tbuckley/cabot-search huggingface dataset:
Abstract 2224: Re-engineering of the duocarmycin structural architecture enables tumour-selective CYP2W1-mediated drug activation in human colon cancer xenografts.
Authors: Klaus Pors, Sandra Travica, Paul M. Loadman, Steven D. Shnyder, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Inger Johansson, Souren Mkrtchian, Magnus IngelmanSundberg, Laurence H. Patterson
Journal: Cancer Research (2013)

Abstract There is now growing evidence that CYP1A1, 1B1, 2J2, 2S1 and 2W1 are over-expressed in many human tumour types. The ultrapotent duocarmycins are ideal candidates for bioprecursor drug development and we have demonstrated that these can be re-engineered into derivatives selectively activated by CYP1A1 in vitro and in vivo.1,2 In the present study, we have focussed on CYP2W1 as a potential therapeutic target. CYP2W1 is detected in 30% of colon cancers, while its protein expression in non-transformed adult tissues is absent or insignificant.3 We have presented results indicating that the immunohistochemically assessed level of CYP2W1 enzyme could fulfil the criteria for being a prognostic biomarker for stages II and III colorectal cancer.4 Here we present data on furanoindole-based duocarmycins that have the potential to be used as a chemical probe (e.g. ICT2726) to show CYP2W1 functional activity. We also report on indoline-based analogues that elicit potent antiproliferative activity after CYP2W1-mediated activation in cancer cells. Specifically, we have transfected human HEK293, Colo320 and SW480 cells to express CYP2W1 and shown that these suffer rapid loss of viability following treatment with two halogenated duocarmycin bioprecursor compounds (ICT2705 and ICT2706) while no activity in mock-transfected cells was seen. Significantly, ICT2706 was shown to totally prevent tumour growth when administered to SCID mice bearing SW480-2W1 xenografts (dosed daily with 100 mg/kg for 8 days) but not the mock-transfected variant. Subsequent to this treatment, the tumours were extracted for further analysis. Using H2A.X phosphorylation as a marker for DNA damage, our data revealed a time-dependent increase in expression supporting CYP2W1-mediated activation of ICT2706 in vivo. Our findings reveal the opportunities in targeting CYP2W1 as a novel therapeutic approach in colon cancer chemotherapy. Citation Format: Klaus Pors, Sandra Travica, Paul M. Loadman, Steven D. Shnyder, Mark Sutherland, Helen M. Sheldrake, Mark Searcey, Inger Johansson, Souren Mkrtchian, Magnus IngelmanSundberg, Laurence H. Patterson. Re-engineering of the duocarmycin structural architecture enables tumour-selective CYP2W1-mediated drug activation in human colon cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2224. doi:10.1158/1538-7445.AM2013-2224
Brachytherapy vs Whole-Breast Irradiation for Breast Cancer
Authors: Atif J. Khan, Frank A. Vicini, Doug Arthur
Journal: JAMA (2012)

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
Prostaglandin E Receptor EP4 Antagonism Inhibits Breast Cancer Metastasis
Authors: Xinrong Ma, Namita Kundu, Salah Rifat, Tonya Walser, Amy M. Fulton
Journal: Cancer Research (2006)

Abstract Cyclooxygenase-2 (COX-2) expression in epithelial tumors is frequently associated with a poor prognosis. In a murine model of metastatic breast cancer, we showed that COX-2 inhibition is associated with decreased metastatic capacity. The COX-2 product, prostaglandin E2 (PGE2), acts through a family of G protein–coupled receptors designated EP1-4 that mediate intracellular signaling by multiple pathways. We characterized EP receptor expression on three murine mammary tumor cell lines and show that all four EP isoforms were detected in each cell. Stimulation of cells with either PGE2 or the selective EP4/EP2 agonist PGE1-OH resulted in increased intracellular cyclic AMP and this response was inhibited with either EP2 or EP4 antagonists. Nothing is known about the function of EP receptors in tumor metastasis. We tested the hypothesis that the prevention of EP receptor signaling would, like inhibition of PGE2 synthesis, inhibit tumor metastasis. Our results show for the first time that antagonism of the EP4 receptor with either AH23848 or ONO-AE3-208 reduced metastasis as compared with vehicle-treated controls. The therapeutic effect was comparable to that observed with the dual COX-1/COX-2 inhibitor indomethacin. EP3 antagonism had no effect on tumor metastasis. Mammary tumor cells migrated in vitro in response to PGE2 and this chemotactic response was blocked by EP receptor antagonists. Likewise, the proliferation of tumor cells was also directly inhibited by antagonists of either EP4 or EP1/EP2. These studies support the hypothesis that EP receptor antagonists may be an alternative approach to the use of COX inhibitors to prevent tumor metastasis. (Cancer Res 2006; 66(6): 2923-7)
Secretion imbalance between tumour necrosis factor and its inhibitor in inflammatory bowel disease
Authors: M Noguchi, N Hiwatashi, Z Liu, T Toyota
Journal: Gut (1998)

Background —Tumour necrosis factor (TNF) α and TNF-β are soluble ligands binding to TNF receptors with similar activities; soluble TNF receptors neutralise TNF activity by acting as inhibitors. Little is known about the cytokine/soluble receptor role in inflammatory bowel disease (IBD). Aims —To test the hypothesis that an imbalance in secretion between TNF and TNF inhibitors plays a role in gut inflammation in patients with IBD. Methods —The secretion of TNF-α, TNF-β, and soluble TNF receptors was compared in the culture supernatants of colonic biopsy specimens and isolated lamina propria mononuclear cells from patients with active colonic IBD. Results —Spontaneous secretion of TNF-α in involved IBD mucosa was higher than in normal control and self limited colitis mucosa. Secretion of TNF-β was higher in patients with Crohn’s disease than in those with ulcerative colitis. Soluble TNF receptor in IBD mucosa inhibited TNF activity. Type 2 soluble receptor release from IBD mucosa was increased in active inflammation; release from lamina propria cells was not increased. Mucosal TNF-α production correlated with severity of disease. Conclusions —Results showed enhanced secretion of TNF-α but failure to release enhanced amounts of soluble TNF receptor in lamina propria mononuclear cells of patients with IBD. An imbalance in secretion between TNF and TNF inhibitor may be implicated in the pathogenesis of IBD.
Bilateral vocal cord paralysis following stent placement for proximal esophageal stricture
Authors: Z. Gellad, D. Hampton, C. Tebbit, L. Puscas, D. Pavey
Journal: Endoscopy (2008)

An 83-year-old man with a history of squamous cell cancer of the esophagus presented for endoscopic management of refractory dysphagia. A malignant-appearing esophageal stricture was identified 20 cm from the incisors ([Fig. 1]). The stricture was dilated with 6- to 8-mm and 8- to 10-mm balloon dilators. An 18 mm × 10 cm Alimaxx fully covered nitinol stent (Alveolus, Inc., Charlotte, North Carolina, USA) was then placed under fluoroscopic guidance across the stricture.
Are Current or Future Mesothelioma Epidemics in Hong Kong the Tragic Legacy of Uncontrolled Use of Asbestos in the Past?
Authors: Lap Ah Tse, Ignatius Tak-sun Yu, William Goggins, Mark Clements, Xiao Rong Wang, Joseph Siu-kie Au, Kai Shing Yu
Journal: Environmental Health Perspectives (2009)

Inhaled asbestos fibers may contribute to three-fourths of malignant mesotheliomas diagnosed in men and almost 40% of cases diagnosed in women. Bans on the manufacture and sale of amphibole asbestos fibers are expected to reduce the incidence of mesothelioma, but the long latency period from initial exposure to clinical disease means that people exposed before bans were enacted will continue to develop asbestos-related mesotheliomas as they age. Tse et al. (p. 382) used historical data on asbestos consumption and mesothelioma diagnoses to predict future mesothelioma trends in Hong Kong. Asbestos use peaked during a construction boom in the early 1960s and subsequently declined by > 90% following a ban on the sale and import of crocidolite and amosite asbestos in 1996, whereas mesothelioma diagnoses in men increased from a single case in 1972–1976 to 63 cases in 2002–2006 (corresponding to crude incidence rates of 0.09 and 3.86 cases/million men, respectively). Assuming an average latency of 42 years, the authors predict that incidence rates will peak in 2009 and that diagnoses will peak in 2014. However, they caution that ongoing use of chrysotile asbestos and the release of asbestos fibers from older buildings during demolition or renovation may slow the projected decline. [corrected]
Role of veins and cerebral venous pressure in disruption of the blood-brain barrier.
Authors: W G Mayhan, D D Heistad
Journal: Circulation Research (1986)

The goal of this study was to determine whether increases in cerebral venous pressure contribute to, and may account for, disruption of the blood-brain barrier during acute hypertension and hyperosmolar stimuli. We studied the relation between pial venous pressure and disruption of the blood-brain barrier during acute arterial hypertension, superior venae cavae occlusion, and superfusion with hyperosmolar arabinose. Sprague-Dawley rats were studied using intravital fluorescent microscopy and fluorescein-labelled dextran (mol. wt. = 70,000). Disruption of the blood-brain barrier was characterized by the appearance of microvascular leaky sites and quantitated by the clearance of fluorescein dextran. We measured pressure (servo null) in pial arterioles and venules 40-60 micron in diameter. Acute hypertension, occlusion of the superior venae cavae, and hyperosmolar arabinose produced leaky sites primarily in venules. Acute hypertension increased arteriolar pressure and also venular pressure, from 7 +/- 1 (mean +/- SE) to 28 +/- 2 mm Hg. Clearance of fluorescein dextran increased from 0.03 +/- 0.01 to 2.90 +/- 0.40 ml/sec X 10(-6). Occlusion of the superior venae cavae increased pial venous pressure from 7 +/- 1 to 30 +/- 3 mm Hg, and clearance of fluorescein dextran, from 0.02 +/- 0.01 to 3.10 +/- 0.59 ml/sec X 10(-6). In contrast to acute hypertension, there was a decrease in arterial and pial arteriolar pressure during occlusion of the superior venae cavae. Thus, similar increases in venous pressure during acute hypertension and superior venae cavae occlusion, despite directionally opposite changes in arterial and arteriolar pressure, produced similar disruption of the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)
US Senate passes health reform bill
Authors: J. H. Tanne
Journal: BMJ (2009)

Early on Christmas Eve the US Senate passed its health reform bill, marking a step closer towards 30 million or more of America’s 46 million uninsured becoming eligible for health care.

In January a conference committee comprising members of both the Senate and the House of Representatives will work to reconcile the bill with a similar, but different, health reform bill passed by the House of Representatives in November. 

There are two health reform bills because bills to raise revenue must originate in the House of Representatives. Both bills are estimated to increase health care spending during the next decade―the Senate bill by nearly $900 billion (£567 billion; €627 billion) and the House bill by just over $1 trillion.

Both houses will then vote on the reconciled bill and, if passed, it will be sent to President Barack Obama for his signature. 

The latest development in the saga follows a 60-40 vote on 21 December ( BMJ 2009;339:b5622, 23 Dec, doi:10.1136/bmj.b5622) that allowed the Senate to proceed to a final vote. The subsequent 24 December vote was 60-39 in favour, but all Republicans voted against it.

The narrow vote margin means that all changes in the reconciled bill must be accepted by 60 senators—all Democrat senators and the independent senators who vote with them. Otherwise, opponents could mount a filibuster and effectively talk the bill to …
An Aid to Parturition, and to the Treatment of Displacements of the Uterus by a New Mechanical Appliance
Authors: P. Smith
Journal: BMJ (1869)

General's reports, is I in i6o.For the towns of Scotland it is I in 178 (from returns of 1860-64).Whatever may be the mortality of lying-in in private practice in Edinburgh, it must be above i in i6o.In the towns of Scotland it must be above i in I78.Second: The Registrar's reports may be corrected so as to bring up their statements of deaths of childbed (metria and childbirth) to the statements wanted-namely, deaths in childbed (from all causes).If this can be satisfactorily done, then we will have a statement of the mor- tality in childbed in home practice.Now, this has already been done in two ways.Dr. McClintock (Dublin; Quarterly .7ournal of Medicin,e, August I 869) has ingeniously suggested that it should be done on the following plan.He finds the figure indicating the excess of the mortality in childbed above the mor- tality ofchildbed (metria and childbirth deaths) and adds this to the mor- tality ofchildbed.In other words, he finds how many lying-in women die of other causes than metria and childbirth, and adds the figure to that indicating the deaths from these causes.I have no objection to this method of calculating when no better is available.But I have used a more direct and safer plan, that is, to search the public records for all deaths of lying-in women from whatever cause.I, some years ago, had this carefully done for Edinburgh and Glasgow in I855.I did not limit the search for deaths to four weeks after delivery, but extended it to six weeks; and this is unfortunate, as four weeks is the usual time under- stood to be adhered to in inquiries like the present.But the error thus introduced must be very trifling and unimportant.Now, this search shewed that the home practitioners of Edinburgh and Glasgow in I855 had, among lying-in women, a mortality of I in 107.
Physiological and pathophysiological roles of eicosanoids in the microcirculation
Authors: M. E. Gerritsen
Journal: Cardiovascular Research (1996)

Eicosanoids are important mediators of both physiological and pathophysiological responses of the microcirculation. These biologically active lipid mediators can be produced locally by the cellular elements within the microvasculature (endothelium, pericytes, smooth muscle cells) as well as interstitial cells (e.g. fibroblasts, mast cells) and by various cells in the vascular compartment (e.g. leukocytes, platelets). Transcellular metabolism of intermediates produced by one cell type in close contact with another also has the potential to generate potent metabolites. This review integrates some of the older literature with recent developments in eicosanoid synthesis and release, the molecular advances in the enzymology and receptor specificity of the eicosanoids and the regulation by autocoids and inflammatory mediators. The potential roles of eicosanoids in regulation of local blood flow, vascular reactivity, angiogenesis and leukocyte adhesion and transmigration are discussed.
Commentary: We don't know; better to err on the safe side from mid-gestation
Authors: V. Glover, N. Fisk
Journal: BMJ (1996)

Some scientists argue that fetuses cannot feel pain.1 Indeed, fetuses are currently treated as though they cannot. By contrast, it is generally agreed that preterm babies—often of the same gestational age as fetuses—should be given analgesia.2 3 In the public arena the pro-life and pro-choice lobbies often adopt opposed stances on the issue. However, attitudes to abortion should not influence our assessment of the evidence.

Currently we have no direct way of assessing pain in fetuses. The most rational approach is to make an informed guess based on our knowledge of the development and function of the nervous system at different gestational ages.4 Studies indicate that cortical, subcortical, and peripheral centres necessary for pain perception begin developing early in the second trimester.2 4 From 14 weeks most of …
Integrase-defective Lentiviral Vectors as a Delivery Platform for Targeted Modification of Adenosine Deaminase Locus
Authors: Alok V Joglekar, Roger P Hollis, Gabriela Kuftinec, Shantha Senadheera, Rebecca Chan, Donald B Kohn
Journal: Molecular Therapy (2013)

We investigated the use of integrase-defective lentiviral vectors (IDLVs) for transient delivery of zinc finger nucleases (ZFNs) and donor templates for site-specific modification of the human adenosine deaminase (hADA) gene. Initially, we constructed IDLVs carrying ZFN monomers (Single-IDLVs) and found them to be able to deliver their gene-editing payload to K562 cells successfully upon cotransduction, with minimal cytotoxicity. To simplify delivery, we designed an IDLV construct to deliver both ZFN monomers from the same vector (Double-IDLV). However, this construct in its original state was prone to rearrangements of the vector genome, resulting in greatly reduced functionality; this was due to recombination between highly similar ZFN monomers arranged in tandem. We modified the Double-IDLV constructs to reduce recombination and restored simultaneous delivery of both ZFNs. We also tested an IDLV construct for delivery of donor templates and demonstrated its efficacy for gene modification. In summary, we highlighted the importance of modifying vector design for co-delivery of highly similar sequences inherent to genome-editing nucleases, and demonstrated significant improvement in the use of IDLVs for delivery of ZFNs and donor templates for genome modification.
Mechanism of change in the excretion of sodium per nephron when renal mass is reduced
Authors: John P. Hayslett, Michael Kashgarian, Franklin H. Epstein
Journal: Journal of Clinical Investigation (1969)

As the population of nephrons is reduced, sodium excretion per nephron must increase if sodium balance is to be maintained. The mechanism of this adjustment was studied in rats in which 50% and approximately 85% of renal tissue was excised. Although glomerular filtration per remaining nephron rose after uninephrectomy, it did not rise further when more renal tissue was removed, even though sodium excretion per nephron mounted. Hyperfiltration does not, therefore, account for the stepwise increase in sodium excretion per nephron with progressive renal ablation. Proximal tubular absorption, estimated by reabsorption half-time, was unchanged by renal insufficiency, indicating that "third factor" did not produce the observed changes in sodium excretion per nephron. It seems likely that the earliest adjustments in sodium excretion in renal failure take place in the distal tubules of healthy nephrons, and that they are conditioned by changes in the osmotic load per nephron.
Influence of Sex and ABO Blood Group on the Normal Lymphocyte Transfer Test
Authors: J. F. Moorhead, A. R. Patel
Journal: BMJ (1964)

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