tbuckley/cabot-search huggingface dataset:
Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with early breast cancer: results from the TEAM trial neuropsychological side study.
Authors: CM Schilder, C Seynaeve, SC Linn, W Boogerd, LV Beex, CM Gundy, HM Huizenga, JW Nortier, CJ v/d Velde, FS van Dam, SB Schagen
Journal: Cancer Research (2009)

Abstract Abstract #1133 Background&amp;#x2028; Adjuvant hormonal therapies (HT) are frequently used in primary breast cancer (BC), yet few studies have examined their potential impact on cognition. Fundamental and human research indicate that estrogens play an important role in certain cognitive functions; therefore it is plausible that HT can affect cognition in BC patients (pts). Due to different mechanisms of action, distinctive effects between selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) are possible.&amp;#x2028; Methods&amp;#x2028; Neuropsychological examinations were used to study cognitive performance before the start of adjuvant HT (T1) and after one year of HT (T2) in postmenopausal BC pts not qualified to receive chemotherapy. Study pts participated in the Dutch part of the international TEAM-trial, a prospective randomized study investigating tamoxifen (SERM) versus exemestane (AI) as adjuvant therapy for hormone-sensitive BC. The study sample consisted of 80 tamoxifen users (mean age 68.7 yrs, range 51-84) and 99 exemestane users (mean age 68.3 yrs, range 50-82). A healthy control group (n=120, mean age 66.2 yrs; range 49-86) was assessed with a similar interval. Differences in performance at T2 on 8 cognitive domains were studied among the three groups by use of ANCOVA twice: (1) adjusting for performance at T1 and (2) with additional adjustment for the covariates anxiety/depression, fatigue and menopausal symptoms at T2.&amp;#x2028; Results&amp;#x2028; After one year of therapy, exemestane users did not perform significantly worse than healthy controls on any cognitive domain. Tamoxifen users performed worse than healthy controls on 'verbal memory' (P=.003, Cohen's d = .43) and 'executive functioning' (P=.005, Cohen's d = .40) and worse than exemestane users on 'information processing speed' (P=.019, Cohen's d = .36). Adjustment for covariates did not change these results. For 'visual memory', 'working memory', 'verbal fluency', 'reaction speed' and 'motor speed' no significant differences between groups were found.&amp;#x2028; Discussion&amp;#x2028; After one year of therapy, tamoxifen has a negative impact on certain cognitive functions, while exemestane does not negatively affect cognition in this population. Although the burden of these effects on the daily life of pts has yet to be determined, intact cognition is known to be an important precondition for independent living and wellbeing. Currently, the options of HT in BC are increasing and optimization of HT with respect to the choice, sequence and duration of treatments is given high research priority. Our results underscore the need to include cognitive effects of HT in long-term safety studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1133.
Myasthenic Antibodies Cross-Link Acetylcholine Receptors to Accelerate Degradation
Authors: Daniel B. Drachman, C. William Angus, Robert N. Adams, James D. Michelson, Gary J. Hoffman
Journal: New England Journal of Medicine (1978)

The decrease of acetylcholine receptors at neuromuscular junctions of myasthenic patients has been attributed to an antibody-mediated autoimmune process that accelerates receptor degradation. We studied the mechanism of this process in skeletal-muscle cultures, using intact antibodies and antibody fragments. Addition of myasthenic IgG or its divalent fragment, F(ab')2, to cultures accelerated the rate of acetylcholine-receptor degradation threefold. By contrast, the monovalent fragment, Fab, from myasthenic serum had no effect on degradation, although it bound to acetylcholine receptors. Addition of a second, "piggyback" antibody to cross-link the Fab:receptor complexes resulted in a threefold increase of the degradation rate. Similarly, when acetylcholine receptors with bound alpha-bungarotoxin were cross-linked by the addition of specific antibody against alpha-bungarotoxin, the degradation rate increased approximately threefold. The effect of myasthenic patients' antibodies in accelerating degradation of acetylcholine receptors is attributed to their ability to cross-link the receptors.
German out of hours locum has conditions placed on practice because of deficient performance
Authors: C. Dyer
Journal: BMJ (2013)

A German GP who worked 13 hour shifts of up to 24 days in a row as an out of hours locum in southern England has had conditions imposed on his registration, after a finding that his fitness to practise was impaired because of misconduct and deficient professional performance.

Volker Bornmann attracted several complaints from patients who said that he wrongly diagnosed their illness or treated them dismissively during telephone triage or face to face consultations. The complaints led one of the four trusts and agencies that used his services, Hampshire Primary Care Trust, to open an investigation.

The Medical Practitioners Tribunal Service found …
THU0356 Presenteeism, Work Disability in the Patients with Chronic Neck Pain
Authors: S. Shyen, B. Amine, I. Binoune, S. Gueddari, N. Hajjaj-Hassouni
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Assess the presenteeism and the work disability in the patients with chronic neck pain, and identify its determinants. <h3>Methods</h3> Cross-sectionalstudy is conducted among active patients, older than 18 years and followed for common chronic neck pain over 3 months, recruited at the consultation of Rheumatology. Socio demographic, clinical and paraclinical parameters related to patients and disease were collected. Pain, functional gene and handicap were explored by visual analogue scales (VAS). Functional disability was assessed by the scale of Copenhagen (French versionvalidated). Anxiety and depression was assessed by Hospital Anxiety and Depression scale (HAD) (Arabic version validated).The presenteeism was evaluated by the number of the days of presence, thedays of absenceand the inefficiency at work. The productivity at work was perceived by the visual analog scaleand two specific questionnaires: the Work limitation Questionnaire (WLQ) and the Stanford presenteeism scale (SPS-6). A descriptive statistical analysis and a linear regression were performed to determine the factors influencing the quality of work. <h3>Results</h3> 65 chronic neck pain patients were included. The average age of patients was 50±11.6 years, with a female predominance (80%). The median evolution of the neck pain was 36 months (12-48 month). The median of the working days per week was 5 days (3-5 days). During the 4 weeks prior to inclusion in the study, the average number of the presence was 14±5.4 days. The average number of the absence was 3 days (2-5). The average number of the work inefficiencywas 4 days [2-7].The average of labor productivity was 41±18. The mean total score ofwork disability (WLQ) was 75.6±10. A low level of presenteeism was observed with an average score of 6-SPS 12.8±3.6. In univariate analysis, both WLQ scores and SPS-6, respectively, havea relationship statistically significant with the VAS pain, VAS functional gene, VAS handicap and total score of Copenhagen (with p&lt;0.05 for all). After multivariate analysis, the inability to work (WLQ) was positively associated with functional disability (p=0.000, B =0.486, 95% CI [0.601, 1.910]). The presenteeism (SPS-6) was negatively associated with functional disability (SPS-6) (p=0.05, B = -0.206, 95% CI [-0.286, -0.052]) <h3>Conclusions</h3> This study suggests that patients with neck pain have awork disability and low level of presenteeism, which were mainly due to their functional disability. <h3>Disclosure of Interest</h3> : None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5349
Abstract 5175: Predictors of metastatic spread and progression free survival in uterine papillary serous carcinoma: A pilot study
Authors: Kevin M. Schuler, Natalie Banet, Victoria Bae-Jump, Ruth Lininger, Paola A. Gehrig
Journal: Cancer Research (2011)

Abstract Background: Uterine Papillary Serous Carcinoma (UPSC) comprises 5-10% of all endometrial cancers but is responsible for nearly 40% of all endometrial cancer-related deaths. Progression-free survival (PFS) controlled for stage is also markedly shorter in UPSC compared to Type 1 endometrial cancers. Unlike endometrioid carcinoma, in which depth of myometrial invasion, grade, and lymphovascular space invasion (LVSI) are risk factors for extrauterine spread, UPSC often metastasizes in those with no myometrial invasion. Objective: The objective of this study is to identify markers that may predict metastatic disease in women with non-invasive UPSC or portend a shorter progression free survival. Materials: A retrospective chart review was performed on women diagnosed with Stage IA or Stage III/IV UPSC without myometrial invasion from 1995-2008. Examined factors include age, parity, race, weight, LVSI, CA125 levels, and tumor location within the endometrium. Tissue microarrays (TMAs) were constructed using paraffin blocked specimens and stained for ER, PR, p53, VEGF, Claudin 3, Claudin 4, Her-2/neu, Her-3, Synuclein gamma, and Maspin. Chi-square analysis, Student's t-test, and Fisher's Exact analysis were used where appropriate to detect statistically significant differences in these 2 groups with Kaplan-Meyer analysis used to determine PFS. Significance was represented at p&amp;lt;0.05. Results: Thirty-two patients were identified to have UPSC without myometrial invasion, 24 (75%) comprising Stage IA and 8 (25%) having Stage III/IV disease. Pathology blocks were available for 21 patients (14 Stage I and 7 Stage III/IV). CA125 was the only factor to achieve significance (p=0.04) in predicting metastatic spread; biomarkers, either alone or in combination, were not predictive of metastatic disease. In Stage I disease, positive ER status was associated with a significantly longer PFS (p&amp;lt;0.001) while in Stage III/IV disease, positive Her-3 status was associated with a shorter PFS (p=0.014). Conclusions: In addition to traditional risk factors not being predictive of metastatic disease, molecular markers that have been associated with metastatic disease and a worsening prognosis do not appear to be predictive in UPSC. However, the contribution of ER status and Her-3 needs to be further evaluated as this may offer new insight into therapeutic options for treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5175. doi:10.1158/1538-7445.AM2011-5175
Abstract 1203: Coordinated regulation of intestinal radio-sensitivity by PUMA and p21
Authors: Brian J. Leibowitz, Lin Zhang, Jian Yu
Journal: Cancer Research (2010)

Abstract p53-upregulated modulator of apoptosis (PUMA) has been shown to be vital for radio-sensitivity in the small intestine. PUMA ablation results in drastic radio-resistance, lengthening the survival of mice exposed to 15 Gy whole body irradiation and blocking apoptosis in the crypts. In contrast, we and others have found that p21 ablation leads to slightly increased radio-sensitivity. To better elucidate the relative and perhaps linked roles of PUMA and p21 in the intestinal responses to irradiation, we produced PUMA/p21 double knockout (DKO) mice. Initial experiments revealed that DKO mice responded similarly to PUMA KO mice within the first 24 hours after 15 Gy ionizing radiation as measured by the DNA damage response and apoptosis in the crypts. Both groups showed more rapid, though less sustained, phosphorylation of H2AX than wild-type (WT) mice, while displaying significantly less apoptosis in the crypts. However, DKO mice were found to have similarly enhanced overall radio-sensitivity as p21 KO mice. Further studies revealed that DKO and PUMA KO mice may not be equally effective at repair despite their similar kinetics in the initial DNA damage response. At 48 and 72 hours post-irradiation, the crypts in DKO mice had a substantial number of TUNEL+ cells, while those in PUMA KO or WT mice had almost none. At 48 hours after irradiation, the crypts in p21 KO mice also had a large number of TUNEL+ cells, which declined by 72 hours. Additionally, the crypt cells in DKO and p21 KO mice, but not in WT or PUMA KO mice, were found to be positive for both γ-H2AX and the mitosis marker phospo-H3, indicating abrogated cell cycle control likely due to a futile attempt at proliferation. These data further suggest that the protection of intestinal epithelium against radiation injury through ablation of PUMA requires a functional p21 checkpoint in addition to inhibition of crypt apoptosis. Additional studies are underway in our laboratory to further elucidate how these two proteins might coordinately regulate intestinal injury and regeneration by modulating the survival and proliferation of intestinal stem cells and progenitors following irradiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1203.
SP0064 Spondyloarthritis: What is new for primary care?
Authors: R.B.M. Landewé
Journal: Annals of the Rheumatic Diseases (2013)

Spondyloarthritis (SpA) is a spectrum of chronic inflammatory diseases of which ankylosing spondylitis (AS) is the best known pendant. SpA is often characterized by inflammatory low back pain (nightpain, morning stiffness, improvement with exercise), and called axial SpA. But patients with SpA can also present with arthritis, enthesitis and/or dactylitis (peripheral SpA). A diagnosis of AS requires radiographic sacro-iliitis, which is often a late feature. Patients may have complaints years before radiographic abnormailities appear, and in some patients these abnormailities will never appear, whilst these patients may suffer from similar levels of pain, stiffness and functional impairment as patients with a classifying diagnosis of AS. In order to fill this diagnostic gap, the Assessment in Spondyloarthritis International Society (ASAS) has recently developed new classification criteria for axial and peripheral SpA, that may help in an earlier detection of patients with SpA, and can serve as eligibility criteria for randomised clinical trials. In order to get the appropriate patients early enough at the appropriate place (the rheumatologist) primary care workers should have knowledge about early signs of SpA, and should have the tools to decide about early referral in the patients that need this. <h3>Disclosure of Interest</h3> None Declared
Management of operable breast cancer in older women
Authors: Ian S Fentiman
Journal: Journal of the Royal Society of Medicine (2013)

Older women are not being given the opportunity to benefit from the improvements in both local and systemic treatment for breast cancer. Mammographic screening call/recall system ceases at age 72, making access more difficult. Knowledge about breast cancer in those aged >75 is significantly reduced in terms of understanding symptoms and personal risk but studies have shown that intervention can improve this, at least in the short term. Although older women are more likely to have estrogen receptor positive tumours, nevertheless, more than one-third of women aged over 70 have grade III, aggressive breast cancers. Whenever possible, older women should be offered breast conserving therapy rather than mastectomy since this not only improves their quality of life but also reduces risk of subsequent mental health problems. Endocrine treatment alone should not be used other than in patients with severe co-morbidity and a life-expectancy of less than a year. As adjuvant treatment in those with estrogen receptor positive cancers, the choice between tamoxifen and an aromatase inhibitor will depend upon co-morbidity, side-effects and patient choice.
Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors
Authors: Vincent-Philippe Lavallée, Jana Krosl, Sébastien Lemieux, Geneviève Boucher, Patrick Gendron, Caroline Pabst, Isabel Boivin, Anne Marinier, Cynthia J. Guidos, Sylvain Meloche, Josée Hébert, Guy Sauvageau
Journal: Blood (2016)
Abstract 2755: Enhanced anti-tumor effects using a combinatorial targeted treatment strategy in a preclinical model of prostate cancer
Authors: Yutaka Yamamoto, Marco A. De Velasco, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Mitsumasa Kodama, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura
Journal: Cancer Research (2012)

Abstract Recently developed strategies use molecular targeting agents specifically designed to target core regulatory signaling pathways of prostate cancers. Growth factors mediate such signaling pathways that include the PI3K/Akt/PTEN/mTOR and Ras/Raf/MEK/MAPK as well as other essential pathways. However various mitigating factors such a genetic variation, molecular diversity, diverging and converging of signaling pathways make it improbable that treatment with any single agent will result in any long-term enhanced tumor. To overcome such problems we investigated the toxicity and antitumor effects of combined targeted therapy with the mTOR inhibitor everolimus and the mulitkinase inhibitor sorafenib in a prostate-specific PTEN conditional knockout mouse model of human prostate cancer. Non-castrated and castrated (castrate-resistant prostate cancer model, CRPC) PSACre;PTENloxP/loxP mutant mice, harboring prostate tumors, were treated with everolimus and sorafenib alone or in combination for 4 weeks beginning at 16 weeks of age. All mice appeared healthy and there were no significant differences in body weights, appearance or histological findings between treatment and control groups at the end of the experiment. Our analysis shows that combination therapy has a significant additive inhibitory effect on tumor growth in non-castrate prostate cancer model (8.8 mm2, 7.7 mm2, 7.1 mm2 and 5.2 mm2 in control, everolimus, sorafenib and combination treatment groups, respectively, p=0.005). Ki67 expression was decreased and positive TUNEL apoptotic bodies was increased in combination treatment groups compared to everolimus and sorafenib monotherapy in both non-castrated and CRPC treatment groups. We also show that combination therapy, but not monotherapy, cooperated to inhibit phosphorylation of the eukaryotic translation initiation factor 4B (eIF4B). Our study provides preclinical evidence that a targeted combination treatment strategy with everolimus and sorafenib is tolerable and leads to improved treatment efficacy over single agent therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2755. doi:1538-7445.AM2012-2755
Abstract 3157: Loss of heterozygosity as a molecular ‘second hit’ In familial pancreatic cancer.
Authors: Zaheer S. Kanji, Stefano Serra, Spring Holter, Ayelet Borgida, Robert Grant, Steven Gallinger
Journal: Cancer Research (2013)

Abstract BACKGROUND/HYPOTHESIS: Familial Pancreatic Cancer (FPC) has an autosomal dominant, variable penetrant mode of inheritance with &amp;gt;80% of its genetic cause yet to be discovered. We hypothesize that a high density DNA microarray analysis of Formalin-Fixed Paraffin Embedded (FFPE) FPC tumors will yield novel regions of genomic loss harboring disease causing FPC gene(s). METHODS: 158 FFPE FPC tumor specimens with matched normal tissue were reviewed by a pancreatic pathologist and tumors with &amp;lt;70% cellularity underwent laser capture microdissection. The samples with &amp;gt;70% cellularity were microdissected directly from marked unstained slides. A total of 74 samples were DNA extracted, whole genome amplified and processed on the Affymetrix 660K Oncoscan Microarray. Copy number analysis was performed using Nexus Copy Number Variation Version 6.1 software employing the SNP-FASST2 segmentation and Allele Specific Copy Number Analysis of Tumors (ASCAT) algorithms. PRELIMINARY RESULTS: A pair-wise analysis of 55 FPC samples with matched normal tissue was performed. Recurrent regions of loss of heterozygosity (LOH) were known loci of importance in pancreatic tumorigenesis, including CDKN2A, p53 and SMAD4. Copy neutral/gain LOH was observed throughout the genome and may account for &amp;gt;35% of chromosomal loss. Recurrent novel genetic loci displaying LOH was observed on chromosomes: 3p(25%), 5q(18%), 6p(22%), 12q(18%) and Xq (42%). Examination of 2 FPC siblings elucidates shared loss regions spanning the 3p22.2-3p22.3 and 17p13.3 loci. Candidate tumor suppressor genes (TSGs) of interest include DCLK3, SERPINF1, SERPINF2 and SMYD4. CONCLUSION: We have described for the first time the presence of copy neutral/gain LOH in FPC highlighting previously unknown regions displaying genetic loss. Further confirmation with quantitative PCR, integrating with germline exome sequencing data, and validation of putative TSGs shared by members of high risk FPC kindreds will help uncover novel genes associated with this disease. Citation Format: Zaheer S. Kanji, Stefano Serra, Spring Holter, Ayelet Borgida, Robert Grant, Steven Gallinger. Loss of heterozygosity as a molecular ‘second hit’ In familial pancreatic cancer. [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 3157. doi:10.1158/1538-7445.AM2013-3157