at 6 and 12 weeks during HD vitD supplementation and at 3 and 6 months after completing HD vitD but while taking maintenance dose of 600–1000 IU of vitamin D3 daily. Results: 40 women that received HD vitD completed the follow-up phase of the study and are included in this analysis. At entry on study, median 25OHD level was 23 ng/ml; 38% of the women had vitD deficiency, 75% had insufficiency, and 93% had 25OHD levels &lt; 40 ng/ml. Six weeks of HD vitD increased median 25OHD level to 60 ng/ml and another 6 weeks increased it further to 66 ng/ml. With only 6 weeks of HD vitD supplementation, 98% of the women achieved a 25OHD level of &gt; 40 ng/ml. Median 25OHD levels 3 and 6 months after completion of HD vitD were 49 and 40 ng/ml, respectively. The median rate of decrease in vitD levels per month was 6.8% of the level at completion of supplementation. Using linear regression analysis, projected changes in 25OHD levels were calculated for each subject. Median extrapolated time to drop to a 25OHD level of &lt; 40 ng/ml was 6.0 months, to &lt;32 ng/ml was 7.8 months, and to &lt;20 ng /ml was 10.6 months. Conclusions: Supplementation with vitD3 at 50,000 IU/week for 6 weeks is sufficient to achieve a 25OHD level of &gt;40 ng/ml in 98% of postmenopausal women with breast cancer on an AI. After 12 weeks of HD vitD, there is a steady decline in 25OHD levels at a rate of about 7% per month despite continuing on 600 to 1000 IU of D3 daily. Thus, standard doses of D3 are not adequate to maintain 25OHD levels achieved by HD vitD. No significant financial relationships to disclose.
Controlled Delivery of Single or Multiple Antigens in Tolerogenic Nanoparticles Using Peptide-Polymer Bioconjugates
Authors: Ryan M. Pearson, Liam M. Casey, Kevin R. Hughes, Leon Z. Wang, Madeleine G. North, Daniel R. Getts, Stephen D. Miller, Lonnie D. Shea
Journal: Molecular Therapy (2017)

Polymeric nanoparticles (NPs) have demonstrated their potential to induce antigen (Ag)-specific immunological tolerance in multiple immune models and are at various stages of commercial development. Association of Ag with NPs is typically achieved through surface coupling or encapsulation methods. However, these methods have limitations that include high polydispersity, uncontrollable Ag loading and release, and possible immunogenicity. Here, using antigenic peptides conjugated to poly(lactide-co-glycolide), we developed Ag-polymer conjugate NPs (acNPs) with modular loading of single or multiple Ags, negligible burst release, and minimally exposed surface Ag. Tolerogenic responses of acNPs were studied in vitro to decouple the role of NP size, concentration, and Ag loading on regulatory T cell (Treg) induction. CD4+CD25+Foxp3+ Treg induction was dependent on NP size, but CD25 expression of CD4+ T cells was not. NP concentration and Ag loading could be modulated to achieve maximal levels of Treg induction. In relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a murine model of multiple sclerosis, acNPs were effective in inhibiting disease induced by a single peptide or multiple peptides. The acNPs provide a simple, modular, and well-defined platform, and the NP physicochemical properties offer potential to design and answer complex mechanistic questions surrounding NP-induced tolerance.Graphical abstract
Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting
Authors: Julie R. Park, Rochelle Bagatell, Susan L. Cohn, Andrew D. Pearson, Judith G. Villablanca, Frank Berthold, Susan Burchill, Ariane Boubaker, Kieran McHugh, Jed G. Nuchtern, Wendy B. London, Nita L. Seibel, O. Wolf Lindwasser, John M. Maris, Penelope Brock, Gudrun Schleiermacher, Ruth Ladenstein, Katherine K. Matthay, Dominique Valteau-Couanet
Journal: Journal of Clinical Oncology (2017)

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (
NHS survives because of the dedication of its staff, says NHS Providers chief
Authors: Abi Rimmer
Journal: BMJ (2017)

The NHS continues to survive because of the dedication and professionalism of its staff, the chief executive of NHS Providers has said.

Speaking at a Westminster Health Forum conference in London last week, Chris Hopson also warned that the goodwill of staff may not last forever.

“The NHS never goes off the edge of the cliff,” he said. “It tends to go into a slow decline and the primary reason for that, in our view, is the dedication and professionalism of our staff …
Alpha‐Tocopheryl Succinate‐Conjugated G5 PAMAM Dendrimer Enables Effective Inhibition of Ulcerative Colitis
Authors: Yunan Wang, Wenwen Shen, Xiangyang Shi, Fanfan Fu, Yu Fan, Wanli Shen, Yini Cao, Qiang Zhang, Rong Qi
Journal: Advanced Healthcare Materials (2017)

Ulcerative colitis (UC) is a severe inflammatory disease in colon, however, the therapeutic efficacy of the standard-of-care in clinic for UC patients is unsatisfactory. To explore new drugs for effective and safe treatment of UC, alpha-tocopheryl succinate (α-TOS) is conjugated to generation 5 (G5) poly(amidoamine) (PAMAM) dendrimer to construct a nanodevice of G5-NH-acetamide (Ac)-TOS. The inhibitory effects of the G5-NH-Ac-TOS on UC are evaluated in vivo in a dextran sulfate sodium induced UC mouse model, and its mechanisms are explored in vitro in lipopolysaccharide stimulated mouse peritoneal macrophages. The results indicate that the G5-NH-Ac-TOS exhibits greater inhibitive effects on UC than free α-TOS, through significant attenuation of the disease activity index and reduction of macrophage infiltration in the colon tissues. The protective mechanisms of the G5-NH-Ac-TOS are revealed to be related to inhibition of expression of nuclear translocation of NF-κB, phosphorylation of Akt, and reduction of reactive oxygen species production in the macrophages.
Comparative Effectiveness of Routine Invasive Coronary Angiography for Managing Unstable Angina
Authors: Sara Vogrin, Richard Harper, Elizabeth Paratz, Andrew MacIsaac, Jodie Burchell, Belinda Smith, Anthony Scott, Jongsay Yong, Vijaya Sundararajan
Journal: Annals of Internal Medicine (2017)

Background: Non–ST-segment elevation acute coronary syndromes include unstable angina and non–ST-segment elevation myocardial infarction. Most randomized controlled trials of routine versus selective invasive coronary angiography have high rates of crossover from control to intervention groups and do not include subgroup analysis for unstable angina. Consequently, no clear, specific recommendations exist regarding the use of angiography in unstable angina. Objective: To assess the effect of angiography on mortality in unstable angina, incorporating the results of additional cardiac procedures and events. Design: Longitudinal study using hospital discharge data, discrete-time survival analysis with propensity score adjustment, and sensitivity analysis. Setting: Victoria, Australia, 2001 to 2011. Participants: All residents, all ages. Intervention: Routine invasive coronary angiography. Measurements: 12-month all-cause mortality. Results: Emergently admitted patients with unstable angina (n = 33 901) who did or did not receive angiography during their first hospitalization were balanced on 44 covariates of propensity score. Routine angiography was associated with a 52% decrease in 12-month mortality (hazard ratio, 0.48 [95% CI, 0.38 to 0.61]); revascularization offered no additional statistical mortality benefit compared with diagnostic angiography alone. The predicted cumulative probability of death at 12 months was 0.024 (CI, 0.021 to 0.027) for patients receiving angiography within 2 months of their index unstable angina versus 0.097 (CI, 0.090 to 0.105) for those not receiving it. Sensitivity analysis demonstrated that to negate the observed effect size, an unmeasured confounder must independently decrease mortality by 90% and have a prevalence gap of 15% or greater between the angiographic groups. Limitation: Nonrandom allocation of angiography. Conclusion: Patients with unstable angina benefit from an invasive management pathway initiated by invasive coronary angiography during their hospitalization and up to 2 months after discharge. Primary Funding Sources: National Health and Medical Research Council, Australia and BUPA Health Foundation.
Pharmacokinetic (PK)-guided optimization of 5-fluorouracil (5FU) exposure in colorectal cancer (CRC) patients: U.S.-based clinical practices experience.
Authors: Fadi S. Braiteh, Salvatore J. Salamone, Yunying Li, Jodi B. Courtney, Michael Duda, Steve Diamond, Michael Craig Miller
Journal: Journal of Clinical Oncology (2014)

3574 Background: Multiple studies have demonstrated how PK-guided dosing to optimize infusional 5FU exposure improves both response rates and toxicities. With 5FU PK testing now available using a rapid, reliable immunoassay, we present US-based oncologists' experience with individualizing 5FU dosing based on PK in patients with adjuvant or metastatic CRC. Methods: Between June 5, 2013 and January 17, 2014, Saladax Biomedical Laboratories (a CLIA-certified lab) determined 5FU plasma levels (My5-FU assay) in 631 samples collected ~24+6Hr after the start of 5FU continuous infusion from 240 CRC patients (n=250 therapy lines). Systemic 5FU exposure (calculated as area under the curve [AUC]) and dose adjustment recommendations to achieve target range (AUC = 20 – 30 mg*hr/L) were reported to physicians. Evaluable cycle pairs were defined as two consecutive cycles with AUC results. Actual vs. target AUC, recommended vs. actual dose adjustment, and ability to adjust exposure to target range were evaluated. Results: Majority of AUC results (62%) were outside the target range in the first sample from each therapy line where exposure was determined, irrespective of 5FU dosing or regimen. In 288 cycle pairs, 201 (69%) were outside the target range: doses were decreased in 48% of the 40 above target range, and doses were increased in 51% of the 161 below target range. No dose change was made in 89% of the 87 within the target range. In 101 cycle pairs out of target range where a dose adjustment consistent with recommendation was made, 42% moved into the target range. Conclusions: 5FU exposure optimization is feasible in the US clinical setting, consistent with other reports. Body surface area based 5-FU dosing results in frequent under dosing (48%). Majority (62%) of dose adjustment recommendations were followed in subsequent cycles. PK-guided dose adjustment is a practical approach to personalize optimal 5FU exposure. AUC range (mg*Hr/L) 5FU Dose (mg/m2) in first samples received for testing All doses (600–3,840) < 2,400 2,400 > 2,400 AUC below range (<=19) 48% 61% 44% 34% AUC in target range (20 – 30) 38% 27% 42% 47% AUC above range (>=31) 14% 12% 14% 19% # of samples 250 74 (30%) 144 (57%) 32 (13%)
18F-Sodium Fluoride PET/CT in Paget Disease
Authors: Francesca Cucchi, Lene Simonsen, Annemette Geilager Abild-Nielsen, Rikke Broholm
Journal: Clinical Nuclear Medicine (2017)

Paget disease (PD) of bone is a benign but chronic disorder of bone metabolism. We report a case of an 85-year-old man with several fractures in the pelvis and radiograph raising suspicion of metastases. An 18F-NaF PET/CT demonstrated high 18F-NaF uptake in the same regions. The integrated assessment of imaging findings, supported by biochemistry, allowed diagnosing PD. The 18F-NaF PET/CT is a supplementary diagnostic instrument in the diagnosis of PD, and use of 18F-NaF PET/CT in this context, especially finalized to the differential diagnosis with metastatic lesions, requires the physician to be familiar with imaging patterns of this disease.
Peptide-Receptor Radiotherapy with CXCR4-Targeting Pentixather Reduces Leukemia Burden in Acute Leukemia PDX and Patients
Authors: Stefan Habringer, Peter Herhaus, Margret Schottelius, Constantin Lapa, Rouzanna Istvanffy, Katharina Götze, Katja Steiger, Binje Vick, Christian Peschel, Robert Oostendorp, Irmela Jeremias, Hans-Jürgen Wester, Goetz Ulrich Grigoleit, Ulrich Keller
Journal: Blood (2016)
Wnt5a induces ROR1 to associate with 14-3-3ζ for enhanced chemotaxis and proliferation of chronic lymphocytic leukemia cells
Authors: J Yu, L Chen, Y Chen, M K Hasan, E M Ghia, L Zhang, R Wu, L Z Rassenti, G F Widhopf, Z Shen, S P Briggs, T J Kipps
Journal: Leukemia (2017)

Wnt5a can activate Rho GTPases in chronic lymphocytic leukemia (CLL) cells by inducing the recruitment of ARHGEF2 to ROR1. Mass spectrometry on immune precipitates of Wnt5a-activated ROR1 identified 14-3-3ζ, which was confirmed by co-immunoprecipitation. The capacity of Wnt5a to induce ROR1 to complex with 14-3-3ζ could be blocked in CLL cells by treatment with cirmtuzumab, a humanized mAb targeting ROR1. Silencing 14-3-3ζ via small interfering RNA impaired the capacity of Wnt5a to: (1) induce recruitment of ARHGEF2 to ROR1, (2) enhance in vitro exchange activity of ARHGEF2 and (3) induce activation of RhoA and Rac1 in CLL cells. Furthermore, CRISPR/Cas9 deletion of 14-3-3ζ in ROR1-negative CLL cell-line MEC1, and in MEC1 cells transfected to express ROR1 (MEC1-ROR1), demonstrated that 14-3-3ζ was necessary for the growth/engraftment advantage of MEC1-ROR1 over MEC1 cells. We identified a binding motif (RSPS857SAS) in ROR1 for 14-3-3ζ. Site-directed mutagenesis of ROR1 demonstrated that serine-857 was required for the recruitment of 14-3-3ζ and ARHGEF2 to ROR1, and activation of RhoA and Rac1. Collectively, this study reveals that 14-3-3ζ plays a critical role in Wnt5a/ROR1 signaling, leading to enhanced CLL migration and proliferation.
The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia
Authors: Donald C. Goff, Peter Falkai, W. Wolfgang Fleischhacker, Ragy R. Girgis, Rene M. Kahn, Hiroyuki Uchida, Jingping Zhao, Jeffrey A. Lieberman
Journal: American Journal of Psychiatry (2017)

Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative nonpharmacologic treatment approaches may benefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.
New insights into the role of adipose tissue in thrombosis
Authors: Gemma Vilahur, Soumaya Ben-Aicha, Lina Badimon
Journal: Cardiovascular Research (2017)

Central obesity is independently associated with an elevated risk of cardiovascular disease, particularly thrombotic complications. Increasing data supports a link between excess body weight and the risk to suffer acute myocardial infarction, stent thrombosis after percutaneous interventions, ischemic stroke and vein thrombosis. Experimental and in vitro data have provided insights as to the mechanisms currently presumed to increase the thrombotic risk in obese subjects. Obesity is characterized by a chronic low grade inflammation and systemic oxidative stress that eventually damage the endothelium losing its antithrombotic properties. Obesity also stimulates the expression of leptin and attenuates adiponectin release, a protective adipokine. Although the contribution of adipokines to thrombosis has been questioned, recent work has suggested that they enhance platelet activation and, although to a lesser extent, induce the coagulation cascade through tissue factor (TF) expression. Increased body weight also impairs platelet sensitivity to insulin signaling and enhances the production of bioactive isoprostanes further promoting platelet reactivity. Finally, obese subjects have shown elevated circulating levels of von Willebrand factor, TF, factor VII and VIII, and fibrinogen, favoring a mild-to-moderate hypercoagulable state, and, on the other hand, increased secretion of plasminogen activator inhibitor (PAI)-1 and thrombin activatable fibrinolysis inhibitor (TAFI) contributing to impair the fibrinolytic system. In the present review, we provide an overview of the impact of excess body weight on thrombosis. We will focus on the link between dysfunctional adipose tissue and endothelial damage, platelet reactivity, enhanced coagulation and impaired fibrinolysis; mechanisms currently recognized to increase arterial thrombotic risk in obese subjects.
A European Respiratory Society technical standard: exhaled biomarkers in lung disease
Authors: Ildiko Horváth, Peter J. Barnes, Stelios Loukides, Peter J. Sterk, Marieann Högman, Anna-Carin Olin, Anton Amann, Balazs Antus, Eugenio Baraldi, Andras Bikov, Agnes W. Boots, Lieuwe D. Bos, Paul Brinkman, Caterina Bucca, Giovanna E. Carpagnano, Massimo Corradi, Simona Cristescu, Johan C. de Jongste, Anh-Tuan Dinh-Xuan, Edward Dompeling, Niki Fens, Stephen Fowler, Jens M. Hohlfeld, Olaf Holz, Quirijn Jöbsis, Kim Van De Kant, Hugo H. Knobel, Konstantinos Kostikas, Lauri Lehtimäki, Jon O. Lundberg, Paolo Montuschi, Alain Van Muylem, Giorgio Pennazza, Petra Reinhold, Fabio L.M. Ricciardolo, Philippe Rosias, Marco Santonico, Marc P. van der Schee, Frederik-Jan van Schooten, Antonio Spanevello, Thomy Tonia, Teunis J. Vink
Journal: European Respiratory Journal (2017)

Breath tests cover the fraction of nitric oxide in expired gas (FeNO), volatile organic compounds (VOCs), variables in exhaled breath condensate (EBC) and other measurements. For EBC and for FeNO, official recommendations for standardised procedures are more than 10 years old and there is none for exhaled VOCs and particles. The aim of this document is to provide technical standards and recommendations for sample collection and analytic approaches and to highlight future research priorities in the field. For EBC and FeNO, new developments and advances in technology have been evaluated in the current document. This report is not intended to provide clinical guidance on disease diagnosis and management.Clinicians and researchers with expertise in exhaled biomarkers were invited to participate. Published studies regarding methodology of breath tests were selected, discussed and evaluated in a consensus-based manner by the Task Force members.Recommendations for standardisation of sampling, analysing and reporting of data and suggestions for research to cover gaps in the evidence have been created and summarised.Application of breath biomarker measurement in a standardised manner will provide comparable results, thereby facilitating the potential use of these biomarkers in clinical practice.
Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non–transferrin-bound iron
Authors: Deborah Stefanova, Antoan Raychev, Joao Arezes, Piotr Ruchala, Victoria Gabayan, Mikael Skurnik, Barbara J. Dillon, Marcus A. Horwitz, Tomas Ganz, Yonca Bulut, Elizabeta Nemeth
Journal: Blood (2017)
Using the NOD/SCID Mice Model of Human Erythroleukemia for Evaluating the Cytotoxicity Activity of CB-CIK/NK Cells Stimulated by K562-DCs Fusion Vaccines.
Authors: Yang Li, Shaoliang Huang, Jianpei Fang, Xuchao Zhang, Jing Wei, Wenge Huang, Yanfeng Wu
Journal: Blood (2005)
Comparison of Micafungin and Liposomal Amphotericin B for Empirical Antifungal Therapy in Febrile Neutropenic Patients with Acute Myeloid Leukemia: A Randomized Controlled Trial
Authors: Tatsuo Oyake, Yuka Fujisawa, Norifumi Sugawara, Ryousei Sasaki, Wataru Izumita, Takahiro Mine, Maki Asahi, Yuzo Suzuki, Yoshiaki Okano, Yukiteru Fujishima, Yasuhiko Tsukushi, Yusei Aoki, Shugo Kowata, Ichiro Hanamura, Kazunori Murai, Shigeki Ito, Yoji Ishida
Journal: Blood (2016)