tbuckley/cabot-search huggingface dataset:
160. Overcoming the Size Limitations of Gene Transfer Vectors: Using Segmental Trans-Splicing To Deliver the Coding Sequence of Von Willebrand Factor
Authors: Robert G. Pergolizzi, Rachel Dragos, Katsutoshi Nakayama, Denisa Wagner, Ronald G. Crystal
Journal: Molecular Therapy (2004)

Von Willebrand Disease (VWD), a common inherited bleeding disorder affecting 1 to 3% of the U.S. population, is caused by abnormalities in the expression and processing of von Willebrand factor (VWF), an adhesion molecule secreted by endothelial cells and platelets. Due to packaging limitations of current viral vectors, the large size of the VWF cDNA (8.6 kb) is a significant challenge to successful gene therapy for VWD, particularly when driven by the 1.7 kb native human VWF promoter. As a means to deliver VWF, we investigated “segmental trans-splicing” (STS), a strategy in which individual “donor” and “acceptor” DNA segments delivered in vitro or in vivo, generate pre-mRNAs which contain 5′ and 3′ splice signals respectively, and complementary “binding domains” through which the two pre-mRNAs bind to each other, permitting contiguous splicing into a final mature mRNA. VWF cDNA was split into two segments at the natural junction of exons 31 and 32 of the 52 exon human gene, yielding a 5.5 kb (5′) donor and a 3 kb (3′) acceptor coding sequence. VWF donor and acceptor constructs co-transfected into 293 cells resulted in the formation of spliced VWF mRNA containing the sequence of the mature, correct VWF mRNA. Although some cryptic splice events were also observed, these could be eliminated by site directed mutagenesis with silent alterations. These results suggest that it will be possible to package a regulated pair of VWF partial cDNAs for delivery in vivo. Since persistence of expression is also a challenge for VWF gene therapy, ex vivo gene transfer to bone marrow cells (BMC) with integrating vectors carrying partial VWF cDNAs, followed by transplantation to an ablated host could potentially achieve long term gene expression. However, it must first be established that VWF secreted from BMC would be sufficient to restore hemostasis in a VWD model system. To determine the feasibility of this approach, BMC from C57Bl/6 wild type (WT) or VWF- knockout (KO) mice were harvested 4 days after administration of 5-fluorouracil (150 mg/kg) and 2 × 106 BMC were transplanted intravenously into lethally irradiated (9 Gy) VWF-KO mice. Transected-tail wounds in untreated VWF-KO mice will bleed to death unless cauterized, whereas similar wounds in WT mice stop bleeding in <1 min. All animals were rescued by the transplant, and 2, 6 and 8 wk after transplantation, bleeding time after wounding was determined. By 8 wk, some VWF-KO mice transplanted with WT BMC exhibited a normal hemostatic pattern, and most showed some improvement in hemostasis. None of the VWF-KO mice transplanted with VWF-KO BMC showed any improvement in bleeding time. Together, these preliminary studies suggest that it may be possible to correct VWD using STS-mediated stem cell gene therapy.
The discovery of GDC-0941: A potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer
Authors: Adrian Folkes, Stewart Baker, Irina Chuckowree, Suzanne Eccles, Angela Hayes, Timothy Hancox, Mohammed Latif, Alan Olivero, Sonal Patel, Giles Pergl-Wilson, Florence Raynaud, Anthony Robson, Nahid Saghir, Sukhjit Sohal, Nan Chi Wan, Christian Weissman, Paul Workman, Marketa Zvelebil, Stephen Shuttleworth
Journal: Cancer Research (2008)

LB-146  Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/Akt signalling pathway in a wide variety of tumours. The consequences of deregulation of this pathway include tumour progression, proliferation, survival, growth, invasion, angiogenesis and metastasis. PI3K signalling is negatively regulated by the dual phosphatase PTEN, and this is one of the most commonly mutated proteins in human malignancy. In addition, persistent signalling through the PI3K/Akt pathway has been shown to be a major mechanism of resistance to therapy. Hence, PI3K, and in particular the p110α subunit of PI3K, is a highly promising candidate for cancer treatment. This poster describes our medicinal chemistry efforts to optimize a series of thieno[3,2-d]pyrimidines that demonstrate potent inhibition of PI3K p110α, culminating in the discovery of GDC-0941. The structure of GDC-0941 will be disclosed. This compound is a potent ATP-competitive PI3 kinase inhibitor with an IC50 of 3 nM against the PI3K p110α subunit, and shows potent growth inhibitory activity in vitro in a range of human tumour cell lines. GDC-0941 is efficacious in xenograft models following oral administration, and is currently being evaluated in human clinical trials for the treatment of cancer.
Stalkers and Their Victims
Authors: John Gunn
Journal: BMJ (2000)

Paul E Mullen, Michele Pathe, Rosemary Purcell

Cambridge University Press, £24.95, pp 322

ISBN 0 521 66950 2

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In just a few years Paul Mullen and Michele Pathe have established themselves as world authorities on stalkers and their victims. Given the enormous pressure they are under in running and developing a comprehensive forensic psychiatry service for the whole state of Victoria in Australia, this is a remarkable achievement.

Stalkers are perhaps more …

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Activin A Mediates Growth Inhibition and Cell Cycle Arrest through Smads in Human Breast Cancer Cells
Authors: Joanna E. Burdette, Jacqueline S. Jeruss, Sarah J. Kurley, Eun Jig Lee, Teresa K. Woodruff
Journal: Cancer Research (2005)

Abstract The transforming growth factor-β (TGF-β) superfamily of growth factors is responsible for a variety of physiologic actions, including cell cycle regulation. Activin is a member of the TGF-β superfamily that inhibits the proliferation of breast cancer cells. Activin functions by interacting with its type I and type II receptors to induce phosphorylation of intracellular signaling molecules known as Smads. Smads regulate transcription of many genes in a cell- and tissue-specific manner. In this study, the role of activin A in growth regulation of breast cancer cells was investigated. Activin stimulated the Smad-responsive promoter, p3TP, 2-fold over control in T47D breast cancer cells. Activin inhibited cellular proliferation of T47D breast cancer cells after 72 hours, an effect that could be abrogated by incubation with the activin type I receptor inhibitor, SB431542. Activin arrested T47D cells in the G0-G1 cell cycle phase. Smad2 and Smad3 were phosphorylated in response to activin and accumulated in the nucleus of treated T47D cells. Infection of T47D cells with adenoviral Smad3 resulted in cell cycle arrest and activation of p3TP-luciferase, whereas a adenoviral dominant-negative Smad3 blocked activin-mediated cell cycle arrest and gene transcription. Activin maintained expression of p21 and p27 cyclin-dependent kinase inhibitors involved in cell cycle control, enhanced expression of p15, reduced cyclin A expression, and reduced phosphorylation of the retinoblastoma (Rb) protein. Smad3 overexpression recapitulated activin-induced p15 expression and repression of cyclin A and Rb phosphorylation. These data indicate that activin A inhibits breast cancer cellular proliferation and activates Smads responsible for initiating cell cycle arrest.
Glutathione-Associated Enzymes In Anticancer Drug Resistance
Authors: Kenneth D. Tew
Journal: Cancer Research (2016)

The importance of thiol-mediated detoxification of anticancer drugs that produce toxic electrophiles has been of considerable interest to many investigators. Glutathione and glutathione S-transferases (GST) are the focus of much attention in characterizing drug resistant cells. However, ambiguous and sometimes conflicting data have complicated the field. This article attempts to clarify some of the confusion. The following observations are well established: (a) tumors express high levels of GST, especially GST psi, although the isozyme components vary quite markedly between tissues and the isozymes are inducible; (b) nitrogen mustards are good substrates for the GST alpha family of isozymes which are frequently overexpressed in cells with acquired resistance to these drugs; (c) most drugs of the multidrug-resistant phenotype have not been shown to be GST substrates and although GST psi is frequently overexpressed in multidrug-resistant cells, most indications are that this is an accompaniment to, rather than a cause of, the resistant phenotype; (d) transfection of GST complementary DNAs has produced some lines with increased resistance to alkylating agents. Most studies of the relationships between GST and resistance have overlooked the potential importance of other enzymes involved in the maintenance of cellular glutathione homeostasis, and this has complicated data interpretation. Translational research aimed at applying our knowledge of glutathione pathways has produced preclinical and clinical testing of some glutathione and GST inhibitors, with some encouraging preliminary results. In brief, GSTs are important determinants of drug response for some, not all, anticancer drugs. Caution should be encouraged in assessing cause/effect relationships between GST overexpression and resistance mechanisms.
Abstract 3768: C3: A small molecule that reverses chemoresistance by inhibition of cell cycle arrest
Authors: Kathryn Elizabeth Wolak, Kenan Onel
Journal: Cancer Research (2014)

Abstract Emergence of chemoresistance is the major cause of death in patients with cancer. To discover compounds that might reverse chemoresistance, we undertook a compound screen to identify molecules that would convert a resistance cell into one that is sensitive. We performed this screen in WTK1, a lymphoblastoid cell line with mutant p53 known to be resistant to chemotherapy. We conducted a high-throughput screen using 83,745 small molecules in the presence or absence of daunorubicin at an IC25 to identify novel compounds that prime cells for chemotherapy-induced apoptosis. We identified C3 as a “hit,” defined as a compound that did not significantly alter viability of cells alone, but significantly increased daunorubicin-induced cell death. We confirmed the effects C3 in a variety of cell types including leukemia, colon, neuroblastoma, breast and ovarian. To determine whether this effect was specific to daunorubicin, we assessed C3's ability to synergize with a wide variety of other genotoxic agents and found that it was highly synergistic with platinating agents. Because cisplatin resistance is the major obstacle in ovarian cancer treatment, we used ovarian cancer lines in our mechanistic studies. We found that C3 synergizes with cisplatin and daunorubicin in a caspase-3 dependent manner, but the mechanism by which C3 primes cells for death did not involve mismatch repair or mitochondrial membrane permeability. Because cisplatin and daunorubicin induce cell cycle arrest, we hypothesized that C3 might alter the regulation of progression of the cell cycle. We found that while cisplatin and daunorubicin have arrested cell cycle profiles on their own, the profiles appear normal when combined with C3 before the cells die. These observations suggest a novel mechanism in which C3 induces apoptosis by forcing cells with damaged genomes through the cell cycle, resulting in apoptosis. Citation Format: Kathryn Elizabeth Wolak, Kenan Onel. C3: A small molecule that reverses chemoresistance by inhibition of cell cycle arrest. [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 3768. doi:10.1158/1538-7445.AM2014-3768
Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D
Authors: Federica Di Palma, Ralph H. Holme, Elizabeth C. Bryda, Inna A. Belyantseva, Richard Pellegrino, Bechara Kachar, Karen P. Steel, Konrad Noben-Trauth
Journal: Nature Genetics (2001)
Educating Physicians and Treating Patients in the Ambulatory Setting
Authors: Robert H. Brook, Arlene Fink, Jacqueline Kosecoff, Lawrence S. Linn, Wendy Everett Watson, Allyson Ross Davies, Virginia A. Clark, Caren Kamberg, Thomas L. Delbanco
Journal: Annals of Internal Medicine (1987)

Abstract We evaluated 15 group practices in general internal medicine in university hospitals with regard to access to and quality of care, patients' satisfaction with that care, and quality of res...
Incorrect <i>ICD-10</i> Code and MACE Endpoint
Authors: Charlotte Andersson
Journal: JAMA Internal Medicine (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 Internal Medicine 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 Internal Medicine journal
New drug discovery screening method based on automated confocal imaging system using in vivo like conditions
Authors: Henriette Skribek
Journal: Clinical Cancer Research (2007)

B80   Discrepancies between the  in vivo  and  in vitro  drug sensitivity patterns of human tumor cells have been reported many times. It is often observed that drug screening tests show major differences in  in vitro  culture as compared to subsequent  in vivo  studies or therapeutic results in patients. This is likely caused by differences in the environmental conditions  in vivo  and  in vitro . Unlike cell lines, primary human tumors are particularly sensitive for oxidative stress which can be caused by exposing them to air during sample taking and culturing. Another important issue is the culturing media which is lacking the important growth factors as compared to the in vivo environment. We aim to decrease this gap by using many new factors which simulates  in vivo  conditions as closely as possible. We have shown that our screening system is superior to support survival of primary tumors as well as to decrease the sensitivity of tumor cells to most commonly used cytotoxic drugs. We use this method to determine the drug sensitivity pattern of cancer patients with the aim to provide support for clinicians for assay guided individualized therapy. We have also identified some alternative treatment options for CLL, late stage Hodgkin disease and PTLD. Our system also allows survival assays in mixed cell culture systems, e.g., fluorescence NK or CTL killing assays or tumor cell/stromal cell drug sensitivity assays.
Abstract 20793: Prostaglandin EP4 Signaling Negatively Regulates Vascular Elastic Fiber Assembly in the Ductus Arteriosus
Authors: Utako Yokoyama, Aki Shioda, Yuko Kato, Toshihide Asou, Hiroki Aoki, Tomoyuki Nakamura, Susumu Minamisawa, Yoshihiro Ishikawa
Journal: Circulation (2010)

Introduction: Elastic fiber formation is essential for elasticity of arteries. However, the hormonal regulation of elastic fiber formation remains largely unknown. Because the ductus arteriosus (DA...
Percutaneous Pulmonary Valve Implantation for Right Ventricular Outflow Tract Obstruction Enhances Cardiac Response to Exercise by Improved Bi-ventricular Stroke Volume
Authors: P Lurz, PK Schuler, Muthurangu, S Schievano, S Khambadkone, G Derrick, P Bonhoeffer, AM Taylor
Journal: Circulation (2009)
Who gets hurt by all these weapons?
Authors: C. Smith
Journal: BMJ (1999)

Papers pp 410, 412, 415 

One of the most tragic manifestations of the post cold war world is the proliferation of weapons. One consequence of the change in the scope and nature of conflicts is that far greater numbers of non-combatants are being directly and indirectly injured, maimed, and killed by weapons that used to be thought of as weapons of war, to be directed against combatants. The extent of the injuries and the proportions of non-combatants affected is documented in this week's issue by three papers that draw on the International Committee of the Red Cross's unique database of wounds treated in its own hospitals (pp 410-7).1–3 Yet, despite burgeoning international concern, we are woefully short of solutions to address this proliferation of illegal weapons.

The studies by Coupland and Meddings show starkly that innocent non-combatants are increasingly both victims and targets of all types of weapons, not just light arms but also landmines, and, importantly, fragmentation munitions.1–3 …
Kinetic Evidence of the Regeneration of Multilineage Hematopoiesis From Primitive Cells in Normal Human Bone Marrow Transplanted Into Immunodeficient Mice
Authors: Johanne D. Cashman, Tsvee Lapidot, Jean C.Y. Wang, Monica Doedens, Leonard D. Shultz, Peter Lansdorp, John E. Dick, Connie J. Eaves
Journal: Blood (1997)
Risk-Treatment Paradox in Use of Statins
Authors: Carlos O. Weiss, Ravi Varadhan
Journal: JAMA (2004)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Psychotherapy for Military-Related PTSD
Authors: Maria M. Steenkamp, Brett T. Litz, Charles W. Hoge, Charles R. Marmar
Journal: JAMA (2015)

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder common among military personnel and veterans. First-line psychotherapies most often recommended for PTSD consist mainly of "trauma-focused" psychotherapies that involve focusing on details of the trauma or associated cognitive and emotional effects.To examine the effectiveness of psychotherapies for PTSD in military and veteran populations.PubMed, PsycINFO, and PILOTS were searched for randomized clinical trials (RCTs) of individual and group psychotherapies for PTSD in military personnel and veterans, published from January 1980 to March 1, 2015. We also searched reference lists of articles, selected reviews, and meta-analyses. Of 891 publications initially identified, 36 were included.Two trauma-focused therapies, cognitive processing therapy (CPT) and prolonged exposure, have been the most frequently studied psychotherapies for military-related PTSD. Five RCTs of CPT (that included 481 patients) and 4 RCTs of prolonged exposure (that included 402 patients) met inclusion criteria. Focusing on intent-to-treat outcomes, within-group posttreatment effect sizes for CPT and prolonged exposure were large (Cohen d range, 0.78-1.10). CPT and prolonged exposure also outperformed waitlist and treatment-as-usual control conditions. Forty-nine percent to 70% of participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement (defined as a 10- to 12-point decrease in interviewer-assessed or self-reported symptoms). However, mean posttreatment scores for CPT and prolonged exposure remained at or above clinical criteria for PTSD, and approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD diagnosis after treatment (range, 60%-72%). CPT and prolonged exposure were marginally superior compared with non-trauma-focused psychotherapy comparison conditions.In military and veteran populations, trials of the first-line trauma-focused interventions CPT and prolonged exposure have shown clinically meaningful improvements for many patients with PTSD. However, nonresponse rates have been high, many patients continue to have symptoms, and trauma-focused interventions show marginally superior results compared with active control conditions. There is a need for improvement in existing PTSD treatments and for development and testing of novel evidence-based treatments, both trauma-focused and non-trauma-focused.
Abstract 13476: Selective Estrogen Receptor Modulator Retards Arterial Senescence and Atherosclerosis Through Restoration of Down-regulated Sirt-1 in Post-menopause Model Mouse
Authors: Takahiro Miyauchi, Yoshiyuki Ikeda, Yuichi Akasaki, Masaaki Iwabayashi, Yuichi Sasaki, Masaaki Miyata, Mitsuru Ohishi
Journal: Circulation (2014)

Background: Incidence of cardiovascular disease (CVD) increases with development of arterial senescence and atherosclerosis, which are accelerated after menopause in women. This study aims 1) to clarify the mechanism of which post-menopose facilitates arterial senescence and atherosclerosis, and 2) to develop optical treatment. Methods and Results: Female Apolipoprotein E deficient (ApoE KO) mice underwent ovariectomy at 8 weeks old were used as post-menopausal model mice (PM). Age-matched female mice with sham operation were used as control (Ctr). We confirmed that serum estrogen concentration was significantly lower in PM than in Ctr. Twelve weeks after surgery, aortas were harvested to examine molecular biological analysis. Sirt-1 and the ratio of p-eNOS/eNOS protein expressions were significantly lower in PM than in Ctr. Ratio of senescence associated β galactosidase (SA-β Gal) positive cells and expressions of acetyl (Ac)-p53, p21, p16, and PAI-1 were significantly higher in PM than in Ctr. Aortic atherosclerotic lesions assessed by Oil Red O staining was significantly greater in PM than in Ctr. Sirt-1 overexpression retarded ovariectomy-induced arterial senescence. These results suggest that ovariectomy accelerates arterial senescence and atherosclerotic development through downregulation of Sirt-1. Next, we administrated selective estrogen receptor modulator (SERM) to PM mice. Sirt-1 and the ratio of p-eNOS/eNOS protein expression were significantly higher in SERM-treated PM mice than in untreated mice. Ratio of SA-β Gal positive cells, protein expressions of Ac-p53, p21, p16, and PAI-1, and aortic atherosclerotic lesions were significantly lower in SERM-treated PM mice than in untreated mice. The effect of SERM on arterial senescence and atherosclerosis was attenuated by administration of either L-NAME, eNOS inhibitor, or sirtinol, Sirt-1 inhibitor. In addition, L-NAME administration decreased Sirt-1 expression in SERM-treated PM mice, suggesting that SERM-induced eNOS activation upregulates Sirt-1. Conclusion: SERM retards development of arterial senescence and atherosclerosis by activation of eNOS and Sirt-1 in postmenopause mice.