tbuckley/cabot-search huggingface dataset:
Manipulation of Base Excision Repair to Sensitize Ovarian Cancer Cells to Alkylating Agent Temozolomide
Authors: Melissa L. Fishel, Ying He, Martin L. Smith, Mark R. Kelley
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To improve the treatment of women with ovarian cancer, we are investigating the modulation of a prominent DNA-damaging agent, temozolomide, by manipulating the DNA base excision repair (BER) pathway via BER inhibitor, methoxyamine, and overexpression of N-methylpurine DNA glycosylase (MPG). Experimental Design: Enhancement of temozolomide via methoxyamine and MPG overexpression was analyzed using in vitro assays, including 3-(4-5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay, apoptosis via Annexin staining, and Western blotting for H2AX phosphorylation to quantitate DNA damage. Results: Our data show that we can effectively modulate the activity of the chemotherapeutic agent, temozolomide, via modulator methoxyamine, in three ovarian cancer cell lines, SKOV-3x, Ovcar-3, and IGROV-1. This enhancement of temozolomide-induced cytotoxicity is not dependent on p53 status as we transfected an ovarian cancer cell line with a dominant-negative p53-expressing plasmid (IGROV-1mp53) and obtained similar results. Our results show that MPG-overexpressing IGROV-1 and IGROV-1mp53 cells are significantly more sensitive to the clinical chemotherapeutic temozolomide in combination with methoxyamine as assayed by cytotoxicity, apoptosis, and levels of DNA damage than either agent alone. Conclusions: These studies show that although clinical trials in ovarian cancer to determine temozolomide single-agent efficacy are in development, through manipulation of the BER pathway, an increase in response to temozolomide is achieved. The combination of temozolomide plus methoxyamine has potential for second-line therapy for patients who have failed standard platinum plus paclitaxel chemotherapy.
QAW039, a slowly dissociating CRTh2 antagonist with potential for improved clinical efficacy
Authors: David Sykes, Michelle Bradley, Darren Riddy, Liz Willard, Ellen Powell-Herlaar, Dave Sandham, Simon Watson, Carsten Bauer, Gerald Dubois, Steven Charlton
Journal: European Respiratory Journal (2014)

Introduction 

QAW039 is an oral, selective, competitive and reversible CRTh2 receptor antagonist currently in clinical development for treatment of asthma. This study describes the detailed investigation of the receptor binding kinetics of QAW039 and compares it to several other known CRTh2 antagonists.

Methods 

Kinetic binding experiments with [3H3]-QAW039 and CRTh2 receptor were carried out at 37oC, [35S]-GTPγS binding at room temperature1. The ability of compounds to inhibit the whole blood shape change (WBSC) response to PGD2 was monitored using flow cytometry.

Results 

The dissociation rate constant for QAW039 was significantly lower than all other clinically relevant CRTh2 antagonists tested (QAV680, OC459 and AZD-1981, Table). QAW039 was the most potent compound tested in the WBSC assay. In the binding assay QAW039 significantly reduced the maximum effect of PGD2 following a 15min incubation.

View this table:

Table. Kinetic parameters and WBSC IC50 values 





Conclusion 

The slower off-rate of QAW039 from the CRTh2 receptor potentially affords it an improved efficacy, as it can insurmountably block the CRTh2 receptor even in the face of high local concentrations of PGD2.

Reference 

1. Sykes et al. Mol Pharm 2009; 76:543-51.
Value of washings and brushings at fibreoptic bronchoscopy in the diagnosis of lung cancer.
Authors: L. Trevisani, P. Pazzi, S. Sartori, A. Potena
Journal: Thorax (1991)

Pde3B hydrolyzes both cAMP and cGMP, important second messengers in a variety of cellular processes. Pde3B has been shown to regulate NLRP3 inflammasome activity in adipose tissue. To understand whether Pde3B plays a role in the macrophage response to bacterial infection, we derived macrophages from the bone marrow of wildtype and Pde3B knockout mice. Macrophages were then stimulated with LPS for 6 h or left untreated, and total RNA was prepared for RNA-seq analyses. Our data indicate that Pde3B expression was inhibited by LPS in macrophages. Knockout of Pde3B resulted in significant changes in the expression of a large group of genes: 427 genes were up-regulated by at least 2-fold while 428 genes were down-regulated by more than 50% in LPS stimulated macrophages as the result of Pde3B deficiency. Gene profiling indicates that a number of biological processes are affected by Pde3B knockout, including cellular ion/cation homeostasis, immune system processes, and chemotaxis. Interestingly, Pde3B deficiency disturbed the expression of several chemokines: Cxcl-1, -2, and -3 expression were decreased by 96, 60, and 75%, respectively. In contrast, Ccl-4, -7, -12, -22, Cxcl-9 and -l11 expression were enhanced 1.8, 1.5, 1.9, 2, 3, and 3-fold, respectively. Differential expression of dual specificity phosphatase (Dusp)-1, -2, -3, -4, -5, -6, -10, -11, and -16 were also seen between LPS-stimulated wildtype and Pde3B-deficient macrophages. Since the Dusps are important regulators of MAP kinases that control the expression of chemokines, alterations in the expression of Dusps provides a plausible explanation for the changes in chemokine expression. Our studies suggest that Pde3B may regulate chemokine expression via modulating MAP kinases.
Expanding Scope of Dermatologic Mid-Level Practitioners Includes Prescription of Complex Medication
Authors: Vanessa L. Pascoe, Alexandra B. Kimball
Journal: JAMA Dermatology (2014)

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 Dermatology 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 Dermatology journal
Cyclosporin for a severe case of aspirin-induced asthma
Authors: E Nizankowska, R Dworski, A Szczeklik
Journal: European Respiratory Journal (1991)

Cyclosporin, an immunosupressive drug, predominantly inhibits T -lymphocyte dependent immune responses by interfering with synthesis of lymphokines.T-lymphocytes are an important source of inflammatory mediators, and some aspects of asthma may be accounted for by alterations in release of cytokines [1].Cyclosporin was used to treat a 42 yr old woman with asthma.She has been under our treatment since 1975 when diagnosis of aspirin intolerance was established (2, 3) by oral provocation tests.Skin tests to common airborne allergens were negative, serum immunoglobulin E (IgE) was 101 IU•m1• 1 • Her asthma was of severe type and over the years 1976-1989 she was on chronic corticotherapy at a dose of 20-30 mg•day• 1 • nature of the present report has to be stressed.We have not observed any side-effects of cyclosporin treatment, possibly because the drug was given at a low-dose.Cyclosporin side-effects are, however, of concern and should be kept in mind in patients with bronchial asthma possibly subjected to cyclosporin treatment in the future.
Interstitial lung disease more than 40 years after a 5 year occupational exposure to talc
Authors: C Gysbrechts, E Michiels, E Verbeken, J Verschakelen, D Dinsdale, B Nemery, M Demedts
Journal: European Respiratory Journal (1998)

A 62 yr old woman was initially diagnosed with sarcoidosis until a thoracoscopic biopsy revealed the presence of numerous birefringent particles in fibrotic areas of the centrilobular lung zones. These particles were examined by electron microscopy and X-ray spectrometry and characterized as impure talc. Further inquiry into her occupational history revealed that she had worked from the age of 14-18 yrs in a factory making rubber hoses, where she had had an intense exposure to talc. There was no evidence of silicosis or asbestosis, and other significant causes of interstitial lung disease were excluded. This case emphasizes the importance of a thorough occupational history, which may reveal a remote and forgotten exposure to a significant cause of interstitial lung disease. Although this presentation of talcosis is unusual, this case suggests that even a relatively short, but presumably intense exposure to talc more than 40 yrs previously may be a cause of progressive lung fibrosis.
Marijuana Legalization: Impact on Physicians and Public Health
Authors: Samuel T. Wilkinson, Stephanie Yarnell, Rajiv Radhakrishnan, Samuel A. Ball, Deepak Cyril D'Souza
Journal: Annual Review of Medicine (2015)

Marijuana is becoming legal in an increasing number of states for both medical and recreational use. Considerable controversy exists regarding the public health impact of these changes. The evidence for the legitimate medical use of marijuana or cannabinoids is limited to a few indications, notably HIV/AIDS cachexia, nausea/vomiting related to chemotherapy, neuropathic pain, and spasticity in multiple sclerosis. Although cannabinoids show therapeutic promise in other areas, robust clinical evidence is still lacking. The relationship between legalization and prevalence is still unknown. Although states where marijuana use is legal have higher rates of use than nonlegal states, these higher rates were generally found even prior to legalization. As states continue to proceed with legalization for both medical and recreational use, certain public health issues have become increasingly relevant, including the effects of acute marijuana intoxication on driving abilities, unintentional ingestion of marijuana products by children, the relationship between marijuana and opioid use, and whether there will be an increase in health problems related to marijuana use, such as dependence/addiction, psychosis, and pulmonary disorders. In light of this rapidly shifting legal landscape, more research is urgently needed to better understand the impact of legalization on public health.
Disparities in melanoma incidence rates in Europe
Authors: W.B. Grant
Journal: British Journal of Dermatology (2012)

Madam, There has been an ongoing debate over the reasons for the rapid increase in incidence rates for cutaneous malignant melanoma over the past seven decades. Melanoma incidence rates have risen by a factor of 10 since 1940 in the U.S.A., and by a factor of five since the mid‐1950s in Northern Europe.1 Incidence rates appear to be still rising in Europe but may be stabilizing in some countries.2 However, melanoma mortality rates in Europe and elsewhere changed little between 1990 and 2006.3 Several papers have suggested that incidence rates have risen rapidly due to more frequent screening and identification of melanoma in situ. In the U.S.A., melanoma in situ comprised about 40% of melanoma incidence in 2006.4 In Germany, median tumour thickness decreased from 1·81 mm in 1976 to 0·53 mm in 2000 (P <0·0001).5 However, as of 2008, the rate of in situ melanoma among diagnosed melanoma cases was only 15%.6 Indeed, a recent paper calls the recent trends in melanoma incidence a ‘pseudo‐epidemic’ due to ‘improved criteria for diagnosis that allow melanomas to be recognized far more accurately and at earlier stages’, and to overdiagnosis of melanoma.7
<i>STIM1</i>Mutation Associated with a Syndrome of Immunodeficiency and Autoimmunity
Authors: Capucine Picard, Christie-Ann McCarl, Alexander Papolos, Sara Khalil, Kevin Lüthy, Claire Hivroz, Francoise LeDeist, Frédéric Rieux-Laucat, Gideon Rechavi, Anjana Rao, Alain Fischer, Stefan Feske
Journal: New England Journal of Medicine (2009)

A mutation in ORAI1, the gene encoding the pore-forming subunit of the Ca(2+)-release-activated Ca(2+) (CRAC) channel, abrogates the store-operated entry of Ca(2+) into cells and impairs lymphocyte activation. Stromal interaction molecule 1 (STIM1) in the endoplasmic reticulum activates ORAI1-CRAC channels. We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition. Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx.
Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer
Authors: A. Nigel Brooks, Elaine Kilgour, Paul D. Smith
Journal: Clinical Cancer Research (2012)

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling axis plays an important role in normal organ, vascular, and skeletal development. Deregulation of FGFR signaling through genetic modification or overexpression of the receptors (or their ligands) has been observed in numerous tumor settings, whereas the FGF/FGFR axis also plays a key role in driving tumor angiogenesis. A growing body of preclinical data shows that inhibition of FGFR signaling can result in antiproliferative and/or proapoptotic effects, both in vitro and in vivo, thus confirming the validity of the FGF/FGFR axis as a potential therapeutic target. In the past, development of therapeutic approaches to target this axis has been hampered by our inability to develop FGFR-selective agents. With the advent of a number of new modalities for selectively inhibiting FGF/FGFR signaling, we are now in a unique position to test and validate clinically the many hypotheses that have been generated preclinically.
Systematic Review of the Technique of Colorectal Anastomosis
Authors: Juliette C. Slieker, Freek Daams, Irene M. Mulder, Johannes Jeekel, Johan F. Lange
Journal: JAMA Surgery (2013)

Many different techniques of colorectal anastomosis have been described in search of the technique with the lowest incidence of anastomotic leak. A systematic review of leak rates of techniques of hand-sewn colorectal anastomosis was conducted to provide a guideline for surgical residents and promote standardization of its technique. Clinical and experimental articles on colorectal anastomotic techniques and anastomotic healing published in the past 4 decades were searched. We included evidence on suture material, suture format, single- vs double-layer sutures, interrupted vs continuous sutures, hand-sewn vs stapled and compression colorectal anastomosis, and anastomotic configuration. In total, 3 meta-analyses, 26 randomized controlled trials, 11 nonrandomized comparative studies, 20 cohort studies, and 57 experimental studies were found. Results show that, for many aspects of the hand-sewn colorectal anastomosis technique, evidence is lacking. A single-layer continuous technique using inverting sutures with slowly absorbable monofilament material seems preferable. However, in contrast to stapled and compression colorectal anastomoses, the technique for hand-sewn colorectal anastomoses is nonstandardized with regard to intersuture distance, suture distance to the anastomotic edge, and tension on the suture. We believe detailed documentation of the anastomotic technique of all colorectal operations is needed to determine the role of the hand-sewn colorectal anastomosis.
Minimal Residual Disease in Acute Myeloid Leukemia Is Predicted by an Apoptosis-Resistant Protein Profile at Diagnosis
Authors: Amber van Stijn, Nicole Feller, Alice Kok, Marjoleine A. van der Pol, Gert J. Ossenkoppele, Gerrit J. Schuurhuis
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Apoptosis is an important mechanism regulating survival of acute myeloid leukemia cells. The apoptosis-related protein profile at diagnosis is important for achieving complete remission thereby affecting survival variables such as disease-free survival (DFS) and overall survival (OS). To investigate the role of the apoptosis protein profile in further response to therapy and outgrowth of disease. Experimental Design: We studied whether Bcl-2, Bcl-xL, Mcl-1, Bax as well as the Bcl-2/Bax ratio and a combination of all (antiapoptosis index, AAI) are related to the frequency of malignant cells surviving the chemotherapy (i.e., minimal residual disease, MRD). MRD cells were identified by leukemia-associated aberrant phenotypes established at diagnosis by flow cytometry. Results: We found that Bcl-2 (R = 0.55, P = 0.002), Bcl-2/Bax (R = 0.42, P = 0.02), and AAI (R = 0.47, P = 0.01) at diagnosis directly correlated with MRD after the first cycle of chemotherapy. In turn, MRD frequency after first cycle correlated with DFS (P = 0.04). Taken together, these results directly explain why Bcl-2/Bax and especially AAI (P = 0.007) at diagnosis correlate with DFS. Conclusion: Our results show that apoptosis resistance plays an important role in the first stage of the therapy (i.e., to eliminate the bulk of malignant cells), in terms of achievement of complete remission and frequency of MRD after first cycle of therapy.
Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation
Authors: Carlos V. Paya, Russell H. Wiesner, Paul E. Hermans, Jeffrey J. Larson-Keller, Duane M. Ilstrup, Ruud A. F. Krom, S. Breanndon Moore, Jurgen Ludwig, Thomas F. Smith
Journal: Hepatology (1992)

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Timedependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome. (HEPATOLOGY 1992;16:66–70.)
An Elastic, Biodegradable Cardiac Patch Induces Contractile Smooth Muscle and Improves Cardiac Remodeling and Function in Subacute Myocardial Infarction
Authors: Kazuro L. Fujimoto, Kimimasa Tobita, W. David Merryman, Jianjun Guan, Nobuo Momoi, Donna B. Stolz, Michael S. Sacks, Bradley B. Keller, William R. Wagner
Journal: Journal of the American College of Cardiology (2007)
Physical Activity and Change in Estimated GFR among Persons with CKD
Authors: Cassianne Robinson-Cohen, Alyson J. Littman, Glen E. Duncan, Noel S. Weiss, Michael C. Sachs, John Ruzinski, John Kundzins, Denise Rock, Ian H. de Boer, T. Alp Ikizler, Jonathan Himmelfarb, Bryan R. Kestenbaum
Journal: Journal of the American Society of Nephrology (2013)

Physical activity may counteract metabolic disturbances that promote the progression of CKD. To address this concept, we performed a longitudinal cohort study of 256 participants in the Seattle Kidney Study, a clinic-based study of CKD. Participants with an estimated GFR (eGFR) of 15–59 ml/min per 1.73 m2 at baseline were eligible for the study. Physical activity was quantified using the Four-Week Physical Activity History Questionnaire. We used generalized estimating equations to test associations of physical activity with change in eGFR determined by longitudinal measurements of serum cystatin C. Mean baseline eGFR was 42 ml/min per 1.73 m2. During a median 3.7 years of follow-up, the mean change in eGFRcystatin C was −7.6% per year (interquartile range, −16.8%, 4.9% per year). Participants who reported >150 minutes of physical activity per week had the lowest rate of eGFRcystatin C loss (mean −6.2% per year compared with −9.6% per year among inactive participants). In adjusted analyses, each 60-minute increment in weekly physical activity duration associated with a 0.5% slower decline per year in eGFR (95% confidence interval, 0.02 to 0.98; P=0.04). Results were similar in sensitivity analyses restricted to participants without cardiovascular disease or diabetes, or to participants with moderate/high physical function. After adjustment for eGFR at the time of questionnaire completion, physical activity did not associate with the incidence of ESRD (n=34 events). In summary, higher physical activity levels associated with slower rates of eGFR loss in persons with established CKD.
T cell surface I-J glycoprotein. Concerted action of chromosome-4 and -17 genes forms an epitope dependent on alpha-D-mannosyl residues.
Authors: K K Klyczek, H Cantor, C E Hayes
Journal: The Journal of Experimental Medicine (1984)

Two genes acting in concert control murine T cell I-Jk expression. We determined I-Jk expression with I-Jk--specific monoclonal antibodies WF8 .C12.8 and five others produced in our laboratory in a cytotoxicity assay. Previous experiments established that an H-2k gene and a chromosome 4 gene, Jt , regulate I-Jk expression. We show here that B10. HTT and B10.S( 9R ) do not differ at the H-2k locus required for I-Jk expression. Rather B10. HTT , like B10.A(3R), lacks some important non--H-2 gene (possibly Jt ). The intra--H-2k I-J--controlling locus maps to the right of the I-A subregion. The I-Jk determinant involves a carbohydrate structure associated with protein; inhibiting either protein synthesis or glycosylation prevents T cell I-Jk reexpression after proteolytic removal. Treatment with alpha-mannosidase destroys I-Jk determinants, implicating terminal alpha-D-mannosyl residues in the I-Jk epitope. Models for H-2 and Jt control of I-J expression are discussed.
Improvement of perinatal and newborn care in rural Pakistan through community-based strategies: a cluster-randomised effectiveness trial
Authors: Zulfiqar A Bhutta, Sajid Soofi, Simon Cousens, Shah Mohammad, Zahid A Memon, Imran Ali, Asher Feroze, Farrukh Raza, Amanullah Khan, Steve Wall, Jose Martines
Journal: The Lancet (2011)
Neuropathic Diabetic Foot Ulcers
Authors: Andrew J.M. Boulton, Robert S. Kirsner, Loretta Vileikyte
Journal: New England Journal of Medicine (2004)

A 58-year-old man with type 2 diabetes mellitus has an asymptomatic plantar ulcer on the left foot that remains unhealed after four months. The ulcer measures 2 by 1 cm and is surrounded by callus under the first metatarsal head. Neurologic examination reveals loss of sensation of touch, pinprick, and vibration below the midcalf level bilaterally and the absence of ankle reflexes; the foot pulses are normal. How should this patient be evaluated and treated?
A conversation with Jeffrey M. Friedman
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2013)

We are joined by Jeffrey M. Friedman of the Rockefeller University, a scientist who has been at the center of discovery of the molecular determinants of why we eat what we eat, and more specifically, why we eat so much of what we eat. Friedman (Figure ​(Figure1)1) has spent his research career on the discovery and characterization of leptin, a key hormone regulating appetite and hunger. The full interview can be seen on the JCI website at http://www.jci.org/kiosk/cgm.