tbuckley/cabot-search huggingface dataset:
New Strategies in the Treatment of Ovarian Cancer: Current Clinical Perspectives and Future Potential
Authors: Susana Banerjee, Stanley B. Kaye
Journal: Clinical Cancer Research (2013)

The treatment of ovarian cancer is set to undergo rapid changes, as strategies incorporating molecular targeted therapies begin to take shape. These are based on a better appreciation of approaches targeting the tumor microenvironment as well as specific subtypes of the disease, with distinct molecular aberrations. Targeting the VEGF pathway through bevacizumab is clearly effective, with positive randomized trials at all disease stages; targeting defective homologous recombination repair pathways with PARP inhibitors is also proving successful in a substantial proportion of patients with high-grade serous ovarian cancer. In this article, we will review progress in these two leading areas and also discuss the potential for targeting other pathways and receptors that may be activated in ovarian cancer, including the RAS/RAF/MEK and PI3K/AKT/mToR pathways, the ErbB and IGF family of receptors, mitotic check points, and also the folate receptor. Here, single-agent therapy may play a role in selected cases but essential components of future strategies should include combination treatments aimed at dealing with the key problem of drug resistance, together with rational approaches to patient selection.
Linking Processes and Outcomes
Authors: Jonathan K. Aboagye, Brandyn D. Lau, Eric B. Schneider, Michael B. Streiff, Elliott R. Haut
Journal: JAMA Surgery (2013)

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 Surgery HomeNew OnlineCurrent IssueFor Authors Podcast 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 Surgery journal
P54 Testing For Blood Borne Viruses in a TB Clinic: Why Discriminate on the Basis of Who Gets TB Treatment?
Authors: TP Cusack, J Sewell, S Chaytor, J Johnson, A Solamalai, P MacKenzie, A Goodburn, S Hopkins, I Cropley, M Lipman
Journal: Thorax (2012)

<h3>Introduction</h3> Testing for blood borne viruses (BBV), in particular HIV, is a standard of care for people on active tuberculosis (TB) treatment. Although individuals with latent TB infection and those with suspected TB disease are drawn from similar populations, with presumably similar risks for BBV, there are little reported data on this. Our TB clinic has a policy of routine testing for HIV, Hepatitis B (HBV) &amp; Hepatitis C (HCV) on those with a diagnosis of active and latent TB. Here we review our data. <h3>Methods</h3> Information on all adults attending TB services between 01/01/2009 and 19/07/2012 at our centre (apart from those known to be HIV infected at the time of TB service encounter) were extracted from hospital clinical and pathology information systems. <h3>Results</h3> 1656 subjects were seen (Active TB: 22%, Latent TB: 11%, Other final diagnosis not TB: 67%). 748 (45%) had all three BBV tests performed. This was significantly different between the groups, as subjects with either latent or active TB were more likely to have all three tests (Active: 90%, Latent: 83% vs Other diagnosis: 24%, P&lt;0.001). In those tested, an HIV positive result was more frequently found in active TB (7.5%), whilst the HIV prevalence was similar in the two other groups (Latent 1.3% vs Other 1.4%). HBV was more common in Active &amp; Latent TB populations compared to the Others (3% vs 0.8%, P&lt;0.001). HCV had a similar prevalence pattern to HIV, in that it was more common in those with Active TB (3% vs Latent TB: 0.6%, Other 1%, P= 0.06). <h3>Conclusion</h3> We find a high rate of uptake for HIV, HBV &amp; HCV testing in our subjects treated for active and latent TB. HIV &amp; HCV were more common in the former population. Adults with latent TB had a similar prevalence of HIV and HCV to those subjects whose final diagnosis was other than TB. However, the latter had a much lower overall uptake of BBV testing. This is of concern and suggests that we are missing opportunities to diagnose unsuspected BBV infection in a large number of clinic attendees.
Pivotal Role of the Lipid Raft SK3–Orai1 Complex in Human Cancer Cell Migration and Bone Metastases
Authors: Aurélie Chantôme, Marie Potier-Cartereau, Lucie Clarysse, Gaëlle Fromont, Séverine Marionneau-Lambot, Maxime Guéguinou, Jean-Christophe Pagès, Christine Collin, Thibauld Oullier, Alban Girault, Flavie Arbion, Jean-Pierre Haelters, Paul-Alain Jaffrès, Michelle Pinault, Pierre Besson, Virginie Joulin, Philippe Bougnoux, Christophe Vandier
Journal: Cancer Research (2013)

The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca(2+) entry and cancer cell migration through an interaction with the Ca(2+) channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3-Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3-Orai1 lipid raft localization. Upon Ohmline treatment, the SK3-Orai1 complex moved away from lipid rafts, and SK3-dependent Ca(2+) entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3-Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases.
PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation
Authors: Lorenzo de la Rica, Javier Rodríguez-Ubreva, Mireia García, Abul BMMK Islam, José M Urquiza, Henar Hernando, Jesper Christensen, Kristian Helin, Carmen Gómez-Vaquero, Esteban Ballestar
Journal: Genome biology (2013)

Abstract Background DNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant knowledge on the sets of transcription factors involved. Results Here we focused on DNA methylation changes during osteoclastogenesis. Hypermethylation and hypomethylation changes took place in several thousand genes, including all relevant osteoclast differentiation and function categories. Hypomethylation occurred in association with changes in 5-hydroxymethylcytosine, a proposed intermediate toward demethylation. Transcription factor binding motif analysis revealed an over-representation of PU.1, NF-κB, and AP-1 (Jun/Fos) binding motifs in genes undergoing DNA methylation changes. Among these, only PU.1 motifs were significantly enriched in both hypermethylated and hypomethylated genes; ChIP-seq data analysis confirmed its association to both gene sets. Moreover, PU.1 interacts with both DNMT3b and TET2, suggesting its participation in driving hypermethylation and hydroxymethylation-mediated hypomethylation. Consistent with this, siRNA-mediated PU.1 knockdown in primary monocytes impaired the acquisition of DNA methylation and expression changes, and reduced the association of TET2 and DNMT3b at PU.1 targets during osteoclast differentiation. Conclusions The work described here identifies key changes in DNA methylation during monocyte-to-osteoclast differentiation and reveals novel roles for PU.1 in this process.
Life-Threatening Thrombosis in Mice With Targeted Arg48-to-Cys Mutation of the Heparin-Binding Domain of Antithrombin
Authors: Mieke Dewerchin, Jean-Pascal Hérault, Goedele Wallays, Maurice Petitou, Paul Schaeffer, Laurence Millet, Jeffrey I. Weitz, Lieve Moons, Désiré Collen, Peter Carmeliet, Jean-Marc Herbert
Journal: Circulation Research (2003)

Antithrombin (AT) inhibits thrombin and some other coagulation factors in a reaction that is dramatically accelerated by binding of a pentasaccharide sequence present in heparin/heparan-sulfate to a heparin-binding site on AT. Based on the involvement of R47 in the heparin/AT interaction and the frequent occurrence of R47 mutations in AT deficiency patients, targeted knock-in of the corresponding R48C substitution in AT in mice was performed to generate a murine model of spontaneous thrombosis. The mutation efficiently abolished the effect of heparin-like molecules on coagulation inhibition in vitro and in vivo. Mice homozygous for the mutation (AT(m/m) mice) developed spontaneous, life-threatening thrombosis, occurring as early as the day of birth. Only 60% of the AT(m/m) offspring reached weaning age, with further loss at different ages. Thrombotic events in adult homozygotes were most prominent in the heart, liver, and in ocular, placental, and penile vessels. In the neonate, spontaneous death invariably was associated with major thrombosis in the heart. This severe thrombotic phenotype underlines a critical function of the heparin-binding site of antithrombin and its interaction with heparin/heparan-sulfate moieties in health, reproduction, and survival, and represents an in vivo model for comparative analysis of heparin-derived and other antithrombotic molecules.
High-resolution mapping of serovar-specific and common antigenic determinants of the major outer membrane protein of Chlamydia trachomatis.
Authors: R S Stephens, E A Wagar, G K Schoolnik
Journal: The Journal of Experimental Medicine (1988)

The principal surface protein antigen of Chlamydia trachomatis is the major outer membrane protein (MOMP). The MOMP is antigenically complex. Among the 15 serovars of C. trachomatis, mAbs define serovar-, subspecies-, and species-specific determinants on MOMP. The molecular basis of the antigenic diversity of these proteins is reflected in amino acid variable sequence domains. We have mapped the dominant topographic antigenic determinants of MOMP that are defined by mAbs. Using recombinant DNA approaches we have identified the linear distribution of two antigenic domains. One domain contains a serovar-specific determinant and the other contains subspecies- and species-specific determinants. These antigenic domains correspond to two amino acid sequence variable domains. Synthetic peptides were immunogenic and these resolved the serovar-specific determinant within a 14-amino acid peptide. The subspecies- and species-specific determinants were overlapping within a 16-amino acid peptide.
VARIATION IN ACCESSIBLE CELL SURFACE IMMUNOGLOBULIN AMONG ANTIBODY-FORMING CELLS
Authors: G. J. V. Nossal, Heather Lewis
Journal: The Journal of Experimental Medicine (1972)

Spleen cells from CBA mice that had been primarily or secondarily immunized with sheep red blood cells were reacted at 0 degrees C with a (125)I-labeled polyvalent rabbit anti-mouse globulin reagent. After suitable washing, the cells were placed in a plaque-revealing monolayer and warmed to 37 degrees C. Plaques appeared within 10-20 min. Single plaque-forming cells (PFC) were taken from the middle of plaques, were washed by micromanipulation, and were singly dried on glass slides. The amount of attached antireceptor was assessed by quantitative radioautography. Great variation in "receptor density" was encountered among the 258 single cells studied. However, early, immature PFC in both primary and secondary responses had statistically significantly more receptors than late, mature PFC. On any given day point, no difference was found between IgM- and IgG-forming cells. The results were consistent with the view that cells still able to be driven to further proliferation by antigen retain receptors, and conversely that cells, as they mature, lose both receptors and ability to be influenced by antigen.
Effect of aclidinium/formoterol fixed-dose combinations on respiratory symptoms in COPD patients
Authors: Paul Jones, Anthony D'Urzo, Stephen Rennard, Eduard Molins, Victor Mergel, Cynthia Caracta, Anne Leselbaum
Journal: European Respiratory Journal (2014)

BACKGROUND: In two 24-week studies (ACLIFORM [S1], AUGMENT [S2]) investigating two fixed-dose combinations (FDCs) of aclidinium bromide/formoterol fumarate in COPD patients, both FDCs improved lung function vs placebo (PBO) and monotherapy components.  AIM: To examine respiratory symptoms in COPD patients participating in trials S1 and S2.  METHODS: Patients were randomized to twice-daily aclidinium/formoterol 400µg/12µg (FDC12), 400µg/6µg (FDC6), aclidinium 400µg (ACL), formoterol 12µg (FOR), or PBO. Respiratory symptoms were evaluated by the Transition Dyspnea Index (TDI) focal score, change from baseline in EXACT-Respiratory Symptoms (E-RS) total score, and rescue medication use.  RESULTS: Compared with PBO, both FDCs significantly improved TDI focal scores above the minimum clinically important difference (MCID) of 1 unit at week 24 (Table) and at all other time points; both FDCs also showed numerically greater improvements vs monotherapies (ITT populations: S1, N=1726; S2, N=1668). The MCID was achieved by more FDC-treated patients than either placebo or monotherapies. Both FDCs significantly improved E-RS score vs PBO and monotherapies. Compared with PBO, both FDCs significantly reduced average daily rescue medication use over 24 weeks.  CONCLUSIONS: In moderate to severe COPD patients, FDCs of aclidinium/formoterol improved respiratory symptoms compared with placebo and monotherapies over 6 months.
TCTAP A-060 Two-Year Results Comparing Cobalt-Chromium XIENCE V and Platinum-Chromium PROMUS Element Everolimus-Eluting Stents
Authors: Pil Hyung Lee, Se Hun Kang, Min Su Kim, Hee-soon Park, Byeong Joo Bae, Sang Soo Cheon, Jae Hyung Roh, Mineok Chang, Hyun Woo Park, Sung Han Yoon, Jung-Min Ahn, Duk-Woo Park, Soo-Jin Kang, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Journal of the American College of Cardiology (2015)
Effect of a Nurse-Directed Diabetes Disease Management Program on Urgent Care/Emergency Room Visits and Hospitalizations in a Minority Population
Authors: Mayer B. Davidson, Adeela Ansari, Vicki J. Karlan
Journal: Diabetes Care (2007)

OBJECTIVE—To evaluate whether nurse-directed diabetes care reduced preventable diabetes-related urgent care/emergency room visits and hospitalizations in a minority population. RESEARCH DESIGN AND METHODS—Diabetic patients who receive care in a county public health clinic were randomly selected for a Diabetes Managed Care Program (DMCP) in which a specially trained nurse followed detailed treatment algorithms to provide diabetes care for 1 year. Preventable diabetes-related urgent care/emergency room visits and hospitalizations for these patients incurred during the intervention year and the year before enrollment were compared. Preventable diabetes-related causes were defined as metabolic (diabetic ketoacidosis, hyperglycemia, or hypoglycemia) or infection (cellulitis, foot ulcer, osteomyelitis, fungal infection, or urinary tract infection). RESULTS—Use of the urgent care/emergency room and hospitalizations during the intervention year and the year prior were available for 331 patients who completed the DMCP intervention. There were 94 total urgent care/emergency room visits and hospitalizations in the year before entering the DMCP and 46 during the DMCP year, a 51% reduction. Preventable diabetes-related episodes were far fewer. During the prior year, 14 patients made 15 urgent care/emergency room visits and 5 patients incurred 6 hospitalizations. During the DMCP year, four different patients made five emergency room/urgent care visits and one other patient was hospitalized. Preventable diabetes-related use was significantly (P &amp;lt; 0.001) lower during the intervention year compared with the prior year. Total charges for urgent care/emergency room visits and hospitalizations only (not other charges related to diabetes care) during the year before entering the DMCP were $129,176 compared with $24,630 during the DMCP year. CONCLUSIONS—When compared with usual care, nurse-directed diabetes care resulted in significantly fewer urgent care/emergency room visits and hospitalizations for preventable diabetes-related causes. Policy makers seeking to improve diabetes care and conserve resources should seriously consider adopting this approach.
Decreased innate immunity proteins in asthmatic respiratory tract lining fluids
Authors: Elif Melis Bicer, Ian Mudway, Ben Forbes, Graham Somers, Anders Blomberg, Nirina Larsson, Annelie Behndig
Journal: European Respiratory Journal (2012)

Human respiratory tract lining fluids (RTLF) contain several innate immunity proteins with microbicidal and bacteriostatic properties. High concentrations of lactoferrin and transferrin are also present, limiting the availability of Fe, which would otherwise support bacterial growth. In the present study we hypothesized that these innate defenses would be impaired in asthma, associated with an increased bacterial burden in the airways.

Antimicrobial protein concentrations were determined in bronchial wash (BW) samples obtained from mild asthmatic and healthy volunteers. To examine the relationship between these proteins and bacterial load, measurements of lipopolysaccharide (LPS) and lipoteichoic acid (LTA) were made.

BW samples were obtained from mild asthmatics (n=16, 26.76.2) and healthy controls (n=16, 25.02.6). Lactoperoxidase, lactoferrin, transferrin, and lysozyme concentrations were determined using ELISAs. RTLF concentrations were established using the urea method. LPS measurements were made using the Limulus Amaebocyte Lysate assay and LTA concentrations determined using ELISA.

Significantly lower BW transferrin (p=0.01 Mann Whitney U-Test) and lysozyme (p=0.03) concentrations were observed in asthmatics. A similar trend was apparent for lactoperoxidase (p=0.08), though for this and the remaining proteins considerable intra-individual variation was apparent. Correspondingly BW LPS was significantly greater (p=0.04) in asthmatics, concentrations were not simplistically related to transferrin or lysozyme levels.

These results reveal impaired microbicidal defense at the air-lung interface of mild asthmatics. Such a deficiency could render the asthmatic airway more susceptible to infection.
Simvastatin is associated with reduced risk of acute pancreatitis: findings from a regional integrated healthcare system
Authors: Bechien U Wu, Stephen J Pandol, In-Lu Amy Liu
Journal: Gut (2014)

To characterise the relationship between simvastatin and risk of acute pancreatitis (AP).We conducted a retrospective cohort study (2006-2012) on data from an integrated healthcare system in southern California. Exposure to simvastatin was calculated from time of initial dispensation until 60 days following prescription termination. AP cases were defined by ICD-9 CM 577.0 and serum lipase≥3 times normal. Patients were censored at death, last follow-up, and onset of AP or end-of-study. Incidence rate of pancreatitis among simvastatin users was compared with the adult reference population. Robust Poisson regression was used to generate risk ratio (RR) estimates for simvastatin use adjusted for age, gender, race/ethnicity, gallstone-related disorders, hypertriglyceridaemia, smoking and alcohol dependence. Analysis was repeated for atorvastatin.Among 3,967,859 adult patients (median duration of follow-up of 3.4 years), 6399 developed an initial episode of AP. A total of 707,236 patients received simvastatin during the study period. Patients that received simvastatin were more likely to have gallstone-related disorders, alcohol dependence or hypertriglyceridaemia compared with the reference population. Nevertheless, risk of AP was significantly reduced with simvastatin use, crude incidence rate ratio 0.626 (95% CL 0.588, 0.668), p<0.0001. In multivariate analysis, simvastatin was independently associated with reduced risk of pancreatitis, adjusted RR 0.29 (95% CL 0.27, 0.31) after adjusting for age, gender, race/ethnicity, gallstone disorders, alcohol dependence, smoking and hypertriglyceridaemia. Similar results were noted with atorvastatin, adjusted RR 0.33(0.29, 0.38).Use of simvastatin was independently associated with reduced risk of AP in this integrated healthcare setting. Similar findings for atorvastatin suggest a possible class effect.