tbuckley/cabot-search huggingface dataset:
The utility of pelvic magnetic resonance imaging post chemoradiation for localized rectal cancer.
Authors: Louise Catherine Connell, Patrick Conway, David Lucey, Paul Kelly, Vivienne Curran, Anne Murphy, Morgan McCourt, Emmet Andrews, Michael O'Riordain, Seamus O'Reilly, Derek Gerard Power
Journal: Journal of Clinical Oncology (2014)

e14550 Background: In locally advanced rectal cancer, neoadjuvant long-course chemoradiotherapy (CRT) is associated with improved local control and superior surgical outcome. In the era of total mesorectal excision (TME) there is no consensus on whether patients(pts) should undergo repeat imaging prior to surgery. The purpose of this study was to assess whether pelvic magnetic resonance imaging (MRI) following CRT altered surgical management. Methods: Data from 2 tertiary cancer referral centres in the our region using prospectively maintained databases were retrospectively reviewed to identify all pts between the time period of January 2010 until December 2013 who had received neoadjuvant CRT for localised (cT3-4 or cN+ by endorectal ultrasound, computed tomography, or MRI) rectal adenocarcinoma. Only pts who had been staged pre- and post-CRT with MRI were eligible for inclusion. Results: One hundred pts had MRI pre and post long course CRT. Overall two thirds of pts were male. The median age was 53 (range 34-86). Abdominoperineal resection was performed in 36 pts, and anterior resection in 64 pts. The median radiation dose was 50.4 Gy with concurrent 5FU-based chemotherapy. Oral capecitabine was the most frequently prescribed form of chemotherapy, with expected toxicities recorded. Median time from completion of CRT to post-treatment MRI was 30 days. The median time to surgery from the 2ndMRI was 23 days. Only 1 of the 100 pts (1%) showed disease progression on the repeat scan and R0 resection was achieved in this case. Ten pts (10%) achieved pathologic complete remission (CR) and none of these had a radiographic CR on post-treatment MRI. Six pts (6%) had positive circumferential resection margins with 4 of these being predicted by post-treatment MRI. Repeat MRI post CRT did not alter the intended surgical approach in a single patient. Conclusions: MRI following neoadjuvant chemoradiation prior to surgical resection for locally advanced rectal adenocarcinoma did not alter clinical management in this small retrospective series. The utility of post CRT MRI prior to definitive resection is unclear as shown in recent publications and international guidelines do not recommend this approach. Better imaging post CRT is required.
Factors associated with adherence to adjuvant endocrine therapy in patients with hormone receptor positive breast cancer.
Authors: Jongjin Kim, Wonshik Han, Hyeong-Gon Moon, Jisun Kim, Jun Woo Lee, Min Kyoon Kim, Eunshin Lee, Tae-Kyung Yoo, Dong Young Noh
Journal: Journal of Clinical Oncology (2014)

e11502 Background: Adjuvant endocrine therapy in patients with hormone receptor positive breast cancer reduces recurrence and mortality, but many patients are non-adherent to anti-hormonal medication. In order to increase the adherence, we investigated factors associated with adherence to anti-hormonal medication using variable questionnaires. Methods: We carried out a cross-sectional survey of a thousand of women who underwent surgery due to breast cancer in our institution from 2007 to 2011 and treated with anti-hormonal medicines. The questionnaires included the Medication Adherence Report Scale-5(MARS-5), Women’s Health Questionnaire(WHQ), Beliefs about Medicine Questionnaire(BMQ), Satisfaction with Information about Medicines Scale(SIMS). And to identify patient’s clinical characteristics, we reviewed electronic medical records, retrospectively. Results: The response rate was 40.8%(408/1,000, tamoxifen(TMX)=263, aromatase inhibitors(AIs)=145). The rate of non-adherence was 48.3%(197/408, TMX=132/263(50.1%), AIs=65/145(44.8%)). Of the all answered patients, non-adherent patients had more depressive mood(p<0.001). Non-adherent patients scored lower on positive beliefs as measured on BMQ-necessity(OR=0.65, 95% CI 0.51-0.82) and higher on negative beliefs as measured on BMQ-overuse(OR=1.81, 95% CI 1.29-2.54). Non-adherent patients also scored lower on SIMS-action and usage(OR = 0.47, 95% CI 0.38-0.65). Of the patients treated with TMX, non-adherent patients had more depressive mood (p=0.003), scored higher on BMQ-overuse(OR=1.97, 95% CI 1.22-3.20) and scored lower on SIMS-action and usage (OR = 0.33, 95% CI 0.22-0.50). Of the patients treated with AIs, non-adherent patients had more depressive mood (p=0.014), scored lower on BMQ-necessity (OR=0.52, 95% CI 0.36-0.75). Conclusions: This study showed associations between depressive mood of patients treated with anti-hormonal therapy and adherence. And beliefs and satisfaction with information about medicine also associated with adherence. To improve adherence, we should correct patient’s mood and provide proper information about medicines.
AZD1152: A highly potent and specific aurora kinase inhibitor.
Authors: Robert W. Wilkinson, Nicholas Keen, Rajesh Odedra, Simon P. Heaton, Stephen R. Wedge, Kevin M. Foote, Andrew A. Mortlock, Frederic H. Jung, Nicola M. Heron, Madeleine C. Brady, Mike Walker, Liz Khatri, Nigel C. Barrass, John J. Foster, Stephen Green
Journal: Cancer Research (2006)

5673  Aurora kinases are serine-threonine kinases that participate in several stages of mitosis including chromosomal segregation and cytokinesis. Aurora A and B kinases are frequently elevated in human cancers making them attractive targets for therapeutic intervention. Here we describe the preclinical development of AZD1152, a specific Aurora kinase inhibitor. AZD1152 is an acetanilide substituted pyrazole-aminoquinazoline dihydrogen phosphate pro-drug with striking solubility (>10 mg/ml) in simple pH-adjusted aqueous vehicles making it suitable for parental administration. AZD1152 is completely converted in human plasma to the active moiety, AZD1152 hydroxy-QPA (HQPA), a reversible ATP-competitive inhibitor with potent activity against Aurora A, B-INCENP and C-INCENP (Ki: 1369 ± 419.2 nM, 0.359 ± 0.386 nM, 17.03 ± 12.2 nM, respectively). AZD1152 HQPA displays high specificity vs 50 additional serine-threonine and tyrosine kinases. Human tumor cell lines (colon, lung, breast, cervical) treated with AZD1152 revealed phenotypes consistent with Aurora B kinase inhibition; phosphorylation of the Aurora B substrate histone H3 at serine 10 (ph-H3-ser10) was completely suppressed (IC50 5.4 –35.0 nM). These treated tumor cells do not arrest in mitosis or exhibit delayed cell cycle progression; rather they progress with normal kinetics through aberrant mitoses, characterized by improper chromosome alignment and segregation. The cells fail to divide, becoming polyploid with reduced viability and increased apoptosis. AZD1152 HQPA has desirable pharmacokinetic (PK) properties in a range of preclinical models, characterized by dose-dependent exposure. In athymic nude mice bearing a range of human tumor xenografts, AZD1152 (iv bolus or subcutaneous mini-pump) reduced ph-H3-ser10, increased the proportion of cells with polyploid DNA (≥8N), and enhanced apoptosis. AZD1152 significantly inhibited tumor growth in human colon (SW620, HCT116, Colo205) and lung (A549, Calu-6) tumor xenografts (mean tumor inhibition range: 69% to ≥100%; p
Avadomide (CC-122), a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
Authors: Jean-Marie Michot, Reda Bouabdallah, Jeanette K. Doorduijn, Umberto Vitolo, Marie José Kersten, Annalisa Chiappella, Pier Luigi Zinzani, Gilles Salles, Fontanet Bijou, Rafael Sarmiento, Silvia Mosulen, Cristina Mendez, Shailaja Uttamsingh, Michael Pourdehnad, Kristen Hege, Li Li, Zariana Nikolova, Vincent Ribrag
Journal: Blood (2018)
Exosome-Transmitted <i>PSMA3</i> and <i>PSMA3-AS1</i> Promote Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Hongxia Xu, Huiying Han, Sha Song, Nengjun Yi, Chen'ao Qian, Yingchun Qiu, Wenqi Zhou, Yating Hong, Wenyue Zhuang, Zhengyi Li, Bingzong Li, Wenzhuo Zhuang
Journal: Clinical Cancer Research (2019)

Abstract Purpose: How exosomal RNAs released within the bone marrow microenvironment affect proteasome inhibitors' (PI) sensitivity of multiple myeloma is currently unknown. This study aims to evaluate which exosomal RNAs are involved and by which molecular mechanisms they exert this function. Experimental Design: Exosomes were characterized by dynamic light scattering, transmission electron microscopy, and Western blot analysis. Coculture experiments were performed to assess exosomal RNAs transferring from mesenchymal stem cells (MSC) to multiple myeloma cells. The role of PSMA3-AS1 in PI sensitivity was further evaluated in vivo. To determine the prognostic significance of circulating exosomal PSMA3 and PSMA3-AS1, a cohort of patients with newly diagnosed multiple myeloma was enrolled to study. Cox regression models and Kaplan–Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS). Results: We identified that PSMA3 and PSMA3-AS1 in MSCs could be packaged into exosomes and transferred to myeloma cells, thus promoting PI resistance. PSMA3-AS1 could form an RNA duplex with pre-PSMA3, which transcriptionally promoted PSMA3 expression by increasing its stability. In xenograft models, intravenously administered siPSMA3-AS1 was found to be effective in increasing carfilzomib sensitivity. Moreover, plasma circulating exosomal PSMA3 and PSMA3-AS1 derived from patients with multiple myeloma were significantly associated with PFS and OS. Conclusions: This study suggested a unique role of exosomal PSMA3 and PSMA3-AS1 in transmitting PI resistance from MSCs to multiple myeloma cells, through a novel exosomal PSMA3-AS1/PSMA3 signaling pathway. Exosomal PSMA3 and PSMA3-AS1 might act as promising therapeutic targets for PI resistance and prognostic predictors for clinical response.
OP0053 Success-1 in osteoarthritis (oa) trial: celecoxib significantly reduces risk of serious upper gi complications compared to nsaids while providing similar efficacy in 13,274 randomised patients
Authors: G Singh, J Goldstein, W Bensen, N Agrawal, G Eisen, J Fort, A Bello, S Boots
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> SUCCESS-1, the largest double-blind, randomised study in rheumatology, compared 2 therapeutic doses of celecoxib to conventional doses of NSAIDs in a trial designed to closely parallel clinical practice in various worldwide settings. <h3>Objectives</h3> To compare the efficacy, safety, and tolerability of celecoxib 200 or 400 mg/d and NSAIDs in OA of the knee, hip, and hand. <h3>Methods</h3> SUCCESS-1 enrolled 13,274 patients with OA from 1142 centres in 39 countries. Patients were randomised to: celecoxib 200 mg/d, celecoxib 400 mg/d, or NSAID (naproxen 100 mg/d in US/Canada, diclofenac 100 mg/d in other 37 countries). Efficacy assessments, stratified by country/subregion, included patient and physician global assessments, pain scale, night pain, and WOMAC. An independent Gastrointestinal Events Committee (GEC) categorised potential clinically significant upper GI (UGI) events in a blinded fashion as ulcer complications (perforations, gastric outlet obstruction, bleeding) or symptomatic ulcerations. <h3>Results</h3> Of 13,194 patients treated, 4393 and 4407 received 200 or 400 mg/d of celecoxib, respectively, 905 received naproxen 1000 mg/d, and 3489 received diclofenac 100 mg/d. Most patients were female (67%); mean age was 62 years. Baseline aspirin use and UGI bleeding history were comparable. Efficacy results between the 2 celecoxib doses and naproxen or diclofenac were comparable for most countries/subregions. UGI events (dyspepsia, abdominal pain, and nausea) were significantly reduced in celecoxib- compared to naproxen- or diclofenac-treated patients. Of 144 possible serious UGI GEC-referred events, 9 met strict ulcer complication definition and 36 patients had confirmed ulcer complications and/or symptomatic ulcers. <h3>Conclusion</h3> Compared to conventional NSAIDs, celecoxib reduced the risk of ulcer complications by almost 87.5%, while providing equivalent efficacy and better tolerability. Sponsored by Pharmacia Corporation and Pfizer Inc.
High Throughput Droplet Single-Cell Genotyping of Transcriptomes (GoT) Reveals the Cell Identity Dependency of the Transcriptional Output of Somatic Mutations
Authors: Anna S Nam, Kyu-Tae Kim, Ronan Chaligne, Franco Izzo, Chelston Ang, Nathaniel Omans, Alessandro Pastore, Justin Taylor, Alicia Alonso, Wayne Tam, Ronald Hoffman, Joseph Scandura, Raul Rabadan, Omar I Abdel-Wahab, Peter Smibert, Dan A. Landau
Journal: Blood (2018)
Commentary: Causal Inference for Social Exposures
Authors: Jay S. Kaufman
Journal: Annual Review of Public Health (2019)

Social epidemiology seeks to describe and quantify the causal effects of social institutions, interactions, and structures on human health. To accomplish this task, we define exposures as treatments and posit populations exposed or unexposed to these well-defined regimens. This inferential structure allows us to unambiguously estimate and interpret quantitative causal parameters and to investigate how these may be affected by biases such as confounding. This paradigm has been challenged recently by some critics who favor broadening the exposures that may be studied beyond treatments to also consider states. Defining the exposure protocol of an observational study is a continuum of specificity, and one may choose to loosen this definition, incurring the cost of causal parameters that become commensurately more vague. The advantages and disadvantages of broader versus narrower definitions of exposure are matters of continuing debate in social epidemiology as in other branches of epidemiology.
Conditional probability of survival (CPS) in ovarian cancer (OC) long-term survivors: Prognostic factors.
Authors: Michel Fabbro, Pierre Emmanuel Colombo, Caroline Mollevi, Julie Bensakkoun, Isabelle Coupier
Journal: Journal of Clinical Oncology (2014)

e16514 Background: In high grade OC, most deaths occur in the first 36-50 months after diagnosis. Beyond the median survival time, mortality decreases down to a plateau observed from 5-6 years. This long-term survivor population represents around 20% of the patients initially treated. Methods: This retrospective study aimed to estimate the CPS and to identify prognostic factors among long-term survivors. From patients (pts) with advanced OC treated at the ICM from 1995 to 2012, we collected the cancer histology, surgical staging (FIGO), BRCA status, delivered chemotherapy and outcome. Overall survival (OS), progression-free survival (PFS), and CPS were calculated. To estimate 95% confidence intervals (CIs) we used a variation of the
Incidence of EGFR, kras, BRAF, ALK, and p53 alterations in a cohort of 218 consecutively tested patients from a certified lung cancer center: Correlation with clinical characteristics and treatment outcome.
Authors: Anne Christina Lueers, Volker Halbfass, Regina Prenzel, Douglas Scriba, Kay Willborn, Markus Falk, Cora Hallas, Markus Tiemann, Frank Griesinger
Journal: Journal of Clinical Oncology (2014)

e19064 Background: The aim of the study was to systematically analyze EGFR, KRAS, BRAF, ALK and p53 within the same cohort of patients, to correlate alterations with clinical characteristics and to potentially identify new prognostic/predictive markers. Methods: 218 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR mutations, ALK rearrangements, KRAS codon 12/13/61 and BRAF V600E and G469A, as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. ALK rearrangements were either tested by RT-PCR or ALK-FISH (break apart probe, Vysis). BRAF mutations were detected by allele specific PCR, KRAS and p53 by Sanger Sequencing. Clinical characteristics including smoking status were available for all patients. Results: 218 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The EGFR mutation rate was 20% (44/217) in all patients, 37% (30/82) in never-light smokers and 10% (14/135) in current/ex-smokers. ALK rearrangements were found in 4% (7/190) of patients. KRAS mutations were as EGFR mutations dependent on smoking status: mutation rate was 25% (49/199) in all patients, 12% (9/75) in never-light smokers and 32% (40/124) in current/ex-smokers. P53 mutation rate was 39% (45/115), and not dependent on smoking status. Interim overall survival data presented at WCLC 2013 showed that p53 mutations in EGFR mt + patients were associated with inferior survival compared to p53WT, updated analyses will be presented at the meeting. BRAF mutations were seldom (2/195). Conclusions: EGFR and ALK mutations were overrepresented in never-light smokers, BRAF and KRAS mutations were underrepresented. P53 mutations occurred independently of smoking status in combination with EGFR mutations, but not ALK- translocations and seem to predispose for inferior survival. OS and PFS data will be presented at the meeting.
<i>Notes from the Field:</i> Environmental Investigation of a Multistate Salmonellosis Outbreak Linked to Live Backyard Poultry from a Mail-Order Hatchery — Michigan, 2018
Authors: Margaret C. Hardy, Scott A. Robertson, Jennifer Sidge, Kimberly Signs, Mary Grace Stobierski, Kelly Jones, Marty Soehnlen, Lisa Stefanovsky, Adeline Hambley, Joshua M. Brandenburg, Haley Martin, A.C. Lauer, Patricia Fields, Lia Koski, Lauren M. Stevenson, Kristy L. Pabilonia, Megin C. Nichols, Colin A. Basler, Efrain M. Ribot, Kelley B. Hise
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

On June 12, 2018, the Michigan Department of Health and Human Services requested assistance from CDC to investigate risk factors for Salmonella infection linked to live backyard poultry originating at a mail-order hatchery in Michigan.
Investigation of the relationship between MITF and POU3F2 expression and the notion of a "genetic switch" underlying phenotype switching in melanoma.
Authors: Michael Roger Eccles, Jyoti Motwani, Aniruddha Chatterjee
Journal: Journal of Clinical Oncology (2014)

e22081 Background: Clear understanding of the transition from non-invasive to an invasive phenotype in melanoma remains elusive. Microphthalmia-associated transcription factor (MITF), a central player in melanoma biology, controls many aspects of the melanocytic lineage. However, recently the POU domain transcription factor family member, POU3F2/BRN2, was shown to directly repress MITF expression, and conversely MITF was shown to repress POU3F2 via the increased expression of microRNA, miR-211. This raises the possibility of a “genetic switch” facilitated by the alternating expression levels of MITF or POU3F2in melanoma. Methods: To characterize whether a “genetic switch” may underlie phenotype switching in melanoma we used RNAi to investigate knockdown of POU3F2 versus MITFin metastatic and primary melanoma cell lines. The cell lines were classified into two groups; “high MITF expression” and “Low MITF expression” by QRT-PCR. The effect of MITF expression level on cell migration was investigated using scratch and Boyden chamber assays. Results: Inhibition of POU3F2 expression by RNAi reduced cell migration in
Effect of Metabotropic Glutamate Receptor 3 Genotype on <char aid="99783077" id="ital">N</char>-Acetylaspartate Measures in the Dorsolateral Prefrontal Cortex
Authors: Stefano Marenco
Journal: American Journal of Psychiatry (2006)

Objective: This study was carried out to confirm prior evidence of an effect of a single nucleotide polymorphism (SNP) in the metabotropic glutamate receptor 3 (GRM3) gene (a putative risk factor for schizophrenia) on measures of N -acetylaspartate in healthy comparison subjects. Method: Fifty-four carefully screened healthy volunteers genotyped at SNP rs6465084 underwent magnetic resonance spectroscopic imaging (MRSI) at 3 T and selected neuropsychological testing. Results: The A/A genotype group exhibited a significant reduction of N -acetylaspartate/creatine levels in the right dorsolateral prefrontal cortex compared to the G carriers. A tendency in the same direction was seen in the left dorsolateral prefrontal cortex and in the white matter adjacent to the prefrontal cortex. Conclusions: These findings provide further evidence that GRM3 affects prefrontal function and that variation in GRM3, monitored by SNP rs6465084, affects GRM3 function.
Abstract 17627: Plaque Erosion, Compared to Plaque Rupture, is Associated With Better Outcomes After Primary Percutaneous Coronary Intervention in Patients With ST-segment Elevation Myocardial Infarction
Authors: Takumi Higuma, Tsunenari Soeda, Naoki Abe, Masahiro Yamada, Hiroaki Yokoyama, Shuji Shibutani, Kei Izumiyama, Fumie Nishizaki, Tomohiro Osanai, Ik-Kyung Jang, Ken Okumura
Journal: Circulation (2014)

Background: Acute coronary syndromes are caused not only by plaque rupture but also by other mechanisms such as plaque erosion or calcified nodule. The aim of the current study was to investigate t...
Ultrasensitive detection and identification of BRAF V600 mutations in fresh frozen, FFPE, and plasma samples of melanoma patients by enhanced-ice-cold-PCR.
Authors: Alexandre How-kit, Celeste Lebbe, AurÃƒÂ©lie Bousard, Antoine Daunay, Nicolas Mazaleyrat, Christian Daviaud, Cécile Pagès, Samia Mourah, Jorg Tost
Journal: Journal of Clinical Oncology (2014)

9020 Background: Two BRAF inhibitors have been approved for patients with BRAF V600 activating mutation. However, to date the different tools developed for the detection of BRAF V600 mutations lack sensitivity and/or specificity or do not allow sequencing-based identification of the mutation. Enhanced-ice-COLD PCR is a very sensitive assay, which enables a strong enrichment of the mutation during the PCR where mutant and WT alleles undergo exponential and linear amplification, respectively. Methods: Methods: Two melanoma-derived cancer cell lines harboring different heterozygous BRAF codon 600 mutations were used in this study for assay optimization. Molecular analyses were performed on 18 fresh frozen, 17 FFPE melanoma and 17 plasma samples from patients suffering from advanced melanoma were used. E-ice-COLD-PCR was performed using a 96-well real-time thermocycler followed by pyrosequencing and automatic mutation identification and quantification. Results: This assay has a large dynamic range as 25 pg to 25 ng can be used as DNA input without any reduction in mutation enrichment efficiency and is ultra-sensitive as it can detect up to 0.01% of mutated alleles in a wild-type background. The assay has been validated on fresh frozen, FFPE and plasma samples of melanoma patients and has allowed the detection and identification of BRAF mutations present in the samples which appear as wild-type using standard pyrosequencing, endpoint genotyping or Sanger sequencing. Conclusions: This BRAF V600 E-ice-COLD PCR assay is currently the most powerful molecular diagnostic tool for ultra-sensitive detection and identification of BRAF codon 600 mutations.