tbuckley/cabot-search huggingface dataset:
Vasodilator Therapy for Congestive Heart Failure—New Use for Old Drugs
Authors: Rex N. MacAlpin
Journal: JAMA (1978)

The magnitude of systolic shortening of cardiac muscle is related directly to the diastolic length of the muscle and to its contractile state, and inversely to the force against which it must shorten (afterload). The normal heart in diastole operates on a compliant part of its tension-length curve, ie, a small increase in distending force (filling pressure or preload) stretches the muscle a relatively large amount and causes a relatively great increase in diastolic volume. If the afterload remains unchanged, this distended ventricle will in systole eject an increased stroke volume. This is a means whereby the normal heart can increase its stroke output in response to an increase in input without resorting to an increase in heart rate or basic contractile state. By the same mechanism it can also<i>maintain</i>its stroke volume in the face of an increased afterload at the expense of a small increase in diastolic
Obamacare: what the Affordable Care Act means for patients and physicians
Authors: M. A. Hall, R. Lord
Journal: BMJ (2014)

The Affordable Care Act's core achievement is to make all Americans insurable, by requiring insurers to accept all applicants at rates based on population averages regardless of health status. The act also increases coverage by allowing states to expand Medicaid (the social healthcare program for families and people with low income and resources) to cover everyone near the poverty line, and by subsidizing private insurance for people who are not poor but who do not have workplace coverage. The act allows most people to keep the same kind of insurance that they currently have, and it does not change how private insurance pays physicians and hospitals. Although the act falls short of achieving truly universal coverage, nine million uninsured people have received coverage so far. Market reforms have not hurt the insurance industry's profitability, prices for individual insurance have been lower than expected, and government costs so far have been less than initially projected. The act expands several ongoing pilot programs in Medicare that reform how doctors and hospitals are paid, but it does not directly change how private insurers pay healthcare providers. Nevertheless, it has set into motion market dynamics that are affecting medical practice, such as limiting insurance networks to fewer providers and requiring patients to pay for more treatment costs out of pocket. In response, many hospitals and physicians are forming closer and larger affiliations. Further time and study are needed to learn whether these evolutionary changes will achieve their goals without harming the doctor-patient relationship.
Skin cancer: preventive photodynamic therapy in patients with face and scalp cancerization. A randomized placebo-controlled study
Authors: Z. Apalla, E. Sotiriou, E. Chovarda, I. Lefaki, D. Devliotou-Panagiotidou, D. Ioannides
Journal: British Journal of Dermatology (2009)

Background Patients with a previous medical history of nonmelanoma skin cancers (NMSCs) often develop multiple or recurrent malignant lesions around the site of the primary tumour. This finding led to the field cancerization theory, which suggests that the entire epithelial surface of the regional skin has an increased risk for the development of malignant lesions. Management of field change is challenging, taking into account the high impact of NMSCs on public health and healthcare costs. Objectives We sought to investigate whether field‐photodynamic therapy (PDT) of extreme photodamaged skin would prevent new NMSCs, in comparison with a control area receiving placebo‐PDT, in patients with clinical and histological signs of field cancerization. Methods Forty‐five patients, previously diagnosed as having NMSCs of the face or scalp, with actinic keratoses symmetrically distributed over the same regions, were randomized for field treatment with 20% aminolaevulinic acid (ALA)‐PDT on one side and placebo‐PDT on the other. During the next 12‐month period of follow up, patients were clinically evaluated for new NMSCs. Results A significant delay in the mean time of appearance and a reduction in the total number of new lesions were observed in the field‐PDT protocol, when compared with the control. Conclusions The results obtained showed that field therapy with ALA‐PDT confers a significant preventive potential against the formation of new NMSCs in patients with field changes.
Comparison of Use of Medications After Acute Myocardial Infarction in the Veterans Health Administration and Medicare
Authors: Laura A. Petersen, Sharon-Lise T. Normand, Lucian L. Leape, Barbara J. McNeil
Journal: Circulation (2001)

Background — There is concern that care provided in the Veterans Health Administration (VA) may be of poorer quality than non-VA health care. We compared use of medications after acute myocardial infarction in the VA with that in non-VA healthcare settings under fee-for-service (FFS) Medicare financing. Methods and Results — We used clinical data from 2486 VA and 29 249 FFS men &gt;65 years old discharged with a confirmed diagnosis of acute myocardial infarction from 81 VA hospitals and 1530 non-VA hospitals. We reported odds ratios (ORs) for use of thrombolytics, β-blockers, ACE inhibitors, or aspirin among ideal candidates adjusted for age, sample design (hospital academic affiliation, availability of cardiac procedures, and volume), and within-hospital clustering. Ideal VA candidates were more likely to undergo thrombolytic therapy at arrival (OR [VA relative to Medicare] 1.40 [1.05, 1.74]) or to receive ACE inhibitors (OR 1.67 [1.12, 2.45]) or aspirin (OR 2.32 [1.81, 3.01]) at discharge and equally likely to receive β-blockers (OR 1.09 [1.03, 1.40]) at discharge. Conclusions — Ideal candidates in VA were at least as likely as those in FFS to receive medical therapies of known benefit for acute myocardial infarction.
Morphology Controlled Porous Calcium Phosphate Nanoplates and Nanorods with Enhanced Protein Loading and Release Functionality
Authors: Philip James Thomas Reardon, Jie Huang, Junwang Tang
Journal: Advanced Healthcare Materials (2013)

Calcium phosphate nanoplates and nanorods with controllable pores and enhanced protein loading and tuneable release characteristics are first synthesized without the use of any toxic surfactants by an energy efficient microwave assisted chemical process, hence demonstrating their viability as a tool for controllable drug delivery in biomaterial systems.
Cigarette smoke condensate inhibits ENaC -subunit expression in lung epithelial cells
Authors: H. Xu, T. J. Ferro, S. Chu
Journal: European Respiratory Journal (2007)

Cigarette smoke has been associated with lung fluid accumulation and increased risk of acute respiratory distress syndrome. It was postulated that ENaC α-subunit, which plays a critical role in lung fluid absorption, is affected by cigarette smoke. Cigarette smoke condensate (CSC) was used to treat a human lung epithelial cell line. ENaC α-subunit expression was measured using immunoblotting, quantitative PCR and promoter–reporter assays. The current authors found that CSC, without affecting cell survival, suppressed α-subunit expression at the transcriptional level in a dose- and time-dependent fashion. This suppression is neither related to nicotine nor due to an increase of hydrogen peroxide levels in CSC-treated cells. CSC also suppressed α-subunit core promoter activity. Dexamethasone, which activates the core promoter, was able to attenuate the inhibitory effect of CSC. However, in the presence of CSC, dexamethasone was unable to elicit a full-scale activation of α-subunit expression. This inhibition of dexamethasone was partially reversed by withdrawal of CSC. The present results demonstrate that cigarette smoke condensate inhibits ENaC α-subunit expression at the transcriptional level through its promoter. This inhibition could be reversed by dexamethasone. The results also suggest that higher doses of dexamethasone may be needed to activate α-subunit expression in smokers’ lungs compared with nonsmokers’ lungs, and that quitting smoking might improve the effectiveness of dexamethasone.
ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia
Authors: Daniel Steinbach, Jean-Pierre Gillet, Axel Sauerbrey, Bernd Gruhn, Kristin Dawczynski, Vincent Bertholet, Françoise de Longueville, Felix Zintl, Jose Remacle, Thomas Efferth
Journal: Clinical Cancer Research (2006)

Abstract Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases. Experimental Design: A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance. Results: Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2, and ABCC10. The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21 patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage (P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin. Conclusion: Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.
Inhibition of poly adenosine diphosphate-ribose polymerase decreases hepatocellular carcinoma growth by modulation of tumor-related gene expression
Authors: Rosa Quiles-Perez, José Antonio Muñoz-Gámez, Ángeles Ruiz-Extremera, Francisco O'Valle, Laura Sanjuán-Nuñez, Ana Belén Martín-Álvarez, David Martín-Oliva, Trinidad Caballero, Paloma Muñoz de Rueda, Josefa León, Raúl Gonzalez, Jordi Muntané, Francisco Javier Oliver, Javier Salmerón
Journal: Hepatology (2009)

Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to a lack of effective treatment options. In HCC a significant role is played by DNA damage and the inflammatory response. Poly (ADP-ribose) polymerase-1 (PARP-1) is an important protein that regulates both these mechanisms. The objective of this study was to examine the effect of pharmacology PARP-1 inhibition on the reduction of tumor volume of HCC xenograft and on the hepatocarcinogenesis induced by diethyl-nitrosamine (DEN). Pharmacologic PARP-1 inhibition with DPQ greatly reduces tumor xenograft volume with regard to a nontreated xenograft (394 mm(3) versus 2,942 mm(3), P < 0.05). This observation was paralleled by reductions in xenograft mitosis (P = 0.02) and tumor vasculogenesis (P = 0.007, confirmed by in vitro angiogenesis study), as well as by an increase in the number of apoptotic cells in DPQ-treated mice (P = 0.04). A substantial difference in key tumor-related gene expression (transformed 3T3 cell double minute 2 [MDM2], FLT1 [vascular endothelial growth factor receptor-1, VEGFR1], epidermal growth factor receptor [EPAS1]/hypoxia-inducible factor 2 [HIF2A], EGLN1 [PHD2], epidermal growth factor receptor [EGFR], MYC, JUND, SPP1 [OPN], hepatocyte growth factor [HGF]) was found between the control tumor xenografts and the PARP inhibitor-treated xenografts (data confirmed in HCC cell lines using PARP inhibitors and PARP-1 small interfering RNA [siRNA]). Furthermore, the results obtained in mice treated with DEN to induce hepatocarcinogenesis showed, after treatment with a PARP inhibitor (DPQ), a significant reduction both in preneoplastic foci and in the expression of preneoplastic markers and proinflammatory genes (Gstm3, Vegf, Spp1 [Opn], IL6, IL1b, and Tnf), bromodeoxyuridine incorporation, and NF-kappaB activation in the initial steps of carcinogenesis (P < 0.05).This study shows that PARP inhibition is capable of controlling HCC growth and preventing tumor vasculogenesis by regulating the activation of different genes involved in tumor progression.
The Chronic Renal Insufficiency Cohort (CRIC) Study
Authors: Harold I. Feldman, Lawrence J. Appel, Glenn M. Chertow, Denise Cifelli, Borut Cizman, John Daugirdas, Jeffrey C. Fink, Eunice D. Franklin-Becker, Alan S. Go, L. Lee Hamm, Jiang He, Tom Hostetter, Chi-yuan Hsu, Kenneth Jamerson, Marshall Joffe, John W. Kusek, J. Richard Landis, James P. Lash, Edgar R. Miller, Emile R. Mohler, Paul Muntner, Akinlolu O. Ojo, Mahboob Rahman, Raymond R. Townsend, Jackson T. Wright
Journal: Journal of the American Society of Nephrology (2003)

Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.
Not another innovation
Authors: James Owen Drife
Journal: BMJ (2006)

Here on the front line, the title of Davies and Elwyn's article strikes no chords.1 The NHS infantry now greet the words “promising innovation” with groans or silence. We used to laugh but not any more. We have spent far too much of our lives coping with new idea after new idea and making them work, no matter how ill thought out. But no sooner has one innovation begun to bed in, as we learn how to use it, bypass it, or ignore it, than the next is on its way. At first we worried about them. Now we feel nothing.

Managing demand …
COMPARATIVE BACTERICIDAL ACTIVITIES OF BLOOD SERUM AND PLASMA SERUM
Authors: James G. Hirsch
Journal: The Journal of Experimental Medicine (1960)

Rabbit and human plasma can be prepared without resort to anticoagulants by employing low temperatures and non-wetting surfaces. Serum formed after clotting of rabbit plasma devoid of cells and platelets manifests essentially no bactericidal activity on Bacillus subtilis, Bacillus megaterium, and a strain of Staphylococcus aureus. In contrast, rabbit blood serum exhibits this activity to a high degree. Rabbit plasma rich in platelets gives rise to a serum with capacity to kill these Gram-positive microbes equal to that of serum prepared from whole blood. This heat-stable antibacterial agent is efficiently formed or released when platelets are present during the coagulation of plasma, but not on incubation of platelets in heparinized or citrated plasma or in saline. Leucocytes and red cells appear to play no significant role in its production. Rabbit blood serum and plasma serum have similar heat-labile lethal effects on enteric bacilli. Human serum, whether from blood or plasma, manifests much less bactericidal activity on Bacillus subtilis than does rabbit blood serum. These findings serve to emphasize the fact that substances formed or released during coagulation of whole blood may impart to the serum activities not present in circulating plasma.
Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis vulgaris: Results of a pilot, multicenter, multiple-dose, placebo-controlled study
Authors: A B Gottlieb, M Lebwohl, S Shirin, A Sherr, P Gilleaudeau, G Singer, G Solodkina, R Grossman, E Gisoldi, S Phillips, H M Neisler, J G Krueger
Journal: Journal of the American Academy of Dermatology (2000)
p38 Kinase Is Crucial for Osteopontin-Induced Furin Expression That Supports Cervical Cancer Progression
Authors: Vinit Kumar, Reeti Behera, Kirti Lohite, Swapnil Karnik, Gopal C Kundu
Journal: Cancer Research (2010)

p38 kinases activated by growth factors, hormones, and environmental stresses exert diverse functions in regulating normal and malignant cell pathophysiology. Enhanced levels of activated p38 isoforms have been linked with poor prognosis in breast cancer, although the mechanistic basis for this association is poorly understood. In this study, we report that p38 activation in cervical cancer cells is driven by osteopontin (OPN), an extracellular matrix-associated cytokine that drives invasive progression. OPN regulates CD44-mediated p38 phosphorylation that induces NF-κB activation and NF-κB-dependent expression of furin, an extracellular protease implicated in human papilloma virus (HPV) processing that enhances cervical cancer cell motility. OPN induces CD44-mediated MKK3/6 phosphorylation which in turn phosphorylates p38 in these cells. OPN-induced furin expression and cell motility was impeded by blockades to MKK3/6, p38α/β or NF-κB signaling. In a mouse xenograft model of human cervical cancer, tumor growth was enhanced by OPN overexpression and blocked by short hairpin RNA (shRNA)-mediated OPN silencing. Furin overexpression similarly augmented tumor growth in the model, whereas blocking MKK3/6, p38, or furin reduced OPN-induced cervical tumor growth. Analysis of clinical specimens revealed that enhanced expression of OPN, phosphorylated NF-κB, p65, and furin correlated with cervical cancer progression, further strengthening the in vitro and in vivo results. In summary, our findings offer a proof of concept for targeting OPN and its downstream p38 signaling as a novel therapeutic strategy to manage cervical cancer.
A conversation with Paul Greengard
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2013)

If you, or someone you know, has Parkinson’s disease, mental health issues, or other neurological disorders, medication can often help. The bulk of these medications have been established based on the work of neuroscientist Paul Greengard (Figure ​(Figure1)1) from the Rockefeller University, who worked out just how the brain responds to neurotransmitters — the chemicals that help the brain signal. The bulk of what most neuroscientists know today about neurotransmission, and specifically the dynamics of slow synaptic transmission, is predicated on the work of Paul Greengard. The full interview, with many more stories about his seminal research discoveries and his competitive streak in potato sack races, can be seen on the JCI website, http://www.jci.org/kiosk/cgm.
Hyperreactivity of aortic smooth muscle to serotonin is related to the presence of atheroma in Watanabe heritable hyperlipidaemic rabbits
Authors: H. Tagawa, H. Tomoike, W. Mitsuoka, S. Satoh, T. Kuga, H. Shimokawa, M. Nakamura, A. Takeshita
Journal: Cardiovascular Research (1993)

The aim was to elucidate the contribution of atheromatous plaque to alterations of smooth muscle contraction to vasoconstrictive agents, by examining vasoreactivity of vascular smooth muscle from the thoracic aorta of 10-13 month old Watanabe heritable hyperlipidaemic rabbits.From the same vascular ring of the lower thoracic aorta, a pair of small medial smooth muscle strips was prepared from the sites beneath the atheroma (atherosclerotic medial muscle strip) and from those beneath the plaque-free intima (normal medial muscle strip), and isometric tension was measured.Contractions to 118 mM KCl, histamine (30 nM to 10 microM), and noradrenaline (3 nM to 0.3 microM) were similar between atherosclerotic and the normal medial muscle strip. The ED50 to serotonin was 49(SD 28) and 116(66) nM (p < 0.05, n = 7) and the maximum tension to serotonin was 125(29)% and 82(29)% of that induced by 118 mM KCl (p < 0.01, n = 7) in atherosclerotic and normal medial muscle strip, respectively. Serotonin specific hyperreactivity of the atherosclerotic strip disappeared in Ca(2+)-free solution or in the presence of 10 microM H-7, an inhibitor of protein kinase C. After incubation with 0.1 microM phorbol 12,13-dibutyrate, an activator of protein kinase C, the isometric contractions induced by Ca2+ were significantly greater in atherosclerotic than in normal medial muscle strip.These results indicate that medial smooth muscle located beneath the atheroma is specifically hyperreactive to serotonin and that altered protein kinase C activity may explain in part the augmented response to serotonin.
A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer
Authors: B. Glimelius, M. Lahn, S. Gawande, A. Cleverly, C. Darstein, L. Musib, Y. Liu, K.L. Spindler, J.-E. Frödin, Å. Berglund, P. Byström, C. Qvortrup, A. Jakobsen, P. Pfeiffer
Journal: Annals of Oncology (2009)
Abstract IA2: Somatic alterations in human cancer genomes
Authors: Matthew Meyerson
Journal: Cancer Research (2013)

Abstract The advent of high-throughput genome sequence analysis has enabled systematic discovery of somatic genome alterations through genome, exome, and transcriptome sequencing of paired human cancer and germline nucleic acids. These discoveries have led to the identification of somatic genome alterations in new pathways including epigenetic regulators, RNA splicing factors, and immune response regulators, in addition to previously known signal transduction, cell cycle, and transcriptional pathways. I will discuss alterations in these pathways by copy number disruption, mutation, and re-arrangement, especially as seen through the lens of recent and ongoing large-scale studies of lung adenocarcinoma and squamous cell lung carcinoma genomes, from The Cancer Genome Atlas and beyond'and will discuss the implications for the understanding of cancer pathogenesis and for the development of targeted and immunomodulatory therapies. Citation Format: Matthew Meyerson. Somatic alterations in human cancer genomes. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA2.