tbuckley/cabot-search huggingface dataset:
Abstract P6-04-25: Genomic Deregulation and Therapeutic Role of Nemo-like Kinase in Luminal B Breast Cancer
Authors: X Cao, L Qin, J-A Kim, Y Tan, X Wang, R Schiff
Journal: Cancer Research (2012)

Abstract Luminal B breast tumors are notoriously known as high grade breast cancer prone to Tamoxifen resistance and early recurrence. Chromosomal abnormalities are a crucial class of drug targets in cancer which can be classified into numerical and structural rearrangements. Gene amplification is the result of numerical rearrangement that generates multiple copies of an otherwise normal human gene, such as Her2 amplification observed in breast cancer. Gene fusion is the result of structural rearrangement that fuses together pieces of two different genes, such as BCR-ABL gene fusion identified in leukemia. Due to their critical role in causing human cancers and their presence exclusively in the tumor tissues, gene amplifications and fusions provide highly specific drug targets with only minimal side effects. In order to identify these chromosome aberrations that can serve as new therapeutic targets in breast cancer, we developed a novel bioinformatics analysis called “copy number signature analysis”. This is based on the observation that driving gene fusions and their original (wild-type) genes are often amplified in fusion-positive tumors, or tumors without the fusions respectively. This suggests that gene fusions and amplifications may synergize to activate important oncogenes; if directly druggable, these aberrations will provide substantial opportunities for new therapies. Applying this analysis to the newly emerged genomic data from the Cancer Genome Atlas (TCGA) project nominated Nemo-like kinase (NLK) as a lead therapeutic target for invasive breast cancer. NLK encodes a serine-threonine mitogen activated protein kinase that plays a pivotal role in transforming growth factor beta pathway and embryo development. Genomic amplifications and rearrangements at NLK locus happen in 7%–9% of breast tumors, which may lead to deregulated serine-threonine kinase activity. Of note, these aberrations preferentially present in luminal B or Her2 positive breast tumors, suggesting their association with these high grade tumors. Most interestingly, transient inhibition of NLK through small RNA interference in multiple breast cancer cell lines harboring NLK deregulations, we observed potent inhibition of cell growth and capability of forming tumor-like colonies, as well as increased sensitivity to Tamoxifen treatment. These data suggest that NLK might be deregulated by genetic events which may promote growth-factor signaling and Tamoxifen resistant phenotype. Molecular assays detecting NLK chromosomal aberrations may serve as a predictive biomarker for endocrine resistance in breast cancer as well as selection of patients for appropriate treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-25.
Carcinoembryonic antigen-related cell adhesion molecule 1 is the 85-kilodalton pronase-resistant biliary glycoprotein in the cholesterol crystallization promoting low density protein-lipid complex
Authors: Milan Jirsa, Lucie Muchová, Lubica Dráberová, Petr Dráber, František Šmíd, Masahide Kuroki, Zdenčk Mareček, Albert K. Groen
Journal: Hepatology (2001)

A pronase resistant 85-kd glycoprotein in the Concanavalin A–binding fraction (CABF) of biliary glycoproteins has been reported to act as a promotor of cholesterol crystallization. De Bruijn et al. (Gastroenterology 1996;110:1936-1944) found this protein in a low-density protein-lipid complex (LDP) with potent cholesterol crystallization promoting activity. This study identifies and characterizes this protein. An LDP was prepared from CABF by discontinuous gradient ultracentrifugation. Proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), blotting and immunochemical staining with anti-carcinoembryonic antigen, CEA-related adhesion molecule 1 (CEACAM1) cross-reacting antibodies. Biliary concentrations of CEA cross-reacting proteins were determined in patients with and without gallstones. Two isoforms of CEACAM1 (85- and 115-kd bands), CEA and 2 CEA cross-reacting protein bands of 40 and 50 kd were found in human bile. All bands were also present in CABF, but only a subfraction of the 85-kd band found in the LDP was resistant to digestion with pronase. CEACAM1-85 exhibited potent cholesterol crystallization promoting activity in vitro and accounted for most of the activity in CABF. Total CEA cross-reacting protein concentrations were the same in gallbladder biles from patients with cholesterol and pigment gallstones but only half of those in biles from nongallstone subjects. In conclusion, we have identified the protein component of the cholesterol crystallization promoting LDP to be CEACAM1-85.
P262 Tiotropium Safety And Performance In Respimat(R) (tiospir ): Safety And Efficacy In Patients With Tiotropium Handihaler(R) Use At Baseline
Authors: P. Calverley, A. Anzueto, R. Dahl, A. Mueller, A. Fowler, N. Metzdorf, R. Wise, D. Dusser
Journal: Thorax (2014)

<h3>Introduction</h3> The TIOSPIR™ trial showed that tiotropium Respimat<sup>®</sup> and HandiHaler<sup>®</sup> have similar safety and exacerbation efficacy profiles in patients with chronic obstructive pulmonary disease (COPD). We present here results for patients from the United States (US) using tiotropium HandiHaler<sup>®</sup> at baseline. <h3>Methods</h3> TIOSPIR™ (n = 17,135), a 2–3 year, randomised, double-blind, parallel-group, event-driven trial, compared safety and efficacy of once-daily tiotropium Respimat<sup>®</sup> 5 and 2.5 µg with once-daily HandiHaler<sup>®</sup> 18 µg in patients with COPD. Primary endpoints were time to death and time to first COPD exacerbation. Safety, including cardiovascular safety, was assessed. Tiotropium Respimat<sup>®</sup> was unavailable in the US (baseline tiotropium HandiHaler<sup>®</sup> use only), therefore this subgroup was analysed. <h3>Results</h3> Overall, 1779 patients from TIOSPIR™ treated with tiotropium HandiHaler<sup>®</sup> 18 µg at baseline in the US were randomised and treated (n = 572, n = 602 and n = 605 for tiotropium Respimat<sup>®</sup> 2.5 and 5 µg and HandiHaler<sup>®</sup> 18 µg). A numerically lower time to death was observed for patients within the Respimat<sup>®</sup> groups versus HandiHaler<sup>®</sup> (vital status follow up: Respimat<sup>®</sup> 5 µg: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.53–1.12; Respimat<sup>®</sup> 2.5 µg: HR, 0.76; 95% CI, 0.52–1.12). Risk of major adverse cardiovascular event (MACE) and fatal MACE was numerically lower for the Respimat<sup>®</sup> groups versus HandiHaler<sup>®</sup> (MACE: Respimat<sup>®</sup> 5 µg: HR, 0.69; 95% CI, 0.41–1.18; Respimat<sup>®</sup> 2.5 µg: HR, 0.83; 95% CI, 0.50–1.39; fatal MACE: HR, 0.60; 95% CI, 0.26–1.37; Respimat<sup>®</sup> 2.5 µg: HR, 0.42; 95% CI, 0.16–1.09). Overall incidence of a fatal event (on-treatment) was lower in the Respimat<sup>®</sup> groups versus HandiHaler<sup>®</sup> (Respimat<sup>®</sup> 5 µg: HR, 0.60; 95% CI, 0.39–0.92; Respimat<sup>®</sup> 2.5 µg: HR, 0.67; 95% CI, 0.44–1.02). Time to first exacerbation was similar across groups (Respimat<sup>®</sup> 5 µg versus HandiHaler<sup>®</sup>: HR, 0.94; 95% CI, 0.82–1.08). <h3>Conclusions</h3> Patients treated with tiotropium HandiHaler<sup>®</sup> 18 µg at baseline, and who were randomised and subsequently received tiotropium Respimat<sup>®</sup> 2.5 or 5 µg, had a similar risk of exacerbation as patients who continued to be treated with tiotropium HandiHaler<sup>®</sup> 18 µg. In this subgroup of patients, all-cause mortality was similar between tiotropium Respimat<sup>®</sup> and HandiHaler<sup>®</sup> 18 µg. <h3>Abstracts M263 to M272 are found on page A218–A223.</h3>
South Asian health: what is to be done?
Authors: Shah A Khan, Azra S Hasan
Journal: BMJ (2004)

Editor—The last few decades have seen technological advancements in surgery and medicine, including in South Asia. The return of Western trained doctors to South Asia, particularly India, has seen the foundation of many corporate hospitals with state of the art technology. Unfortunately these hospitals serve the elite few, less than 1% of the general population. They also breed superspecialisation.

Superspecialisation is justified only in a health system that has achieved an accessible primary health care for all, a distant dream in the developing countries of South Asia. Here it becomes an excuse for many to escape the mind boggling, perplexing health problems faced by the common man. With it comes more knee surgeons and fewer orthopaedic surgeons, more neonatologists and fewer paediatricians who can treat diarrhoeal illnesses, breeding mediocrity with dangerous implications.

Trainee and junior doctors are pressurised to adopt superspecialist skills from an early stage in their careers. Orthopaedic residents in training are now more keen to perform total knee or hip replacements than treat chronic osteomyelitis. The end result is a massive pool of infectious patients who are ignored and develop preventable illnesses or die.

A solution would be to develop government aided specialist centres accessible to all. However, primary health for all should not be sacrificed at the altar of these centres. More generalists with specialist training are needed.

The South Asian community should learn its lessons not through Western literature but through its own experimentation and commitment. We should change our approach from “who cares?” to “we care.”
Pyruvate ameliorates the defect in ureogenesis from ammonia in citrin-deficient mice
Authors: Mitsuaki Moriyama, Meng Xian Li, Keiko Kobayashi, David S. Sinasac, Yukiko Kannan, Mikio Iijima, Masahisa Horiuchi, Lap-Chee Tsui, Masashi Tanaka, Yoichi Nakamura, Takeyori Saheki
Journal: Journal of Hepatology (2005)
Vascular endothelial growth factor up-regulates nitric oxide synthase expression in endothelial cells
Authors: A Bouloumié
Journal: Cardiovascular Research (1999)

Objective: Vascular endothelial growth factor (VEGF), secreted by vascular cells and a variety of tumour cells, is a potent angiogenic factor. Since nitric oxide (NO) seems to play a key role in the VEGF-induced proliferation of endothelial cells, the aim of the present study was to determine whether VEGF stimulates endothelial NO synthase (eNOS) expression and hence results in a maintained increase in NO formation. Methods: Experiments were performed using cultured human umbilical vein endothelial cells (HUVEC) and isolated rat aortic rings. eNOS expression was assessed by Western blotting and RT-PCR analysis. Results: Exposure of either confluent HUVEC or rat aortic rings to VEGF165 significantly increased eNOS mRNA and protein levels. This stimulatory effect of VEGF165 on eNOS expression was associated with an elevation in the basal production of cGMP in HUVEC, and with a leftward shift of the concentration–relaxation curve to acetylcholine in aortic rings. The VEGF-induced increase in eNOS mRNA levels was abolished by tyrosine kinase inhibitors suggesting involvement of a tyrosine kinase-dependent pathway. Since eNOS mRNA levels remained elevated in VEGF-treated cells in the presence of actinomycin D, it is likely that the VEGF-induced up-regulation of eNOS expression may be a consequence of a post-transcriptional effect on eNOS mRNA stability. Conclusion: The results demonstrate that VEGF enhances the expression of eNOS in native and cultured endothelial cells, an effect which may be important in the process of VEGF-induced angiogenesis.
Induction of Ovulation with MRL/41
Authors: Robert B. Greenblatt
Journal: JAMA (1961)

MRL/41, an analogue of the nonsteroid estrogen, chlorotrianisene, was evaluated in the human female because it was shown to possess pituitary gonadotropin-inhibiting and antifecundity properties in rats. Although structurally related to a hormone-like chemical agent, this compound does not exhibit estrogenic, progestogenic, or androgenic activity in the human. Studies with this drug were initiated primarily because of its potential as an antifertility agent. Contrary to expectations, some unsuspected and interesting biological activities were observed, one of which was the induction of ovulatorytype menses in amenorrheic anovulatory females.
INFECTION FROM THE MOUTH.Read in the Section on Dental and Oral Surgery, at the Forty-fourth Annual Meeting of the American Medical Association.
Authors: E. L. CLIFFORD
Journal: JAMA (1894)

Each and every day brings the thoughtful student more and more to face the fact that the scientific world is progressing; and he who has kept<i>au courant</i>with the literature of medicine must acknowledge that the results of such investigations as are now being pursued have, for a principal object, the unfolding of the prime factors in the causation of diseases, with a view to their prevention. Recent investigators have sought to open up new fields; they have tried, and found wanting, in many instances, the beaten track, and their efforts tend to the opening of new lines and a practical departure from the pathology of the past, with an ever increasing tendency to lead us to cultivate and entertain broader, or at any rate less narrow views, as to the elements which play an important part as etiologic factors in the causation and origin of diseases. It is
Incidence and causes of colonoscopic perforations: a single-center case series
Authors: R. Loffeld, A. Engel, P. Dekkers
Journal: Endoscopy (2010)

Perforations are known to occur after colonoscopy. In a consecutive study the localization of the perforation was determined, and the etiology of the perforation was classified as: therapeutic, barotraumatic or mechanical. A colonic perforation occurred in 26 of 19,135 patients (0.14%). In 13 cases (50.0%) the cause of perforation was mechanical, in nine (34.6%) the cause was a barotrauma (cecal blow-out), and in three cases (11.5%) it was due to a therapeutic procedure (coagulation or polypectomy). In one case (3.8%) data were not available. Cecal blow-out occurred significantly more often as a result of barotrauma, whereas perforation of the sigmoid occurred more often as a result of direct mechanical trauma. The risk of perforation after colonoscopy is rather low. Barotrauma due to insufflated air occurs more often than therapeutic perforation due to polypectomy or coagulation. Patients with a higher risk of perforation are those with diverticula in the sigmoid.
Toward a Cure for Multiple Myeloma?
Authors: Bart Barlogie
Journal: New England Journal of Medicine (1991)

THERE has been little progress in the treatment of multiple myeloma since the introduction of the melphalan—prednisone regimen about 25 years ago (for review, see Barlogie et al.1). The lack of benefit from the addition of alkylating agents and anthracyclines has been well documented in multidrug trials and probably reflects the low level of activity of the individual drugs involved.2 Such regimens are designed to minimize myelosuppression, because of the immunodeficiency caused by the disease in what are typically elderly patients. Unfortunately, the marked efficacy of the VAD (vincristine—doxorubicin [Adriamycin] —dexamethasone) regimen in melphalan-resistant myeloma did not translate into . . .
Zinc supplements improve children's health
Authors: N. Macready
Journal: BMJ (1998)

Zinc supplementation reduces the incidence and severity of childhood infections and may lower child mortality in impoverished areas, according to studies conducted by members of the Child Health Research Project.

The project is a collaboration of the World Health Organisation, Harvard University in Massachusetts, Johns Hopkins University in Maryland, and the International Centre for Diarrhoeal Disease Research in Bangladesh. It carried out a number of studies, which are published in a special 200 page supplement to the August issue …
Dictators and their doctors
Authors: T. Dalrymple
Journal: BMJ (2012)

There is something fascinating about the memoirs of the servants or confidants of great dictators. They allow us to see raw power close up, and to thrill to its horror. Personally, I can never resist a book with the title I Was X’s Y , where X was a dictator and Y was his maid, secretary, or chauffeur.

Doctors have written memoirs of dictators. Among the most famous, or infamous, are those of Dr Li Zhisui, The Private Life of Chairman Mao . When they were published there was a controversy as to how genuine they were, with both translator and publisher accused of spicing them up to attract sales. The author himself was accused of claiming …
Case of Encephaloid Tumour of the Bladder, with Observations
Authors: G. P. May
Journal: BMJ (1846)

being previously in good health, and actively employed in the duties of teacher in a ladies' seminary, about two years since, was attacked with hbematuria, accomnpanied with pain in the loins, and a sense of bearing-down in the perineum.These symptoms ceased under the use of refrigerant medicines, and acidulated drinks, rest in the recumbent posture being at the same time enjoined.Immunity froin this malady however, was not of long duration; any active exertion, or extended walking exercise being fieqtiently sufficient to induce its recurrence.The liamorrbage at this time was never excessive, the urine exhibiting no trace of blood for more than two or three days at a time.Shc was able to retain her situation, and to discharge the duties attaching to it until the end of the last year.Whilst spending the Christmas vacation in London, she was attacked with severe bhamorrhage from the urinary organs, the quantity amounting, according to her own estimate, to several pounds of blood.She returned homne in January of the present year, her complexion pallid and pasty, physical energies much reduced, and complaining of
Interplay between oxidative stress and hepatic steatosis in the progression of chronic hepatitis C
Authors: Matteo Vidali, Marie-Francoise Tripodi, Alesandra Ivaldi, Rosa Zampino, Giuseppa Occhino, Luciano Restivo, Salvatore Sutti, Aldo Marrone, Giuseppe Ruggiero, Emanuele Albano, Luigi E. Adinolfi
Journal: Journal of Hepatology (2007)
The selective cyclooxygenase-2 inhibitor celecoxib modulates the formation of vasoconstrictor eicosanoids and activates PPARγ. Influence of albumin
Authors: Marta López-Parra, Joan Clària, Esther Titos, Anna Planagumà, Marcelina Párrizas, Jaime L. Masferrer, Wladimiro Jiménez, Vicente Arroyo, Francisca Rivera, Joan Rodés
Journal: Journal of Hepatology (2004)
The frequency of reactions to sunscreens: results of a longitudinal population-based study on the regular use of sunscreens in Australia
Authors: P. FOLEY, R. NIXON, R. MARKS, K. FROWEN, S. THOMPSON
Journal: British Journal of Dermatology (1993)

Six‐hundred‐and‐three people aged 40 or more years, from Maryborough in central Victoria, were enrolled in a randomized longitudinal study, which required daily application of either a SPF 15+. broad‐spectrum, water‐resistant sunscreen cream or the cream base without the active ingredients. The study duration was 7 months, from September 1991 until April 1992. One‐hundred‐and‐fourteen (18.9%) of these subjects developed an adverse reaction to the cream they were applying. Patch testing, photopatch testing and scratch testing with the ingredients of the creams revealed that only a small proportion (<10%) of the intlammatory eruptions were allergic in nature. None of the people tested was allergic to the sunscreen active ingredients. History and examination findings, where available, suggested that the majority of adverse responses were consistent with an irritant reaction, both to the sunscreen preparation and the base cream control. A higher than expected proportion of the people who developed an adverse reaction had a personal history consistent with atopy. Other reactions included acneiform eruptions and contact urticaria. A frequency of reactions to sunscreen preparations of over 15% means that further work is necessary to improve both the formulation of such products, and the manner and conditions nnder which they are used, to ensure satisfactory compliance.
1088. Antigen Epitopes Expressed in Different Adenovirus Capsid Proteins Induce Different Levels of Epitope-Specific Immunity
Authors: Anja Krause, Stefan Worgall, Ju H. Joh, Neil R. Hackett, Peter W. Roelvink, Joseph T. Bruder, Thomas J. Wickham, Imre Kovesdi, Ronlad G. Crystal
Journal: Molecular Therapy (2005)

Top of pageAbstract
The immune response against adenovirus gene transfer vectors (Ad) is directed against the capsid proteins and transgene expressed by the vector. Incorporation of pathogen-derived epitopes into capsid proteins may be a useful strategy to evoke an anti-pathogen immunity and may complement the anti-transgene immune response. Our previous data (Worgall et al Mol Ther 2004; 9:S261) demonstrate that incorporating an epitope of the outer membrane protein of Pseudomonas aeruginosa into the hexon of the adenovirus capsid provides protection against pulmonary challenge by P. aeruginosa in experimental animals. In this study, we compare the immune response against an epitope incorporated into different capsid proteins (hexon, fiber, penton base and protein IX) and determine if the immune response against the epitopes will be proportional to the number of copies of that protein in the capsid. To test this hypothesis, we used the major antigenic site HA from the hemagglutinin protein of influenza virus type A as model epitope. Replication deficient Ad vectors were engineered expressing the HA sequence YPYDVPDYAGG on the surface of the adenoviral virion as part of following 4 capsid proteins: in HVR5 loop of hexon protein (Ad.Hexon-HA), in HI loop of fiber protein (Ad.Fiber-HA), in RGD loop of penton protein (Ad.Penton-HA), and attached to the C-terminus of Protein IX (Ad.pIX-HA). The HA epitope is present at various copy numbers in each virion: hexon, 720; protein IX 240; penton base 60; and fiber 36. Using an anti-HA antibody, in vitro studies demonstrated that the modified capsid proteins were incorporated into virions and express the HA-sequences in the expected capsid proteins of each recombinant vector. CBA mice were immunized by the intramuscular route with the same dose of adenoviral vectors (5|[times]|109 particle units) and serum anti-HA titer was evaluated at 4 wk by ELISA against purified recombinant HIS-tagged HA fusion protein. Titers against HA in Ad.Fiber-HA immunized mice were three times higher compared to Ad.Hexon-HA immunized mice (555|[plusmn]|40 vs 162|[plusmn]|36, p  IgG2b for Ad.Fiber-HA and Ad-Hexon-HA. In contrast to the variable response to a specific antigen inserted into different locations of the capsid, anti-Ad capsid titer were the same for all 4 HA modified vectors and also for an AdNull vector with the wild type capsid delivered by the same dose and route. We conclude that incorporation of an epitope into the fiber gene is the most potent strategy to elucidate an anti-epitope response, at least for this model system . The fact that immune response was independent of the dose of the epitope suggested that antigen position in the capsid and its recognition by B cells is the critical component of the response to the epitope incorporated into the Ad capsid.