tbuckley/cabot-search huggingface dataset:
Tolerogenic bone marrow-derived dendritic cells induce neuroprotective regulatory T cells in a model of Parkinson’s disease
Authors: Charles R. Schutt, Howard E. Gendelman, R. Lee Mosley
Journal: Molecular Neurodegeneration (2018)

Administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) increases regulatory T cell (Treg) number and function with control of neuroinflammation and neuronal protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). Recently, we demonstrated in an early phase 1 clinical trial that GM-CSF also improves motor skills in PD patients. However, the mechanisms of Treg induction and its effects on neuroprotective responses remain unknown. As GM-CSF induces tolerogenic dendritic cells (DCs) that in turn convert conventional T cells to Tregs, the pathways for DC induction of Tregs were assessed. Following differentiation, bone marrow-derived dendritic cells (BMDCs) were cultured in media or GM-CSF with or without post-culture stimulation with nitrated α-synuclein (N-α-Syn). Expression of cell surface co-stimulatory molecules and proinflammatory cytokines, and induction of Tregs were evaluated. The neuroprotective capacity of tolerogenic BMDCs was assessed by adoptive transfer to MPTP-intoxicated mice. The extent of neuroinflammation and numbers of surviving dopaminergic neurons were assessed in relation to Treg numbers. Co-culture of differentiated BMDCs with conventional T cells led to Treg induction. Stimulation of BMDCs with N-α-Syn increased expression of co-stimulatory molecules and proinflammatory cytokines, with modest increases in Treg numbers. In contrast, continued culture of BMDCs with GM-CSF modestly altered expression of co-stimulatory molecules and proinflammatory cytokines and chemokines, but decreased Treg induction. Continued culture in GM-CSF and combined stimulation with N-α-Syn reduced Treg induction to the lowest levels. Adoptive transfer of tolerogenic BMDCs to MPTP-intoxicated mice increased splenic Tregs, attenuated neuroinflammatory responses, and protected nigrostriatal dopaminergic neurons. GM-CSF acts broadly to differentiate DCs and affect immune transformation from effector to regulatory immune responses. DCs skew such immune responses by increasing Treg numbers and activities that serve to attenuate proinflammatory responses and augment neuroprotection.
Outcomes of Pregnancy After Right Ventricular Outflow Tract Reconstruction With an Allograft Conduit
Authors: Jamie L.R. Romeo, Johanna J.M. Takkenberg, Jolien W. Roos-Hesselink, Milad Hanif, Jerome M.J. Cornette, Wouter J. van Leeuwen, Arie van Dijk, Ad J.J.C. Bogers, M. Mostafa Mokhles
Journal: Journal of the American College of Cardiology (2018)
Effect of denosumab on bone mineral density in postmenopausal Japanese women with osteopenia receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.
Authors: Katsuhiko Nakatsukasa, Takayuki Matsuda, Tetsuya Taguchi
Journal: Journal of Clinical Oncology (2018)

e12536 Background: Patients receiving aromatase inhibitor (AI) are at increased risk for bone fracture, which can reduce their quality of life. Efforts to prevent BMD loss are thus needed. Thus far, in Japan, the efficacy of denosumab in the treatment of AI-associated bone loss has not been evaluated in a prospective study. We previously reported the results of a 12-month, nonrandomized prospective study, which demonstrated that denosumab, a fully human monoclonal antibody against receptor activator of nuclear-factor kappa-B ligand (RANKL), increased the bone mineral Density (BMD) at the lumbar spine and femoral necks in patients with hormone receptor-positive breast cancer who were receiving adjuvant AI therapy and had evidence of low bone mass. Herein, we present the results of these therapeutic effects of 24-month denosumab therapy on the percentage change in BMD from baseline at the lumber spine and femoral necks. Methods: This non-randomized prospective study was conducted in Japan. we prospectively evaluated the BMD of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n = 103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The secondary endpoint was percentage change from baseline in lumbar spine BMD at 24 months. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 24 months, lumber spine BMD increased by 7.0 %. The patients who were administered prior AI therapy (n = 62) had a 7.0 % increase, and the patients without prior AI therapy (n = 29) had a 6.8 % increase. At 24 months, the right and left femoral neck BMD increased by 3.4 % and 3.6 %. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000022256.
Effects of oral vitamin B12 for the treatment of aromatase inhibitors (AI)-related musculoskeletal symptoms in women with early stage breast cancer.
Authors: Zeina A. Nahleh, Aleli Campbell, Rosalinda Heydarian, Alok Kumar Dwivedi
Journal: Journal of Clinical Oncology (2018)

86 Background: Breast cancer patients receiving Aromatase Inhibitor (AI) therapy experience many side effects including arthralgias, myalgias and stiffness of joints. The objective of this study was to evaluate the effect of vitamin B12 supplements on pain related symptoms. Methods: In this study, patients taking AIs and experiencing pain at baseline were given 2500 mcg of vitamin B12 sublingually daily for 90 days. The validated Brief Pain Inventory-Short Form (BPI-SF) questionnaire using a 10 scale rating was evaluated prior and post- intervention. The BPI-SF asseses pain level and its interference with other daily life events on a scale from one to ten, one meaning pain does not interfere. Item 9 from the BPI assesses 7 important dimensions that are reported here. Results: 36 patients were recruited and scores were evaluated at baseline and at 90 days after taking vitamin B12 for general activity, mood, walking ability, normal work, relations with people, and for enjoyment of life post interventions as shown in the table. Conclusions: This study suggests that by taking a high dose of vitamin B12, significant improvement was observed in several dimensions related to pain scales in patients with AI -related musculoskeletal symptoms. Preliminary data confirms that vitamin B12 not only help improve pain, but it also aids in improving patient’s mood, well-being and relations with others. Larger randomized studies are warranted to confirm these promising findings. Clinical trial information: NCT03069313. [Table: see text]
Artificial Intelligence in Cardiology
Authors: Kipp W. Johnson, Jessica Torres Soto, Benjamin S. Glicksberg, Khader Shameer, Riccardo Miotto, Mohsin Ali, Euan Ashley, Joel T. Dudley
Journal: Journal of the American College of Cardiology (2018)

Artificial intelligence and machine learning are poised to influence nearly every aspect of the human condition, and cardiology is not an exception to this trend. This paper provides a guide for clinicians on relevant aspects of artificial intelligence and machine learning, reviews selected applications of these methods in cardiology to date, and identifies how cardiovascular medicine could incorporate artificial intelligence in the future. In particular, the paper first reviews predictive modeling concepts relevant to cardiology such as feature selection and frequent pitfalls such as improper dichotomization. Second, it discusses common algorithms used in supervised learning and reviews selected applications in cardiology and related disciplines. Third, it describes the advent of deep learning and related methods collectively called unsupervised learning, provides contextual examples both in general medicine and in cardiovascular medicine, and then explains how these methods could be applied to enable precision cardiology and improve patient outcomes.
A phase I/II trial of NBTXR3 nanoparticles activated by SBRT in the treatment of liver cancers.
Authors: Enrique Chajon, Marc Pracht, Thierry De Baere, France Nguyen, Jean-Pierre Bronowicki, Veronique Vendrely, Anne-Sophie Baumann, Valérie Croisé-Laurent, Eric Deutsch
Journal: Journal of Clinical Oncology (2018)

TPS551 Background: A new class of material with high electron density, hafnium oxide, was designed at the nanoscale (NBTXR3) to efficiently enhance the energy dose deposit from within the tumor cells and increase lethality of tumors, when exposed to radiotherapy (RT). The physical mode of action of NBTXR3 may represent a breakthrough approach for the local treatment of liver cancers, as it does not engage liver and renal functions, i.e. nanoparticles are not metabolized and not excreted by kidney. A phase I/II trial has been implemented for the treatment of hepatocellular carcinoma and liver metastasis [NCT02721056]. The study is currently recruiting patients. Methods: Patients (pts) receive a single intralesional (IL) injection of NBTXR3 (53.3g/L) at Volume levels equivalent to 10%, 15%, 22% and 33% of the baseline tumor volume, followed by RT (SBRT, 45Gy / 3 fractions / 5 to 7 days). For the Phase I part, primary endpoints include determination of the Recommended Dose and Dose Limiting Toxicities (DLT). The Phase II part will test three different groups of patients, HCC with portal vein thrombus, HCC without portal vein thrombus and a third cohort with liver metastases. Primary endpoints are complete response rate and safety. Results: Enrollment was completed for Volume levels 10% (6 pts) and 15% (4 pts) and is currently recruiting patients at 22% level. The NBTXR3 injections were successful in all cases. Radiotherapy has been delivered as planned without any DLT occurrence. No serious adverse event (SAE) related to NBTXR3 or the treatment procedure occurred. Three adverse events related to the injection were reported and no adverse event related to NBTXR3. Importantly, NBTXR3 nanoparticles did not have any impact on the reliability of image-guided radiation therapy (IGRT). Conclusion: The injection of NBTXR3 was safe and well tolerated at these levels. Patients received the planned RT. No DLT occurred. Enrollment is now opened at the 22% level. NBTXR3 shows promising results in terms of safety and antitumor activity and is also currently evaluated in other six clinical studies. Clinical trial information: NCT02721056.
Distress screening, intervention, and follow-up outcomes among Hispanic and Caucasian women with newly diagnosed breast cancer.
Authors: Rebecca C. Shay, Gregory Joseph Britt
Journal: Journal of Clinical Oncology (2018)

163 Background: We describe acceptance and impact of mental health (MH) interventions provided to an English speaking Caucasian and Spanish speaking Hispanic female breast cancer (BC) population reporting symptoms of depression and anxiety. Methods: Records of 170 women with newly diagnosed BC at Cancer Centers of Colorado at SCL Health/Saint Joseph Hospital in 2015 were retrospectively assessed for record of a distress screening questionnaire (DSQ), administered in each patients’ native language. Among patients who reported psychosocial distress (PD), records were reviewed for an outreach phone call and visit with social work (SW) or MH, new antidepressant or anxiolytic prescription, and completion of a second DSQ. SCL Health IRB approval obtained. Results: Of 170 subjects, 94 (68% (n = 64) Caucasian, 19% (n = 18) Hispanic, 13% (n = 12) other) completed an initial DSQ. Scores reflecting PD were seen in 57 DSQs; 15 were high-grade PD (HPD). Nearly half (49%; n = 28) of those with PD had been called by MH or SW; 93% (n = 14) with HPD were called. Anxiety scores (AS) improved in 78% (n = 18) and depression scores (DS) in 74% (n = 17) of subjects called. AS and DS improved in 67% (n = 8) and 75% (n = 9), respectively, of Caucasian patients and in 89% (n = 8) and 67% (n = 6) of Hispanic patients called. Of 35 patients who completed follow-up DSQ, 17 visited with MH or SW. AS and DS improved in 65% (n = 11) of these. Improved AS and DS were seen in 38% (n = 3) and 63% (n = 5) of Caucasian patients, respectively, and 88% (n = 7) and 63% (n = 5) of Hispanic patients who had a visit. An antidepressant or anxiolytic was prescribed for 7 patients; AS and DS improved for 33% (n = 1) of Caucasian patients and 67% (n = 2) of Hispanic patients given prescriptions. Conclusions: Outreach to patients with PD and HPD correlated with improved AS and DS. Hispanics were more likely than Caucasians to accept a visit from MH or SW and were more likely to improve AS and DS following a visit with these services or antidepressant or anxiolytic prescription, demonstrating the importance of intervention in this group. This study does not account for patients’ initial staging, progression or regression, therapy pursued, nor presence of other psychosocial concern.
Engineering the Mucus Barrier
Authors: T.L. Carlson, J.Y. Lock, R.L. Carrier
Journal: Annual Review of Biomedical Engineering (2018)

Mucus selectively controls the transport of molecules, particulate matter, and microorganisms to the underlying epithelial layer. It may be desirable to weaken the mucus barrier to enable effective delivery of drug carriers. Alternatively, the mucus barrier can be strengthened to prevent epithelial interaction with pathogenic microbes or other exogenous materials. The dynamic mucus layer can undergo changes in structure (e.g., pore size) and/or composition (e.g., protein concentrations, mucin glycosylation) in response to stimuli that occur naturally or are purposely administered, thus altering its barrier function. This review outlines mechanisms by which mucus provides a selective barrier and methods to engineer the mucus layer from the perspective of strengthening or weakening its barrier properties. In addition, we discuss strategic design of drug carriers and dosing formulation properties for efficient delivery across the mucus barrier.
The survivorship tsunami: Sustainability of current models of follow-up care.
Authors: Deborah Mayer, George Knafl, Brendan Fitzpatrick, Brenda Marion Nevidjon
Journal: Journal of Clinical Oncology (2018)

48 Background: Annual statistics describe the number of anticipated new cancer cases and deaths as well as the prevalence of those living with cancer. In practice, the number of new cases is used as a proxy for cancer program size, planning program growth and determining workforce needs. While the number of new cases and prevalence has been growing linearly, it may be a poor measure for anticipating health care workforce and clinical resource needs. We explored modeling growth curves of follow-up visits based on anticipated number of new cases alone or with follow-up visits to compare these two approaches. Methods: We used the following assumptions in creating the growth curves: 1) only 50% of new cancer cases would be counted to adjust for those with metastatic disease or different follow-up schedules; 2) the first year of diagnosis would be considered treatment; 3) a common solid tumor follow-up regimen would be used that included 4 visits in year 2, 3 visits in year 3, 2 visits in year 2 and 1 visit in year 5 and thereafter; and 4) new cases would grow at a rate of 10%/year. We then modeled discharging the 50% included in the model at 5 or 10 years. We did not factor in existing patients being seen in a program. Results: If a program had 5,000 new cases in the first year, with a 10% annual growth, there would be 11,790 new cases at 10 years. If you just looked at the 50% receiving follow-up care for 10 years after diagnosis, there would be 35,928 follow-up visits at 5 years and 70,662 visits at 10 years. If you just looked at the 50% receiving follow-up care for only 5 years after diagnosis, there would be 33,428 follow-up visits at 5 years and 53,870 visits at 10 years. Further analysis based on different program sizes and assumptions will be presented. Conclusions: Planning workforce and clinical resources based on number of new cancer cases alone will be inadequate to predict those needs. Risk based modeling and triage will be needed in a new model of follow-up or survivorship care that remains to be developed, tested and deployed to avoid a crisis in cancer survivorship care.
“Getting to Know You and Your Child” screening questionnaire: Results from a Chicago pediatric collaborative.
Authors: Eugene Suh, Erika D Owen, Jennifer Reichek, Betty Roggenkamp, Julia Rachel Trosman, Tara O. Henderson, Nupur Mittal, Dipti Dighe, Asneha Iqbal, Rosa Berardi, Daniel K. Choi, Natasha Pillay Smiley, Caroline Hesko, Jason Andrew Canner, Zayda Stewart, Stacy D. Sanford, Christine B. Weldon
Journal: Journal of Clinical Oncology (2018)

163 Background: In 2012, a congressional symposium identified the need for services to address psychosocial issues of children with cancer. In 2013, the Institute of Medicine recommended supportive oncology services be initiated at cancer diagnosis. Chicago providers of pediatric cancer are collaborating to improve care for children with cancer and their families focusing on psychosocial stressors and quality of life. Methods: The collaborative conducted a structured review of tools: Psychosocial Assessment Tool (PAT), Social Work Assessment Tool (SWAT), National Comprehensive Cancer Network (NCCN) Problem List, and √IN; with input from providers on stressors throughout the care continuum. The resulting screening tool was created and piloted in English and Spanish at 7 pediatric cancer hospitals. Social workers (SW) informally reported assessment of its usefulness. Results: Parents (n = 85) completed “Getting to Know You and Your Child” screening tool which inquired about caregivers, siblings, child’s interests, school, SSI/SNAP, challenges, and cultural/religious preferences. Providers reported families found the tool useful “to think about support needs.” The tool assessed 12 psychosocial stressors; the mean per patient/family was 2.4 (range 0-11). Most frequent stressors included: lack of support from friends, family, community (29%), paying for food (26%), job flexibility (26%), paying for utilities (25%), medical costs (23%), emotional support for family (22%), school concerns (21%). All who reported temporary residence also reported difficulty paying for housing (p &lt; 0.01). Ten SWs reported this screening tool generated new insight into family structures, identified stressors and informed resolution efforts. Provider recommended adjustments to the screening tool: simplify terms for siblings, hobbies and spiritual, add pet question. Conclusions: Pilot testing of a psychosocial screening tool for pediatric and adolescent oncology informed providers of patient/family needs in a standard manner. Six of the seven pilot sites are implementing this tool as a standard practice. Preliminary data suggests patients and providers find the screener easy to use and informative.
Abstract 18269: Regional Longitudinal Deformation Improves Prediction of Ventricular Tachyarrhythmias in Heart Failure Patients With Reduced Ejection Fraction - A MADIT-CRT Sub-Study
Authors: Tor Biering-Sørensen, Dorit Knappe, Anne-Catherine Pouleur, Brian Clagett, Arthur J Moss, Scott D Solomon, Valentina Kutyifa
Journal: Circulation (2015)

Background: Abnormalities of regional function are known predictors of ventricular arrhythmia. We assessed whether measures of regional longitudinal deformation by speckle tracking echocardiography improve prediction of ventricular tachyarrhythmias over clinical, echocardiography parameters, or biomarkers. Methods: We studied 1064 patients enrolled in MADIT-CRT with speckle-tracking data available. Peak longitudinal strain was obtained for the septal, lateral, anterior and inferior myocardial walls. The endpoint was the first event of ventricular tachycardia (VT) or fibrillation (VF). Results: During the median follow-up of 2.9 years, 254 (24%) patients developed VT/VF. Patients with VT/VF had significantly lower LVEF (28.3% vs 29.5%, p&lt;0.001) and longitudinal strain in all myocardial walls compared to patients without VT/VF (Figure). After multivariate adjustment for clinical and conventional echocardiographic predictors of VT/VF, only longitudinal strain in the anterior and inferior myocardial walls remained independent predictors of VT/VF (anterior: HR 1.08 [1.03; 1.13], p=0.001; inferior: HR 1.08 [1.04; 1.12], p&lt;0.001; per 1% increase for both). After including BNP in the model, only a decreasing myocardial function in the inferior myocardial wall predicted VT/VF (HR 1.05 [1.00; 1.10], p&lt;0.05) (Figure). Additionally, only strain in the inferior myocardial wall provided incremental prognostic information on the risk of VT/VF when added to a model already including clinical parameters and LVEF, determined by a significant increase in the Harrell’s C-statistic (0.70 vs 0.67, p=0.002). Conclusion: In MADIT-CRT, assessment of regional longitudinal myocardial deformation in the inferior myocardial wall provided incremental prognostic information over clinical, conventional echocardiographic risk factors, or biomarkers in predicting ventricular tachyarrhythmias.
Fecal Microbiota Transplantation for Primary <i>Clostridium difficile</i> Infection
Authors: Frederik E Juul, Kjetil Garborg, Michael Bretthauer, Hilde Skudal, Mari N Øines, Håvard Wiig, Øystein Rose, Birgitte Seip, J Thomas Lamont, Tore Midtvedt, Jørgen Valeur, Mette Kalager, Øyvind Holme, Lise Helsingen, Magnus Løberg, Hans-Olov Adami
Journal: New England Journal of Medicine (2018)

To the Editor: Clostridium difficile infection is a major health problem. 1 Antibiotic treatment is associated with a considerable rate of recurrence of infection and is related to the emergence of antibiotic-resistant bacteria.Recently, fecal microbiota transplantation has been shown to be effective in the treatment of recurrent C. difficile infection. 2 We undertook a proof-of-concept trial (ClinicalTrials.govnumber, NCT02301000) to evaluate the use of fecal microbiota transplantation as treatment for primary C. difficile infection.The trial began on November 25, 2014, and the first patient underwent randomization on February 22, 2015.From February 2015 through November 2017, at six hospitals in Norway, we randomly assigned 21 adult patients with acute C. difficile infection (≥3 loose stools per day and a positive C. difficile stool test) who had not had previous C. difficile infection to recommended treatment in Norway 3 (oral metronidazole at a dose of 400 mg three times a day for 10 days) or fecal microbiota transplantation (one 60-ml enema of anaerobically cultivated human intestinal microbiota) (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). 4,5 Achim Biotherapeutics, which provided the fecal microbiota suspension free of charge to the investigators for the purpose of the trial, had no role in the design, conduct, or analyses of the trial.The protocol, available at NEJM.org, was approved by the institutional review board, and all patients provided written informed consent.The primary end point was clinical cure (firm stool consistency or ≤3 bowel movements per day) with no evidence of recurrence of C. difficile infection when the patient was evaluated at day 70 by an assessor who was unaware of the treatment assignment.Secondary end points were