tbuckley/cabot-search huggingface dataset:
Abstract 4397: Therapeutic microRNA agaisnt KRAS mutant colorectal cancer
Authors: Masayuki Hiraki, Junichi Nishimura, Mamoru Uemura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori
Journal: Cancer Research (2014)

Abstract Background: The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are the molecular target drugs, dependent on v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations status in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibody based chemotherapy is the standard treatment for mCRC with KRAS wild-type. However, the issue of resistance to this therapy in CRC with KRAS mutations (approximately 50% of CRC) remains unresolved. The aim of this study is to identify microRNAs (miRNAs) that govern the resistance to anti-EGFR monoclonal antibody in CRC with KRAS mutations. Experimental Design: We first established the KRAS mutant cell model using HEK293 and MRC5 cells by introducing KRASG12V plasmid. The miRNA expression profiles were compared between these cells using miRNA microarray analysis. We selected the candidate a miRNA which down-regulates the downstream signal of KRAS using luciferase reporter assays. Assessment of target genes of the candidate a miRNA was performed in vitro. Next, anti-tumor effects by supplement of a miRNA were evaluated in vitro and in vivo. Results: We picked up miRNAs, of which expressions decreased in both HEK293 and MRC5 cells by introduction of KRASG12V plasmid in miRNA array analysis. Among them, administration of mature-miR-X suppressed SRE and AP1 activity in KRAS mutant CRC cell lines such as DLD1G13D, SW480 G12V, and HCT116 G13D using dual luciferase reporter assay. Furthermore, miR-X regulated not only Ras/Raf/MAPK pathway but also suppressed PI3K/Akt pathway in vitro. Administration of mature-miR-X suppressed proliferation and induced apoptosis of the CRC cell lines with KRAS mutations in vitro. Systemic mature-miR-X administration into tail veins of nude mice significantly inhibited the growth of pre-established DLD1G13D xenografts. miR-X level was significantly lower in tumor tissues compared to normal mucosa. Conclusions: miR-X may overcome anti-EGFR therapy resistance in CRC with KRAS mutations by regulating Ras/Raf/MAPK pathway and PI3K/Akt pathway. Our data suggests that miR-X could be suitable for a novel therapy for mCRC patients with KRAS mutations. Citation Format: Masayuki Hiraki, Junichi Nishimura, Mamoru Uemura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Therapeutic microRNA agaisnt KRAS mutant colorectal cancer. [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 4397. doi:10.1158/1538-7445.AM2014-4397
Abstract 11741: Severe Aortic Stenosis With Normal Left Ventricular Ejection Fraction, Normal Flow and Low Gradients. Another Paradox or Only Moderate Stenosis?
Authors: Dragos Alexandru
Journal: Circulation (2014)

Background: Among the 4 hemodynamic subsets of severe AS with preserved EF, based on LV stroke volume index (SVi) and mean pressure gradients, normal flow with a low gradient (NF/LG) has been attributed to measurement errors, small body size or inconsistencies in guideline criteria and associated with a favorable prognosis. We hypothesized that AV weight (AVW) in NF/LG AS, would be lower than that in other hemodynamic groups. Methods: Between 2010-13, 403 consecutive patients (pts) undergoing AV replacement (AVR) for severe isolated AS, (mean age 76.8 (9.3) yrs, 56% men, AVA index 0.36 (0.10 cm2)/m2, EF = 61.3 ± 4.6%, 11% bicuspid valves, mean follow-up 18 ± 9 months), underwent intraoperative TEE and had the AV weighed after excision (AVW = 2.4 ± 0.9 g), and excised valves were collected in formaldehyde, dried and weighed. All echo variables were measured off-line by a single observer on a dedicated reading station (Agfa). Medical records were reviewed to extract clinical data and all-cause mortality determined from the Social Security Death Index. Analysis of covariance (ANCOVA), Chi-square test, and Cox proportional hazards regression models were used as appropriate. Results: (for unadjusted comparisons see table.) In models adjusted for age, gender BSA, EF and annular area, AVW and AVW index remained lower in NF/LG than that in the high gradient groups (p&lt;.01 for both). Although the number of deaths was small, no significant difference in all-cause mortality or time from AVR to death was found among the 4 groups (p=0.27 and p=0.28, respectively). AVR improved survival to a similar degree regardless of hemodynamic phenotype. Conclusions: 1. Compared with high gradient groups, pts with normal flow-low gradient have a lower AVW and AVW/aortic annulus area, a lower severity of stenosis and less LV remodeling. 2. These findings support the recent recommendation to categorize these pts as having only moderate AS.
Abstract IA20: Targeting AMPK signaling in melanoma
Authors: Bin Zheng
Journal: Cancer Research (2015)

Abstract Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated anti-tumor activity both in vitro and in vivo. The energy-sensing AMP-activated protein kinase (AMPK) is known to be a major cellular target of biguanides. We have previously reported that AMPK signalling is attenuated by BRAFV600E in melanoma through phosphorylation of LKB1, a major upstream kinase of AMPK. More recently, we have also discovered that BRAF is directly phosphorylated by AMPK, leading to impaired BRAF-KSR1 association and MEK-ERK signalling (Mol Cell, 2013, 52:161). Based on this crosstalk between the AMPK and BRAF signaling pathways, we investigated the anti-tumor effects of combining phenformin with a BRAF inhibitor PLX4720 on the proliferation of BRAF mutated melanoma cells in vitro and on BRAF-driven tumor growth in vivo. Co-treatment of BRAF mutated melanoma cell lines with phenformin and PLX4720 resulted in synergistic inhibition of cell viability, compared to the effects of the single agent alone. Moreover, treatment with phenformin significantly delayed the development of resistance to PLX4720 in cultured melanoma cells. Biochemical analyses showed that phenformin and PLX4720 exerted cooperative effects on inhibiting mTOR signaling and inducing apoptosis. Noticeably, phenformin selectively targeted subpopulations of cells expressing JARID1B, a marker for slow cycling melanoma cells. In contrast, PLX4720 selectively targeted JARID1B negative cells, which represents the majority of cells in the tumors, and spared the JAR1D1B-positive slowing cycling population. Finally, in contrast to their use as single agents, the combination of phenformin and PLX4720 induced tumor regression in both nude mice bearing melanoma xenografts and in a genetically engineered BRAFV600E/PTENnull-driven mouse model of melanoma. These results strongly suggest that significant therapeutic advantage may be achieved by combining AMPK activators such as phenformin with BRAF inhbitors for the treatment of melanoma. Citation Format: Bin Zheng. Targeting AMPK signaling in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA20.
Use of Dimethylmyleran in Adoptive Chemoimmunotherapy of Two Murine Leukemias 2
Authors: Albert B. Einstein, Martin A. Cheever, Alexander Fefer
Journal: JNCI Journal of the National Cancer Institute (1976)

Dimethylmyleran (DMM) is an antitumor agent that has minimal effects on immunity. In a study of its usefulness in adoptive chemoimmunotherapy, C57BL/6 mice inoculated on day 0 with C57BL/6 Friend virus-induced leukemia (FBL-3) were treated on day 5 with 12 mg DMM/kg [<LD10 (lethal dose for 10% of mice)] plus C57BL/6 spleen cells. All untreated mice died, with a median survival time (MST) of 17 days. DMM alone or with nonimmune cells prolonged survival to day 20, and 3/53 mice survived beyond day 60. By contrast, 12/25 mice treated with DMM plus ceUs immune to FBL-3 were cured. Similar results were obtained in C57BL/6 mice with syngeneic Rauscher virus-induced leukemia (RBL-5). Untreated mice died, with an MST of 14 days. DMM alone or with nonimmune cells prolonged the MST to 21 and 26 days, respectively, and 3/26 and 6/28 mice were long-term survivors. However, 13/28 mice were cured by DMM plus cells immune to antigenically related FBL-3. Lethal irradiation of cells immune to FBL-3 abolished their efficacy. Finally, in contrast to the efficacy of sublethal DMM plus immune cells, an LD100 of DMM (20 mg/kg) plus hematopoietic reconstitution with nonimmune syngeneic cells was not effective against FBL-3 or RBL-5. The results emphasized the critical role of immune cells in chemoimmunotherapy even when the drug used is nonimmunosuppressive.
Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer
Authors: Mahadev Rao, Nachimuthu Chinnasamy, Julie A. Hong, Yuwei Zhang, Mary Zhang, Sichuan Xi, Fang Liu, Victor E. Marquez, Richard A. Morgan, David S. Schrump
Journal: Cancer Research (2011)

Abstract Cancer–testis antigens (CTA), such as NY-ESO-1, MAGE-A1, and MAGE-A3, are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells but are activated by ill-defined epigenetic mechanisms in human tumors, including lung cancers. Previously, we reported induction of these CTAs in cancer cells, but not normal cells, by DNA-demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer–testis genes in lung cancer cells to further develop gene-induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment, and binding of polycomb-group proteins, and histone heterochromatin modifications within the promoters of these genes. Derepression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. Short hairpin RNAs were used to inhibit several histone methyltransferases (KMT) and histone demethylases (KDM) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1, or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer–testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knockdown. Following DAC–DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T-cell receptors recognizing NY-ESO-1 and MAGE-A3. Combining DNA-demethylating agents with compounds, such as DZNep, that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer–testis gene expression as an adjunct to adoptive cancer immunotherapy. Cancer Res; 71(12); 4192–204. ©2011 AACR.
Ads: Selling drugs to consumers
Authors: A. Ferriman
Journal: BMJ (1999)

Time was when fat people were counselled to eat less and shy people were advised to get out more. Now, if they are living in the United States, such people are exhorted to take pills. Hoffman-La Roche is spending $75m (£47m) persuading Americans to take its slimming pill Xenical (orlistat), and SmithKline Beecham is spending $30m promoting its anti-shyness pill, Paxil (paroxetine).

In Britain, however, consumers are protected from, or deprived of (depending on your point of view), such blandishments. Both products are prescription only medicines, and the pharmaceutical industry is not allowed to promote them direct to the general public.

But how long will this last? The British drugs industry sees changing the law as its most pressing task. It is promoting discussion of the issue throughout the media. You can hardly open a newspaper today without seeing another article on the subject. And last week, the King's Fund, an independent think tank, held a debate on the issue entitled: “Drug companies should be able to advertise their prescription products to the public.”

Margot James, chief executive of Shire Hall Group, a public relations company whose clients include several large drug …
Abstract P275: Physical Activity Among Married Couples in the Atherosclerosis Risk in Communities Study
Authors: Laura K Cobb, Job G Godino, Elizabeth Selvin, Anna Kucharska-Newton, Josef Coresh, Silvia Koton
Journal: Circulation (2015)

The positive impact of physical activity on health is broadly recognized; however, there has been little progress toward meeting population targets for physical activity levels. Although similarities in some health behaviors have been shown in couples, there are few reports on the concordance of change in physical activity among married couples. We studied this concordance and changes over time in physical activity among 3,261 married couples from the Atherosclerosis Risk in Communities (ARIC) Study during a 6-year period (from visit 1: 1987-1989 to visit 3: 1993-1995). Physical activity was measured using the Baecke questionnaire and indices ranged from 1 (low) to 5 (high). At visit 1, mean (SD) sport/exercise index was 2.6 (0.8) for men and 2.4 (0.8) for women, while the leisure index was 2.4 (0.5) for men and 2.5 (0.6) for women. Correlations between spouses were 0.20 for the sport/exercise index and 0.22 for the leisure index. In linear regression models adjusted for individual and spousal characteris...
An Introduction to Practical Bacteriology: A Guide to Bacteriological Laboratory Work.
Authors: T. J. Mackie, J. E. McCartney
Journal: JAMA (1931)

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
The ‘eyes’ or ‘goggles’ as a clue to the histopathological diagnosis of primary lymphocytic cicatricial alopecia
Authors: M. Miteva, F. Torres, A. Tosti
Journal: British Journal of Dermatology (2011)

Journal Article The 'eyes' or 'goggles' as a clue to the histopathological diagnosis of primary lymphocytic cicatricial alopecia Get access M. Miteva, M. Miteva Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, U.S.A Search for other works by this author on: Oxford Academic Google Scholar F. Torres, F. Torres Department of Dermatology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil E‐mail: mmiteva@med.miami.edu Search for other works by this author on: Oxford Academic Google Scholar A. Tosti A. Tosti Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, FL 33136, U.S.A Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 166, Issue 2, 1 February 2012, Pages 454–455, https://doi.org/10.1111/j.1365-2133.2011.10578.x Published: 01 February 2012
Routine vaccination and child survival in Guinea-Bissau
Authors: P. Aaby
Journal: BMJ (2001)

The paper by Kristensen et al describes improved survival in infants in GuineaBissau who received measles or BCG vaccines but increased mortality in those who received diphtheria, tetanus, and pertussis vaccine.1 At the request of the World Health Organization we visited GuineaBissau durng 815 October 2000 to review this study.
Excessive false-positive errors in single-arm phase II trials: A simulation-based analysis
Authors: H. Tang, N. R. Foster, A. Grothey, S. M. Ansell, D. J. Sargent
Journal: Journal of Clinical Oncology (2009)

6512 Background: The use of randomized phase II designs with an experimental arm and a standard-treatment control arm (R2PII) instead of a conventional single-arm design is clearly increasing in oncology. In practice, sample size, related cost issues, the belief that historical controls are adequate, and the use of a standard-treatment control arm in a phase II setting are frequently raised objections to R2PII trials. As the expense and complexity of definitive phase III trials increase, the ability of phase II trials to provide reliable and accurate results is critical. Methods: We investigated the ability of single arm vs R2PII trials to provide accurate conclusions by modeling variability in historical controls, patient outcome drifts independent of the tested therapy, and patient selection effects. Simulations compared R2PII and single-arm designs with binary endpoints under realistic parameters (e.g. alpha = beta = 0.10, historical control success rate = 20%, target success rate = 40%). Results: In the absence of variability in historical controls, estimated false positive and negative rates in both designs mirror the designated specifications. However, even in the presence of a modest drift effect in the population (mean 5% absolute shift in true control success rate), the false positive rate in single-arm designs is inflated two to three fold (to 20%-30%), while the R2PII retains the desired error rates. Greater confidence in historical controls in the single-arm design corrects only a small portion of the deviations. Increasing the sample size in each trial inflates the false positive error rate further to as much as 50%. Varying several sets of parameters gave similar results. Conclusions: In the presence of variability in historical controls, patient drift and/or selection effects, the false positive error rate of a single arm design is unacceptably high. In contrast, the R2PII design is reliable and robust despite the complexities in patient outcome drift and selection effects, and variability in historical control success rates. Given the rapid improvements in outcomes of many tumor types, the R2PII design should be the preferred method to evaluate novel agents in oncology in spite of the associated costs and the use of a reference control arm. No significant financial relationships to disclose.
Fluticasone propionate/formoterol fumarate combination therapy is equally effective and well-tolerated when administered with or without a spacer device to patients with asthma
Authors: David Price, Alberto Papi, Kirsten Kaiser, Brigit Grothe, Mark Lomax
Journal: European Respiratory Journal (2011)

Background: Phase 3 studies involving a new asthma therapy combining fluticasone (FLUT) and formoterol (FORM) in a single aerosol inhaler (FLUT/FORM; flutiform ®) either used a spacer or did not. This is the first comparison of the efficacy and tolerability of treatment with or without the use of a spacer device.

Methods: Adults and adolescents with mild, moderate or moderate-severe asthma were treated with FLUT/FORM 100/10μg or 250/10μg b.i.d. delivered either with (N=195) or without (N=532) a spacer in 6 randomised, double-blind and open-label, parallel group studies. The endpoint was non-inferiority between spacer and non-spacer groups (concluded if the lower bound of the 95% CI was ≥-0.2L) in terms of changes in morning pre-dose FEV1 and morning pre-dose to 2h post-dose FEV1 over 12 weeks. The incidence of adverse events (AEs) was analysed over 8 weeks.

Results: FLUT/FORM was consistently as effective when delivered with or without a spacer at all dose strengths and asthma severities. From baseline to end of study, the LS mean treatment difference in morning pre-dose FEV1 was 0.067L greater without spacer (95% CI: -0.149, 0.015) and in morning pre-dose to 2h post-dose FEV1 was 0.015L greater with spacer (95% CI: -0.051, 0.081). AEs were reported with similar frequency both with and without a spacer (nasopharyngitis: 14 (2.1%) vs 34 (3.2%); asthma: 12 (1.8%) vs 17 (1.6%) patients; cough: 4 (0.6%) vs 10 (0.9%); dysphonia: 5 (0.7%) vs 7 (0.7%)).

Conclusions: Pooled analysis showed that fluticasone/formoterol may be given with or without a spacer device with both approaches providing similar efficacy and tolerability.
Treatment of infantile haemangioma with captopril
Authors: S.T. Tan, T. Itinteang, D.J. Day, C. O’Donnell, J.A. Mathy, P. Leadbitter
Journal: British Journal of Dermatology (2012)

Infantile haemangioma (IH) has recently been reported as an aberrant proliferation and differentiation of a primitive mesoderm-derived haemogenic endothelium regulated by the renin-angiotensin system (RAS), leading us to propose angiotensin converting enzyme (ACE) as a potential therapeutic target.To present initial results of our open-labelled observational clinical trial using captopril, an ACE inhibitor (ACEi), in the treatment of problematic proliferating IH.After initial screening investigations, infants with problematic IH were admitted for initiation of captopril with a 0·1 mg kg(-1) test dose orally, followed by 0·15 8-hourly over 24 h. This was then followed by dose escalation to 0·3 mg kg(-1) 8-hourly for another 24 hours. The dosage was increased to 0·5 mg kg(-1) 8-hourly 1 week later, if a noticeable involution had not already occurred. The response of IH to captopril was documented clinically and photographically before and after treatment and any side-effect was recorded.Two boys and six girls aged 5-22 weeks (mean 12·9) with problematic IH were recruited with the lesions located in nasal tip (n = 1), cervicofacial (n = 3), periorbital (n = 1) and perineal (n = 2) areas, and shoulder (n = 1). Transient mild renal impairment occurred in one subject but resolved spontaneously. No other complication was observed. The IHs in all patients responded to captopril at a dosage of 1·5 mg kg(-1) daily which led to a dramatic response in three, moderate response in two, and slow response in three patients. Continued involution of IHs was observed during the follow-up period of 8-19 months (mean 15·8) in all subjects. Treatment was ceased at 14 months of age in seven patients with no rebound growth. In the remaining patient, rapid healing occurred with ongoing gradual reduction in the size and colour of a large ulcerated retroauricular lesion following 5·5 months of treatment. The lesion was excised to address its persistent distortion of the ear.The response of IH to an ACEi supports a critical role for the RAS in IH and represents a paradigm shift in the understanding and treatment of this enigmatic condition.