tbuckley/cabot-search huggingface dataset:
Effects of broad spectrum tyrosin kinase inhibitor on pulmonary circulation homeostasis
Authors: Andrei Seferian, Ly Tu, Alice Huertas, Carole Phan, Morane Le Hiress, Nicolas Ricard, Frederic Perros, Peter Dofmüller, Gerald Simonneau, Marc Humbert, David Montani, Christophe Guignabert
Journal: European Respiratory Journal (2013)

The platelet derived growth factor (PDGF) pathway is altered in pulmonary hypertension (PH) and imatinib a tyrosine kinase inhibitor (TKI) of PDGF has shown encouraging results in animal models of PH. In the meantime, there is an increasing number of PH cases induced by dasatinib, a broad spectrum TKI.

We studied the effects of dasatinib administration in rats: i) chronically and ii) as a pre-treatment before monocrotaline (MCT) injection; and secondary, the impact of dasatinib on cultured human pulmonary endothelial cells was examined by MTT and AnnexinV-PI assay.

Forty rats, divided into three groups received daily intraperitoneal (IP) injections of: vehicle, dasatinib 1x and 10x the clinical dose/day, for maximum 8 weeks. Three rats developed mild PH with a normal cardiac output, but with pulmonary arterial remodeling. One-week pretreatment by dasatinib (same doses) before MCT administration was dose-dependently associated with a more severe hemodynamic profile, greater right ventricular hypertrophy and increased muscularization of distal pulmonary arteries, while imatinib (clinical dose) had a protective effect. In vitro, dasatinib had an important cytotoxic effect on cultured human pulmonary endothelial cells - MTT(50) between 100-200nM, effect due to a dose-dependent increase in apoptosis.

In conclusion, chronic dasatinib treatment in rats causes mild PH and as pretreatment aggravates the MCT-induced PH model. Pulmonary endothelial dysfunction may play a fundamental role in dasatinib-induced PH.
Culture of human epidermal Langerhans cells in a skin equivalent
Authors: None Fransson, None Heffler, None Tengvall Linder, None Scheynius
Journal: British Journal of Dermatology (1998)

Langerhans cells (LCs) have been cultured in a skin equivalent (SE). Seventy‐two SEs were produced by inserting skin biopsies from nine subjects into dermal equivalents consisting of fibroblasts in a collagen matrix. The SEs were cultured in a serum‐free medium containing 2‐mercaptoethanol with or without 5 ng/mL granulocyte–monocyte colony‐stimulating factor (GM‐CSF). The SEs were cultured for 12 or 15 days. In the latter case, 0, 1 or 10 μg/mL cyclosporin A (CyA) was added for the last 3 days. The SEs were then snap frozen for immunohistochemistry. The migration of LCs was evaluated by measuring the distances from the inserted skin biopsy in the SEs to the HLA‐DR + and CD1a+ dendritic cells localized at the longest distance from the biopsy in the epidermal outgrowth on both sides of the biopsy. The density of these cells was estimated in 15‐day‐old SEs by counting them on both sides of the inserted skin biopsy and dividing the number of positive cells by the migrated distances. All epidermal outgrowths (range 0.6–3.7 mm) were well differentiated and displayed HLA‐DR+, CD1a+ and Lag+ dendritic cells. Only occasionally were CD83+ cells observed. In the 15‐day‐old SEs cultured with GM‐CSF, a few CD86+ cells were seen in the epidermal outgrowths and occasionally CD80+ cells. The median (n = 4) density of CD1a+ and HLA‐DR+ cells in the epidermal outgrowths at day 15 was 5.2 and 9.1 cells/mm, respectively. GM‐CSF did not influence migration in 12‐day‐old SEs, but there was a tendency to increased migration of HLA‐DR+ dendritic cells in 15‐day‐old SEs. CyA did not affect migration or density. We conclude that LCs can be cultured with an in vivo‐like density in a SE. They express the phenotype of immature antigen‐presenting cells efficient in capturing and processing antigen. This model may be suitable for studies of the initial phase of contact allergic reactions.
Outlook for Alternative Payment Models in Fee-for-Service Medicare
Authors: Jeffrey D. Clough, Barak D. Richman, Seth W. Glickman
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 4536: ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells
Authors: Amina Abdul-Aziz, Francis Burrows, Ning Yu, Nigel H. Russell, Claire H. Seedhouse, Monica Pallis
Journal: Cancer Research (2014)

Abstract TG02 is a novel multikinase inhibitor currently in Phase 1 trials for AML and CLL, with a unique spectrum of molecular targets. We have previously shown that TG02 significantly downregulates MCL1 but not BCL2 or BCL2L2 in AML cells at nanomolar concentrations. ABT-737 is a BH3 mimetic which inhibits BCL2, but its effects are impaired in cells which over-express MCL1. Both these agents are documented to target dormant as well as proliferating leukaemia cells and thus have the potential to reduce relapse risk, but cellular responses are heterogeneous. In primary AML samples, BCL-2 expression correlated with that of BCL-XL but not of MCL-1. The response at 48 hours to 100 nM TG02 was measured in primary samples. (This concentration did not inhibit clonogenic growth of haematopoietic stem cells from healthy donors). We show that resistance to TG02 is significantly associated with BCL2 over-expression (P=0.001) but not with MCL1. In CD34+CD38- KG1-a cells, using TG02 with ABT-737 or with the novel and more specific BCL-2 inhibitor ABT-199 at a fixed dose ratio of 1(TG02):20, the combination indices for drug interactions were calculated. For TG02 with ABT-737 and ABT-199 respectively these were IC50 0.59 and 0.26; IC90 0.13 and 0.14, indicating strong synergy, particularly at the IC90. We also show that the OCI-AML-3 cell line, which is resistant to both ABT compounds, was sensitive to TG02 (TG02 IC50 43 nM, IC90 97 nM; ABT-737/199 IC50&amp;gt;4,000nM). All three agents exposed activation-specific epitopes of bax, reduced mitochondrial membrane potential, cleaved caspase 3 and induced phosphatidylserine exposure. 50 nM TG02 + 50 nM ABT199 or ABT-737 was significantly (P&amp;lt;0.05) more toxic than 100 nM of any of the 3 agents individually in a cohort of 12 patient samples treated in vitro for 48 hours. Moreover samples which were sensitive to ABT-199 alone clustered separately from samples sensitive to TG02 alone (p=0.03), indicating that in this heterogeneous disease, the combinatorial approach broadens the range of samples that can be targeted as well as enhancing individual toxicities. We conclude that the cytotoxic actions of TG02 and ABT-737 /ABT-199 are complementary. Citation Format: Amina Abdul-Aziz, Francis Burrows, Ning Yu, Nigel H. Russell, Claire H. Seedhouse, Monica Pallis. ABT-737 and ABT-199 complement the multikinase inhibitor TG02 to induce apoptosis in acute myeloid leukemia cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4536. doi:10.1158/1538-7445.AM2014-4536
Abstract 16327: Resident Cardiac Stem Cell Growth Determines the Number of Ventricular Cardiomyocytes in the Mouse Heart
Authors: Barbara Ogorek, Joao Ferreira-Martins, Donato Cappetta, Alex Matsuda, Sergio Signore, Domenico D'Amario, James Kostyla, Elisabeth Steadman, Virginia Caballero, Noriko Ide-Iwata, Fumihiro Sanada, Toru Hosoda, Piero Anversa, Annarosa Leri, Marcello Rota, Jan Kajstura
Journal: Circulation (2011)

The objective of this study was to determine the role of c-kit-positive cardiac stem cells (CSCs) in the formation of the heart during prenatal life, and immediately after birth. Mice in which EGFP...
Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers
Authors: Marius C. Van Den Heuvel, Maarten J.H. Slooff, Lydia Visser, Michael Muller, Koert P. De Jong, Sibrand Poppema, Annette S.H. Gouw
Journal: Hepatology (2001)

Following hepatic injury, proliferation of anastomosing ductules can be observed. The origin of this ductular reaction is not completely clear, although there is considerable evidence for proliferation of a putative hepatic progenitor cell, reported to be located in the canals of Hering (CoH) and showing morphologic similarities with rat oval cells. In this study, we analyzed the immunophenotype of solitary oval cell-like cells (SOC), intralobular groups of cuboidal cells that might represent lining cells of CoH, bile ductular cells (BDC), bile duct epithelial cells (BEC), and hepatocytes. We used the antibodies OV6, CK19, and CD56 (NCAM) in a double-staining method in a series of 111 liver specimens. The series consisted of a variety of liver diseases, primary liver tumors, and normal livers. In normal livers, SOC, CoH, BDC, and BEC were uniformly and predominantly CK19+, OV6+, and CD56-. In diseased livers SOC and BDC were CK19+, OV6+, and also CD56+. Occasionally, BEC was CD56+ in damaged bile ducts in diseased liver, e.g., PSC. CoH lining cells were not present in cirrhotic nodules and were indistinguishable from BDC in the fibrous septa. The consistent and uniform staining patterns of SOC, CoH, and BDC support the concept that these cells share the same biliary lineage and might represent one biliary structure. The expression of CD56 on these cells in diseased livers indicates that CD56 is a useful marker for a reparative or regenerative state of the biliary liver-cell constituents but not to discriminate a putative hepatic stem cell.
Abstract 13358: Prediction of Sudden Death in Patients With Chronic Heart Failure: A Prospective Comparative Study of Cardiac I-123 Metaiodobenzylguanidine Imaging, QT dispersion and Signal-Averaged ECG: A 10-Year Follow up Study
Authors: Hiromichi Ueda, Takahisa Yamada, Yuji Okuyama, Takashi Motrita, Yoshio Furikawa, Koji Tanaka, Yusuke Iwasaka, Yakeshi Okada, Masato Kawasaki, Yuki Kuramoto, Tadao fujimoto, Takashi Naito, Masatake Fukunami
Journal: Circulation (2010)

Background: The identification of patients at risk for sudden cardiac death in chronic heart failure (CHF) still remains to be an important goal. Although it is shown that ICD therapy could prevent...
Lesson of the week: Delayed presentation of handlebar injuries in children
Authors: J. P H Lam
Journal: BMJ (2001)

<h3>Summary</h3> Animals must adapt their behavior to survive in a changing environment. Behavioral adaptations can be evoked by two mechanisms: feedback control and internal-model-based control. Feedback controllers compare current with desired sensory state and generate motor output to minimize this difference. In contrast, internal models use previous sensory-motor history to update parameters required for predictive motor control. In this study we use multiple perturbations in visual feedback to show that larval zebrafish acutely adapt their swimming behavior depending on the feedback received while swimming. These short-term changes do not affect an initial stereotyped ballistic portion of the swimming event and are unaffected by the ablation of cerebellar Purkinje cells. Contrarily, consistent long-term changes induce larvae to gradually change their behavior, including the ballistic period kinematics, in a cerebellar-dependent process. We conclude that swimming in larval zebrafish can be understood as a feedback control system that is recalibrated by cerebellar output. <h3>Highlights</h3> Larval zebrafish acutely adapt their ongoing behavior to changed visual reafference This acute motor adaptation is likely to be implemented by a feedback controller Persistent change in reafference modifies the parameters of this controller The cerebellum is required for this recalibration
Abstract 2329: Donor Pretreatment with Hypertonic Saline Attenuates Primary Cardiac Allograft Dysfunction
Authors: Mitesh V Badiwala, Danny Ramzy, Laura C Tumiati, Elissa D Tepperman, Rohit Sheshgiri, Jessica L Prodger, Christopher M Feindel, Vivek Rao
Journal: Circulation (2008)

Objective: Hypertonic saline (HTS) has been previously demonstrated to have immune modulatory and vascular protective effects. We assessed the effect of donor pretreatment with HTS on allograft myocardial function in a porcine model of orthotopic heart transplantation. We hypothesized that HTS infusion prior to donor heart arrest and storage would limit ischemia-reperfusion injury and improve myocardial performance following transplantation. Methods: Orthotopic transplants were performed after 6 hours of ischemic allograft storage. Donor pigs were randomly assigned to pretreatment with (n = 7) or without (n = 6) HTS (4.5 ml/kg of 7.5% NaCl) administered 1 hour prior to donor heart arrest. Left ventricular performance was determined after caval occlusion using a Millar micromanometer and conductance catheter. Hemodynamic measurements were obtained using a Swan-Ganz catheter. Results: Administration of hypertonic saline increased serum sodium level from 138 ± 2 mmol/L to 154 ± 4 mmol/L, which normalized to 144 ± 3 mmol/L 1 hour post-infusion. Weaning from CPB and LV performance after transplantation was improved after donor HTS treatment. Successful weaning from CPB was significantly greater in HTS treated hearts (6/7 versus 1/6, p &lt; 0.05). Preload recruitable stroke work post-transplantation was improved compared to control (88 ± 21% versus 35 ± 8% of baseline, p &lt; 0.01). Similarly, maximal elastance was improved compared to control (85 ± 17% versus 42 ± 12% of baseline, p = 0.03). No significant differences in post-transplant central venous, pulmonary artery or pulmonary capillary wedge pressures were observed between groups. However, post-transplant systolic blood pressure was significantly higher in the donor HTS group (60 ± 9 mmHg versus 35 ± 6 mmHg, p = 0.04). Conculsions: Donor HTS pretreatment attenuates post-transplant cardiac allograft myocardial function and improves post-transplant systemic hemodynamic function. HTS may be a novel organ donor intervention to prevent primary graft dysfunction. Further clinical evaluation of this simple and potentially cost-effective intervention is warranted.
Abstract 2936: JNJ-47117096, a selective small molecule inhibitor of the MELK oncogene decreases DNA damage tolerance in highly proliferating cancer cells
Authors: Lijs Beke, Joannes T.m. Linders, Cenk Kig, An Boeckx, Erika van Heerde, Dirk Wuyts, Marc Parade, Lieven Meerpoel, Chris Johnson, Monique Beullens, Mathieu Bollen, Dirk Brehmer
Journal: Cancer Research (2014)

Abstract Maternal embryonic leucine zipper kinase (MELK, hMP38, pEG3), a Ser/Thr protein kinase, is highly overexpressed in stem cells and cancer cells. The oncogenic role of MELK is attributed to disabling critical cell cycle check points as well as enhancing replication. Most functional studies have relied on the use of siRNA/shRNA mediated gene silencing, but this often can be associated with off-target effects. Here we want to present a novel, potent and selective small molecule inhibitor JNJ-47117096 that has enabled us to validate the biological function of MELK kinase. Outcome: MELK inhibition in cancer cells with an intact p53 signaling pathway is linked to a replicative senescence phenotype. This phenotype correlates with a rapid ATM activation and phosphorylation of CHK2 without any effects on the alternative ATR/ CHK1 DNA damage pathways. Furthermore, JNJ-47117096 induces strong phosphorylation of p53 and prolonged up-regulation of p21 without the induction of apoptosis. Strikingly, MELK inhibition in several p53 disabled cancer cells showed induction of a mitotic catastrophe phenotype followed by prominent cell killing. Finally, JNJ-47117096 triggers a rapid degradation of cellular MELK protein, independent of the cell cycle phase and its regulation by the E2F pathway. This observation can clearly be linked to a direct binding effect of JNJ-47117096 to cellular MELK protein confirmed by chemical proteomics. Conclusion: Our data generated with JNJ-47117096, confirmed by selective siRNAs, indicate MELK as a key stimulator of proliferation and replication by its ability to increase the threshold for DNA damage tolerance. Targeting MELK function by selective small molecule inhibitors might sensitise tumors to DNA-damaging agents or radiation therapy. Citation Format: Lijs Beke, Joannes T.m. Linders, Cenk Kig, An Boeckx, Erika van Heerde, Dirk Wuyts, Marc Parade, Lieven Meerpoel, Chris Johnson, Monique Beullens, Mathieu Bollen, Dirk Brehmer. JNJ-47117096, a selective small molecule inhibitor of the MELK oncogene decreases DNA damage tolerance in highly proliferating cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2936. doi:10.1158/1538-7445.AM2014-2936
Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin,a component of the presenilin protein complex
Authors: M. Nishimura, G. Yu, G. Levesque, D.M. Zhang, L. Ruel, F. Chen, P. Milman, E. Holmes, Y. Liang, T. Kawarai, E. Jo, A. Supala, E. Rogaeva, D -M. Xu, C. Janus, L. Levesque, Q. Bi, M. Duthie, R. Rozmahel, K. Mattila, L. Lannfelt, D. Westaway, H.T.J. Mount, J. Woodgett, P.E. Fraser, P. St George–Hyslop
Journal: Nature Medicine (1999)
Abstract P100: Trends in gestational weight gain: Results from the Pregnancy Risk Assessment Monitoring System, 2000-2009
Authors: Jonetta L Johnson, Sherry L Farr, Patricia M Dietz, Andrea J Sharma, Wanda D Barfield, Cheryl L Robbins
Journal: Circulation (2014)

Introduction: Excessive gestational weight gain (GWG) is associated with adverse outcomes for women and infants (gestational hypertension, cesarean delivery, postpartum weight retention and large for gestational-age infants). Current population-based trends in GWG are unknown. This study estimates current trends in mean GWG and trends in gaining below, within, and above the 1990 IOM recommendations among women who delivered live births in multiple states from 2000-2009. Methods: We included Pregnancy Risk Assessment Monitoring System (PRAMS) data from 95,025 women ≥18 years of age, who delivered a singleton infant between 39-40 weeks gestational age in one of 14 states during 2000 through 2009. We defined self-reported GWG in pounds as a continuous variable and as a three-level categorical variable according to 1990 IOM recommendations (below, within and above recommendations). Self-reported pre-pregnancy weight and height from PRAMS were used to calculate pre-pregnancy body mass index and gestational weight gain was extracted from the birth certificate. We grouped live births into 5 biennial intervals and estimated percentage point changes in prevalence using the beta coefficient of the biennial intervals. Adjusted trends in gaining below or above (compared to within) IOM recommendations for GWG from 2000-2001 to 2008-2009 were assessed using multivariable multinomial linear regression. We examined the trend in mean GWG from 2000-2001 to 2008-2009 using multivariable linear regression adjusted for maternal and pregnancy characteristics. SUDAAN was used to account for the complex sampling design and weights were used to provide population-based estimates. Results: There was a 0.9 biennial percentage point increase in the percent of women gaining above IOM recommendations, from 43% in 2000-2001 to 46% in 2008-2009 (p- trend &lt; 0.01). Women gaining within IOM recommendations decreased at a rate of 1.1 percentage points biennially, from 38% in 2000-2001 to 34% in 2008-2009 (p-trend &lt;0.01). There was a statistically significant increase in the adjusted odds of gaining above (odds ratio (OR) = 1.2, 95% confidence interval (CI: 1.1-1.2) and below (OR= 1.2, 95% CI: 1.1-1.3) IOM recommendations over time. From 2000-2009, there was no change in mean GWG. Conclusion: From 2000-2009, there was a modest increase in the percent of women gaining above IOM recommendations while mean GWG remained constant. These seemingly contradictory findings may be due to a larger percentage of women entering pregnancy overweight and obese and gaining above recommended limits. Results from this analysis highlight the need for continued clinical and public health efforts to develop and implement effective strategies to ensure women enter pregnancy at a healthy weight and achieve recommended GWG.
Pseudomonas cepacia Peritonitis Associated with Contamination of Automatic Peritoneal Dialysis Machines
Authors: R L Berkelman, J Godley, J A Weber, R L Anderson, A M Lerner, N J Petersen, J R Allen
Journal: Annals of Internal Medicine (1982)

During a 3-month period, Pseudomonas cepacia was recovered from the peritoneal fluid of 10 patients having chronic dialysis therapy at a peritoneal dialysis center. Six patients developed clinical evidence of peritonitis; one patient developed septicemia. Epidemiologic studies showed that dialysis on specific peritoneal dialysis machines was associated with an increased risk of infection. Laboratory investigation showed contamination of two machines with P. cepacia. Inadequacies in the cleaning and disinfection practices of the automatic peritoneal dialysis machines were identified. Cross-contamination between machines probably occurred through the peritoneal fluid discharge from infected patients during dialysis. Also, the intermittent 2-hour exposure of the machine to 2% formaldehyde may have been inadequate. P. cepacia has not been isolated from the peritoneal fluid of any peritoneal dialysis patient after machine cleaning and disinfection practices were altered.