tbuckley/cabot-search huggingface dataset:
Abstract 18831: Utilization of Palliative Care Consultation During Therapeutic Hypothermia Following Cardiac Arrest
Authors: Emily K Zern, Michael N Young, Meng Xu, Taylor S Triana, Benjamin B Holmes, Nyal Borges, John A McPherson, Mohana B Karlekar
Journal: Circulation (2015)

Background: Palliative care (PC) is integral in the care of patients with advanced medical illnesses. The significant morbidity and mortality associated with therapeutic hypothermia (TH) after cardiac arrest calls for improved end-of-life care. The goal of this descriptive study was to review our institutional experience with PC consultation in this critically ill population. Methods: We conducted a retrospective study of 319 consecutive patients undergoing TH post-cardiac arrest at Vanderbilt University Medical Center from May 2007 to April 2014. We compared intensive care unit characteristics of patients who received PC consultation (n=125) to those who did not (n=194). We performed Wilcoxon rank sum analyses for time on mechanical ventilation and vasopressor support and Pearson chi-square analyses for inpatient mortality, placement of a Do Not Resuscitate (DNR) order and withdrawal of life support. Results: The number of TH patients and PC consultations in this population increased over time (Figure 1). In the overall cohort, the mean age was 57.3 years (+/- 15.3), and 61% of patients were male. The PC group was mechanically ventilated longer (mean 5.18 vs. 3.45 days, p&lt;0.001) with a trend toward longer vasopressor support (47.2 vs. 40.8 hours, p=0.055) and higher inpatient mortality (68% vs. 49%, p=0.001). PC consultation was also associated with a higher frequency of DNR order placement during hospitalization (75% vs. 36%, p&lt;0.001) and increased frequency of withdrawal of life support (64% vs. 42%, p&lt;0.001). Conclusions: In our TH population, PC consultation increased over time, corresponding to our institution’s expansion of staffing, opening of a PC unit and integration of this service into our published TH protocol. Future studies may delineate the appropriate patient selection for PC consultation to better facilitate goals of care and medical decision-making.
The effects of tetrathiomolybdate (TM) on prostate cancer motility, invasion and adhesion to bone
Authors: Lisa K. Jones, Rebecca A. Philips, Jennifer L. Carroll, Briana J. Williams
Journal: Cancer Research (2006)

3430   Prostate cancer is often curable when detected early, but for many men, it is a progressive disease that ultimately metastasizes to the bone. Metastases are the primary reason for prostate cancer mortality, and the best current treatments for advanced disease only extend life for a relatively short period. Metastasis to bone is a complex process. A fraction of cancer cells that enter the bloodstream reach the bone marrow, adhere to cellular components and develop into aggressive metastases. Adhesion of cancer cells is a necessary step to productive metastatic growth and therefore an obvious target for therapeutic intervention. Elevated NF-κB expression has been implicated in prostate cancer cases with poor prognoses and is a pivotal transcription factor for induction and maintenance of bone metastases. Our goals were to investigate the effects of TM on motility, invasion, and adhesive properties of the human PC-3M prostate cancer cell line. These processes are controlled by a number of signal transduction pathways, including NFκB, which may be inhibited by TM. We show here a variety of effects of TM on prostate cancer motility, invasion, and adhesion of prostate cancer cells to components of the bone environment. Using a modified Boyden chamber assay, TM blocked 24 hour motility of PC-3M cells by over 50% and invasion through a Matrigel barrier by greater than 80%. In addition, by ELISA, TM significantly inhibited both VEGF and FGF-2 expression in a dose-dependent manner. In bone adhesion assays, TM significantly inhibited PC-3M adhesion to hFOB1.19 and also blocked TNF-α induced adhesion. Possible mechanisms to account for these changes are both NFκB-dependent and NFκB-independent and include inhibition of IL-8, MIP-1α, and MIG. IL-8 has been shown to be a poor prognostic factor in human prostate cancer and is critical to bone metastases, while MIP-1α promotes adhesion of cancer cells to bone stroma. MIG, or CXCL9, is a recruitment factor for T cells, maintains tumor angiogenesis and is induced by NFκB signaling. TM’s inhibition of NFκB-dependent angiogenic factors such as VEGF and MIG as well as other non-NFκB targets make TM a promising adjuvant therapeutic for advanced prostate cancer.
RETRACTED: Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease
Authors: Alexander Liu, Rohan S. Wijesurendra, Joanna M. Liu, Andreas Greiser, Michael Jerosch-Herold, John C. Forfar, Keith M. Channon, Stefan K. Piechnik, Stefan Neubauer, Rajesh K. Kharbanda, Vanessa M. Ferreira
Journal: Journal of the American College of Cardiology (2018)

Novel cardiac magnetic resonance (CMR) stress T1 mapping can detect ischemia and myocardial blood volume changes without contrast agents and may be a more comprehensive ischemia biomarker than myocardial blood flow.This study describes the performance of the first prospective validation of stress T1 mapping against invasive coronary measurements for detecting obstructive epicardial coronary artery disease (CAD), defined by fractional flow reserve (FFR <0.8), and coronary microvascular dysfunction, defined by FFR ≥0.8 and the index of microcirculatory resistance (IMR ≥25 U), compared with first-pass perfusion imaging.Ninety subjects (60 patients with angina; 30 healthy control subjects) underwent CMR (1.5- and 3-T) to assess left ventricular function (cine), ischemia (adenosine stress/rest T1 mapping and perfusion), and infarction (late gadolinium enhancement). FFR and IMR were assessed ≤7 days post-CMR. Stress and rest images were analyzed blinded to other information.Normal myocardial T1 reactivity (ΔT1) was 6.2 ± 0.4% (1.5-T) and 6.2 ± 1.3% (3-T). Ischemic viable myocardium downstream of obstructive CAD showed near-abolished T1 reactivity (ΔT1 = 0.7 ± 0.7%). Myocardium downstream of nonobstructive coronary arteries with microvascular dysfunction showed less-blunted T1 reactivity (ΔT1 = 3.0 ± 0.9%). Stress T1 mapping significantly outperformed gadolinium-based first-pass perfusion, including absolute quantification of myocardial blood flow, for detecting obstructive CAD (area under the receiver-operating characteristic curve: 0.97 ± 0.02 vs. 0.91 ± 0.03, respectively; p < 0.001). A ΔT1 of 1.5% accurately detected obstructive CAD (sensitivity: 93%; specificity: 95%; p < 0.001), whereas a less-blunted ΔT1 of 4.0% accurately detected microvascular dysfunction (area under the receiver-operating characteristic curve: 0.95 ± 0.03; sensitivity: 94%; specificity: 94%: p < 0.001).CMR stress T1 mapping accurately detected and differentiated between obstructive epicardial CAD and microvascular dysfunction, without contrast agents or radiation.
Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery
Authors: Angela M. Wagner, Margaret P. Gran, Nicholas A. Peppas
Journal: Acta Pharmaceutica Sinica B (2018)

Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties, therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal (GI) tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drug delivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.
Developing Anticancer Drugs in Orphan Molecular Entities — A Paradigm under Construction
Authors: Fabrice André
Journal: New England Journal of Medicine (2018)

Genomic characterization of cancers has shown that some oncogenic alterations occur at very low frequency and are shared across tumor types. For example, NTRK translocations mediate malignant transformation and are observed in less than 1% of cancers and in more than 20 cancer types.1 The genes NTRK1, NTRK2, and NTRK3 encode for the tropomyosin receptor kinase (TRK) proteins TRKA, TRKB, and TRKC, respectively. In this issue of the Journal, Drilon et al.2 report a pooled analysis of three prospective clinical trials testing larotrectinib, a TRK inhibitor, in 55 patients. The overall response rate was 80%, and 71% of the responses . . .
A large electronic-health-record-based genome-wide study of serum lipids
Authors: Thomas J. Hoffmann, Elizabeth Theusch, Tanushree Haldar, Dilrini K. Ranatunga, Eric Jorgenson, Marisa W. Medina, Mark N. Kvale, Pui-Yan Kwok, Catherine Schaefer, Ronald M. Krauss, Carlos Iribarren, Neil Risch
Journal: Nature Genetics (2018)
Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness
Authors: Andrew L Durham, Mei Y Speer, Marta Scatena, Cecilia M Giachelli, Catherine M Shanahan
Journal: Cardiovascular Research (2018)

Vascular calcification is associated with a significant increase in all-cause mortality and atherosclerotic plaque rupture. Calcification has been determined to be an active process driven in part by vascular smooth muscle cell (VSMC) transdifferentiation within the vascular wall. Historically, VSMC phenotype switching has been viewed as binary, with the cells able to adopt a physiological contractile phenotype or an alternate 'synthetic' phenotype in response to injury. More recent work, including lineage tracing has however revealed that VSMCs are able to adopt a number of phenotypes, including calcific (osteogenic, chondrocytic, and osteoclastic), adipogenic, and macrophagic phenotypes. Whilst the mechanisms that drive VSMC differentiation are still being elucidated it is becoming clear that medial calcification may differ in several ways from the intimal calcification seen in atherosclerotic lesions, including risk factors and specific drivers for VSMC phenotype changes and calcification. This article aims to compare and contrast the role of VSMCs in driving calcification in both atherosclerosis and in the vessel media focusing on the major drivers of calcification, including aging, uraemia, mechanical stress, oxidative stress, and inflammation. The review also discusses novel findings that have also brought attention to specific pro- and anti-calcifying proteins, extracellular vesicles, mitochondrial dysfunction, and a uraemic milieu as major determinants of vascular calcification.
ADVANCED PRACTICE PROVIDERS UTILIZE A PRE-CATHETERIZATION SCREENING TOOL TO DECREASE CONTRAST INDUCED NEPHROPATHY
Authors: Jennifer K. McCullough, Ralph G. Smith, Timothy J. Boyek, Sharon M. Delaney, Valerie J. Dziados, Joette C. Hughes, Lauren D. Waronker, Monica R. Pammer, Laura Butera-Belton, Katherine McLeod, Joanne Seward, Jennifer Seneca, Christine Guilday
Journal: Journal of the American College of Cardiology (2018)
Utility of comprehensive genomic profiling (CGP) to distinguish neoplasms pathologically diagnosed as PanNETs and PanNECs and identify potentially actionable genomic alterations (GA).
Authors: Aatur D. Singhi, Philip J. Stephens, Jeffrey S. Ross, Vincent A. Miller, Siraj Mahamed Ali, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2018)

274 Background: The majority of pancreatic neuroendocrine neoplasms are classified as pancreatic neuroendocrine tumors (PanNETs) or carcinomas (PanNECs). These are distinct entities with respect to clinical presentation, prognosis and treatment; however, locally advanced/metastatic cases may exhibit overlapping histopathologic features and, thus are challenging to differentiate and may result in inappropriate management. Recent sequencing studies have identified key differences between PanNETs and PanNECs. PanNECs often harbor recurrent GA in RB1, and members of the RAS/MAPK and TGF-β pathways. In contrast, PanNETs frequently exhibit GA in chromatin remodeling genes (e.g., MEN1, DAXX and ATRX). The purpose of this study was to evaluate the utility of CGP in the pathologic assessment of locally advanced/metastatic pancreatic neuroendocrine neoplasms. Methods: Hybrid-capture based CGP was performed for up to 315 cancer-related genes and intronic regions of up to 28 genes rearranged in cancer on 318 locally advanced/metastatic pancreatic neuroendocrine neoplasms. Results were correlated with submitting histopathologic diagnoses. Results: Among 50 pathologically-classified PanNETs, 41 (82%) and 9 (18%) cases harbored GA consistent with a PanNET and PanNEC, respectively. In comparison, among 268 pathologically-classified PanNECs, 209 (78%) and 59 (22%) cases had GA compatible with a PanNET and PanNEC, respectively. Commonly altered genes in CGP-classified PanNETs include: MEN1 (37%), DAXX (21%), CDKN2A/B (20%), ATRX (11%), TSC2 (10%), TP53 (8%), PTEN (8%), ARID1A (7%) and SETD2 (5%). Defects in the BRCA pathway were seen in 10% of PanNETs. Conversely, CGP-classified PanNECs had GA in TP53 (54%), RB1 (49%), KRAS (46%), CDKN2A/B (21%), GNAS (10%), PTEN (9%), SMAD4 (7%), MYC (7%) and ARID1A (6%). Conclusions: Pathologic discrimination between PanNETs and PanNECs can be difficult, but incorporating CGP improves the classification of these neoplasms. Further, the identification of recurrent GA in members of the BRCA family highlights a potential therapeutic target for locally advanced/metastatic PanNETs.
Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes
Authors: Caroline E. Broos, Laura L. Koth, Menno van Nimwegen, Johannes C.C.M. in ‘t Veen, Sandra M.J. Paulissen, Jan Piet van Hamburg, Jouke T. Annema, Roxane Heller-Baan, Alex Kleinjan, Henk C. Hoogsteden, Marlies S. Wijsenbeek, Rudi W. Hendriks, Bernt van den Blink, Mirjam Kool
Journal: European Respiratory Journal (2018)

The lung-draining mediastinal lymph nodes (MLNs) are currently widely used to diagnose sarcoidosis. We previously reported that T-helper (Th) 17.1 cells are responsible for the exaggerated interferon-γ production in sarcoidosis lungs. In this study, we aimed to investigate 1) whether Th17.1 cells are also increased in the MLNs of sarcoidosis patients and 2) whether frequencies of the Th17.1 cells at diagnosis may correlate with disease progression.MLN cells from treatment-naive pulmonary sarcoidosis patients (n=17) and healthy controls (n=22) and peripheral blood mononuclear cells (n=34) and bronchoalveolar lavage fluid (BALF) (n=36) from sarcoidosis patients were examined for CD4+ T-cell subset proportions using flow cytometry.Higher proportions of Th17.1 cells were detected in sarcoidosis MLNs than in control MLNs. Higher Th17.1 cell proportions were found in sarcoidosis BALF compared with MLNs and peripheral blood. Furthermore, BALF Th17.1 cell proportions were significantly higher in patients developing chronic disease than in patients undergoing resolution within 2 years of clinical follow-up.These data suggest that Th17.1 cell proportions in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and could serve as a new therapeutic target.
CCGs want more information on commissioning support offerings
Authors: Helen Jaques
Journal: BMJ (2012)

Clinical commissioning groups (CCGs) want more information and advice on the choice of commissioning support services (CSSs) available in their area to help them deal with the high levels of uncertainty about their commissioning support arrangements.

A survey commissioned on behalf of the NHS Commissioning Board by NHS Clinical Commissioners—a membership organisation for CCGs run by the National Association of Primary Care, NHS Alliance, and the NHS Confederation—found that more than half (59%) of emerging CCGs want more information about …
Endobronchial coil penetration into the pleural space
Authors: Giampietro Marchetti, David J McCracken, Najib M Rahman
Journal: Thorax (2018)

A patient with severe emphysema, post pulmonary rehabilitation and on full inhaled treatment underwent elective placement of eight endobronchial coils (RePneu Lung Volume Reduction Coils) in the right lung to attempt endoscopic lung volume reduction, targeted at the upper and lower lobes. The patient was not suitable for surgical open lung volume reduction and was unable to undergo valve treatment due to homogenous disease and an incomplete fissure on thoracic CT. Twelve hours post …
Extracellular Vesicles in Human Reproduction in Health and Disease
Authors: Carlos Simon, David W Greening, David Bolumar, Nuria Balaguer, Lois A Salamonsen, Felipe Vilella
Journal: Endocrine Reviews (2018)

Extensive evidence suggests that the release of membrane-enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communication both in normal physiology and in pathological conditions. This review presents evidence about the formation and release of different EVs, their definitive markers and cargo content in reproductive physiological processes, and their capacity to convey information between cells through the transfer of functional protein and genetic information to alter phenotype and function of recipient cells associated with reproductive biology. In the male reproductive tract, epididymosomes and prostasomes participate in regulating sperm motility activation, capacitation, and acrosome reaction. In the female reproductive tract, follicular fluid, oviduct/tube, and uterine cavity EVs are considered as vehicles to carry information during oocyte maturation, fertilization, and embryo-maternal crosstalk. EVs via their cargo might be also involved in the triggering, maintenance, and progression of reproductive- and obstetric-related pathologies such as endometriosis, polycystic ovarian syndrome, preeclampsia, gestational diabetes, and erectile dysfunction. In this review, we provide current knowledge on the present and future use of EVs not only as biomarkers, but also as therapeutic targeting agents, mainly as vectors for drug or compound delivery into target cells and tissues.
Welsh GP contract changes will remove “treadmill of bureaucracy” by cutting QOF by a third
Authors: Abi Rimmer
Journal: BMJ (2014)

Changes to the GP contract in Wales have been agreed for 2014-15, including the removal of a third of points from the Quality and Outcomes Framework (QOF) and the phasing out of the minimum practice income guarantee (MPIG) over seven years.1

As part of the changes, agreed by the British Medical Association’s Welsh General Practitioners Committee and the Welsh government, 300 points will be removed from QOF, leaving a total of 669 points. Mark Drakeford, health minister for Wales, said that the changes would “remove the treadmill of bureaucracy and place greater reliance and trust in the professionalism of GPs to …
Front-line therapies for elderly patients with transplant-ineligible multiple myeloma and high-risk cytogenetics in the era of novel agents
Authors: Herve Avet-Loiseau, Thierry Facon
Journal: Leukemia (2018)

In multiple myeloma, certain cytogenetic abnormalities, such as t(4;14), t(14;16), and del(17p), are considered high risk and are associated with worse prognosis. Patients with these high-risk cytogenetic abnormalities, as well as those who are elderly and transplant ineligible, have not experienced the same degree of improved survival outcomes that other patients have seen with recent advances in the treatment of multiple myeloma. To date, no treatment regimen has demonstrated sustained and consistent survival benefits in elderly, transplant-ineligible patients with high-risk cytogenetic abnormalities and newly diagnosed multiple myeloma. Thus, there is an unmet need to identify effective treatment options for these patients and achieve outcomes parity with standard-risk patients. In this review, we assessed clinical trials of both doublet and triplet regimens for newly diagnosed multiple myeloma that included elderly, transplant-ineligible patients with high-risk cytogenetic abnormalities and that provided outcomes data stratified by cytogenetic risk status. We concluded that regimens containing an IMiD agent as the foundation of therapy, combined with agents that have synergistic mechanisms of action—including novel therapies—may in future investigations help overcome the poor prognosis of high-risk cytogenetic abnormalities in this vulnerable patient population.
International medical graduates more likely to defer revalidation, GMC says
Authors: Abi Rimmer
Journal: BMJ (2014)

International medical graduates are more likely to defer their revalidation date than doctors who qualified in the UK, the General Medical Council has said.

Speaking at the British Association of Physicians of Indian Origin conference in Manchester on Saturday 29 November, Niall Dickson, chief executive of the GMC, said that the regulator knew about the potential for bias in the revalidation process.

“We are acutely aware of the …
Eradication of Glioblastoma Multiforme stem-cells with Immunotargeted-molecular-robotic-NANOSURGERY (ITMRN)
Authors: John Giannios
Journal: Neuro-Oncology (2018)

GBM stem cells are resistant to conventional treatment forming recurrent-tumors via angiogenesis.Thus,they are considered primary targets for novel therapeutic strategies for GBM. We obtain relapsed chemo-radioresistant GBM stem cells overexpressing CD133 from which we develop a GBM model that we treat with immunotargeted pegylated silver nanobots(PEG-AgNPs) which are covalently conjugated to anti-CD133 MAbs for targeting Brain-Cancer-Stem-Cells(BCSCs) after receptor-mediated-endocytosis.Then,we treat them with radiofrequency-dielectric-heating(RFDH) as a novel postsurgical-adjuvant-treatment. Post-treatment,the silver nanobots AgNPs release Ag+ ions which disrupt mitochondrial-respiratory-chain(MRC) blocking ATP-synthesis by production of ROS which damage the DNA of CSCs leading to cell-cycle arrest at G2/M phase and type-1 PCD of stage-D2 or apoptosis.The capacitive nonionizing radiofrequency-dielectric-heating of 13.56MHz exerts hyperthermic cytotoxicity increasing the intracellular-Temperature of BCSCs up to 50 degrees Celcius leading to the necrosis of Brain-Cancer-Stem-Cells(BCSCs). This immunotargeted molecular robotic nanosurgical approach may be used as an adjuvant treatment against GBM which is resistant to conventional chemo/radiation therapy by eradicating its cancer-stem-cells.