tbuckley/cabot-search huggingface dataset:
Minimal clinically important difference (MCID) for the functional assessment of cancer therapy: Cognitive function (FACT-Cog) in breast cancer patients.
Authors: Alexandre Chan, Yu Lee Foo, Maung Shwe Ham Guo, Yuan Chuan Kee, Yee Pin Tan, Wei Sean Yong, Preetha Madhukumar, Wei Seong Ooi, Wen Yee Chay, Rebecca Alexandra Dent, Soo Fan Ang, Soo Kien Lo, Yoon Sim Yap, Raymond C.H. Ng, Yin Ting Cheung
Journal: Journal of Clinical Oncology (2013)

6589 Background: Establishing the Minimal Clinically Important Difference (MCID) is essential for interpreting the clinical relevance of patient reported outcomes. This is the first study to date to determine the MCID of FACT-Cog, a 37-item validated subjective neuropsychological instrument designed to evaluate cancer patients’ perceived cognitive deterioration on their quality of life. Methods: This prospective, observational study involved 220 breast cancer patients who have completed FACT-Cog and EORTC-QLQ-C30 at two time points: baseline and at least 3 months following chemotherapy. The MCID was computed using 3 approaches: 1) an anchor-based approach utilized the validated EORTC-QLQ-C30-Cognitive Functioning scale (CF) as the anchor for patients who showed a minimal deterioration on the CF (defined as a one-step deterioration on the CF scale); 2) a Receiver Operating Characteristic (ROC) curve was used to identify an optimal MCID cut-off point for deterioration; 3) a distribution-based approach utilized the 0.33 SD, 0.5 SD and one standard error of measurement (SEM) of the total FACT-Cog score (148 points) to estimate the MCID. Results: There was moderate correlation between the mean change scores of FACT-Cog and CF (r p = 0.43, p&lt;0.001). The CF-anchored MCID was 9.6 points (95% CI 4.4 - 14.8). MCID derived from the ROC method was 7.5 points (AUC: 0.75; sensitivity: 75.6%; specificity: 68.8%). Using the distribution-based approach, MCID corresponding to effect sizes of 0.33SD to 0.5SD of the total FACT-Cog score ranged from 6.9 – 10.3 points and one-SEM criterion resulted in a MCID estimate of 10.6 points. Combining results from all approaches, the MCID identified for FACT-Cog ranged from 6.9 – 10.6 points (4.7% to 7.2% of total score). Conclusions: A 6.9 to 10.6 points reduction of the FACT-Cog score corresponds to the smallest clinically-relevant perceived cognitive deterioration. These estimates are important as they can facilitate the interpretation of patient-reported cognitive changes and sample size estimation in future studies.
Wellness for Families of Children With Chronic Health Disorders
Authors: Thomas F. Boat, Stephanie Filigno, Raouf S. Amin
Journal: JAMA Pediatrics (2017)

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Targeting the mitochondria for the treatment of MLH1-deficient disease.
Authors: Sukaina Rashid, Gemma Bridge, Zhi Yao, Gyorgy Szabadkai, Sarah Anne Martin
Journal: Journal of Clinical Oncology (2016)

e23182 Background: The DNA Mismatch repair (MMR) pathway is responsible for the repair of DNA replication errors. MMR deficiency is estimated to be present in 15-17% of colorectal cancers. MLH1 is one of the key proteins involved in the MMR pathway. MMR deficient tumours are often resistant to standard chemotherapies, therefore there is a need to identify new therapeutic strategies to treat MMR deficient disease. We have performed synthetic lethal compound and RNAi screens to identify potential therapeutic targets for the treatment of MLH1 deficient tumours. Strikingly, several of the hit compounds have been shown to target mitochondrial function. Our previous work has shown that MLH1 can localize to the mitochondria and silencing of the mitochondrial genes, POLG and PINK1 are synthetically lethal with MLH1 deficiency. Methods: We carried out short-term cell viability assays to identify mitochondrial targeted drugs that have a synthetic lethal relationship with MLH1-deficient cell lines. The mechanism of selectivity was investigated by measuring ROS levels, examining oxidative phosphorylation complexes, Complex I activity by ELISA and the oxygen consumption rate (OCR). Furthermore qRT-PCR was used to determine differences in expression of antioxidant defence enzymes and mitochondrial copy number in MLH1 deficient and proficient cells. Results: We demonstrate that MLH1 deficient tumours are synthetically lethal with the mitochondrial targeted agent Parthenolide, which is known to induce ROS and cause oxidative stress.. Upon functional analysis, we show that loss of MLH1 is associated with areduction in Complex I activity, reduced basal OCR and spare respiratory capacity. This phenotype is accompanied by a reduction in the expression of the antioxidant defence enzymes NRF1, NRF2, Catalase, GPX1 and SOD1. Furthermore, we show evidence of decreased mitochondrial copy number in MLH1-deficient cells and reactive mitochondrial biogenesis (upregulation of pgc1β). Conclusions: Taken together, our results thus far suggest that MLH1-deficient cancers could be selectively targeted by exploiting the fact that they have deregulated mitochondria and a decreased antioxidant defence mechanism making them more sensitive to ROS inducing agents.
Controlled Exposure of Bioactive Growth Factor in 3D Amyloid Hydrogel for Stem Cells Differentiation
Authors: Subhadeep Das, Rakesh Kumar, Narendra Nath Jha, Samir K. Maji
Journal: Advanced Healthcare Materials (2017)

Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering both in vitro and in vivo. A pH responsive self‐assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage. Diffusion studies with fluorescence recovery after photobleaching and bulk release with the model protein fluorescein isothiocyanate‐bovine serum albumin show that encapsulated protein molecules can be released in a sustained fashion from the hydrogel over a considerable period of time (30 d). Moreover, by modulating the porosity of the hydrogel by the simple addition of salt, the encapsulated protein molecules can be retained for a longer period of time within the hydrogel. Mesenchymal stem cells, when cultured in 3D amyloid hydrogels with growth factors fibroblast growth factor 8 and sonic hedgehog, show more neuron specific differentiation as compared to hydrogel alone. This higher differentiation potential of growth factor encapsulated amyloid hydrogels can be due to concomitant exposure of cells to biomechanical as well as biochemical cues during the course of differentiation. The present study suggests that amyloid based hydrogel can be exploited for controlled growth factor delivery as well as directed stem cell differentiation to neuron.
The Population-Based ‘real world’ of Low Risk Myelodysplastic Syndromes; Second Interim Analysis of the European LeukemiaNet MDS Registry at 800 Registered New Patients
Authors: David Bowen, Alex Smith, Jackie Droste, Pierre Fenaux, Argyris Symeonidis, Eva Hellstrom-Lindberg, Guillermo F Sanz, Jaroslav Cermak, Otilia Georgescu, Ulrich Germing, Marius MacKenzie, Reinhard Stauder, Odile Beyne-Rauzy, Luca Malcovati, Theo de Witte
Journal: Blood (2010)
Impact of GvHD and Other Patient-, Disease-, Donor and Transplantation-Related Factors on 5 Year Relapse after Unrelated Cord Blood Transplantation for Children with Acute Lymphoblastic Leukemia in Remission
Authors: Kristin M Page, Myriam Labopin, Annalisa Ruggeri, Gerard Michel, Cristina Diaz de Heredia, Tracey O'Brien, Alessandra Picardi, Mouhab Ayas, Henrique Bittencourt, Ajay J. Vora, Fernanda Volt, Eliane Gluckman, Peter Bader, Joanne Kurtzberg, Vanderson Rocha
Journal: Blood (2015)
Sensitive Windows for <i>In Utero</i> Exposures and Asthma Development. Layers of Complexity
Authors: Cindy T. McEvoy, Byung S. Park, Eliot R. Spindel
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

partly to the airway eosinophilia, were inadequately attenuated by anti-IL-5 treatment.Although eosinophil progenitor cells were not measured in the study by Kelly and coworkers, others have shown that in those with severe asthma treatment with low doses of mepolizumab does not suppress sputum eosinophilia in approximately 50% of patients, and these patients have more modest exacerbation reduction and prednisone sparing, compared with patients whose sputum eosinophilia is suppressed ( 14).The results from the study by Kelly and coworkers help to explain why a reduction in circulating eosinophils does not necessarily prevent activation of eosinophils within the airways.However, whether or not activated eosinophils within the airways are the cause of asthma exacerbations remains to be confirmed.
WWP1 E3 ubiquitin ligase is a potential oncogene in human prostate and breast cancer
Authors: Ceshi Chen, Wei Zhou, John Petros, Henry F. Frierson, Robert L. Vessella, Qunna Li, Jonathan W. Simons, Jin-Tang Dong
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

2574 

The ARF tumor suppressor prevents cancer through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. To identify new regulators of ARF signaling, we performed a two-hybrid screen using ARF as bait and discovered a novel 55-kDa nuclear protein that binds both ARF and the p53 antagonist, Mdm2. Endogenous NIAM ( N uclear I nteractor of A RF and M dm2) is an ubiquitinated protein normally expressed at low to undetectable levels in cells, but its expression is induced by treatment with DNA damaging agents and transforming growth factor (TGF)-β1. Endogenous NIAM levels in primary mouse embryo fibroblasts are also increased by loss of p53 and Mdm2. Mdm2, an E3 ubiquitin ligase, binds and negatively regulates NIAM by promoting its ubiquitination and proteasomal degradation. ARF blocks Mdm2-mediated ubiquitination of NIAM and stabilizes the protein. When ectopically expressed, NIAM activates p53, collaborates with ARF to suppress growth, and causes a G1-phase cell cycle arrest. Notably, NIAM can also effectively suppress growth in cells lacking ARF and/or p53. Conversely, silencing of NIAM enhances the basal rate of primary cell proliferation. Together, these results imply NIAM is an effector of ARF and p53 signaling that can also feedback to stimulate p53. Finally, RT-PCR and microarray data show reduced NIAM mRNA expression in human cancer cell lines and advanced primary tumors, especially hepatocellular carcinoma and diffuse large B-cell lymphoma. This study identifies a potential tumor suppressor that is regulated by ubiquitination, DNA damage and TGF-β1, and is functionally linked to ARF, Mdm2 and p53 signaling.
Impact of Wait Times for Autologous Stem Cell Transplantation in Patients with Aggressive Non-Hodgkin Lymphoma, a Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial
Authors: Tanya Skamene, Wenyu Jiang, Ralph M. Meyer, Michael Crump, John Kuruvilla, C. Tom Kouroukis, Stefano Luminari, Stephen Couban, Matthew C. Cheung, David A Rizzieri, Peter G Bardy, Joseph Pater, Marina S. Djurfeldt, Lois E. Shepherd, Bingshu E Chen, Annette E Hay
Journal: Blood (2016)
Advertisements for medical vacancies increase by 8% in a year
Authors: Tom Moberly
Journal: BMJ (2017)

NHS trusts are increasing their recruitment efforts to fill vacancies, posting 8% more advertisements for medical jobs on NHS Jobs in 2016-17 than in the previous year.

In the year to March 2017, NHS trusts in England advertised to fill 32 153 full time equivalent medical jobs, up from 29 776 in the year to March 2016.

The increase in the number of posts advertised was greatest among foundation doctors and specialty doctors. The …
Abstract O.75: Factors Associated With Illness Impact After Diagnosis Of Kawasaki Disease And Coronary Artery Complications
Authors: Nita Chahal, Ahlexxi Jelen, Janet Rush, Katherine Boydell, Cedric Manlhiot, Renee Sananes, Brian W McCrindle
Journal: Circulation (2015)

Background: Families with Kawasaki disease (KD) experience profound anxiety, part of which is related to uncertainties about the future. We sought to understand the personal and emotional impact of uncertainty for both parents and children with coronary artery complications. Method: During 2013-14, 31 participants were recruited. Data collection included chart reviews of demographic factors, relevant medical history, investigations, and treatments. Parents and children completed questionnaires (uncertainty, intrusiveness, self-efficacy) and were interviewed. The qualitative data were analyzed for common themes and exemplars in order to complement the quantitative questionnaire data. Findings: Descriptive data were compared with questionnaire scores to identify factors associated with high, negative impact using univariable linear regression models. High intrusiveness scores among parents were associated with having a child who had previous cardiac catheterization (p =.05), received anticoagulant medications (p = .04), lower education (p = .02 [mother], p = .04 [father]) and income (p = .05), and for those in whom the KD diagnosis was initially missed (p &lt;.001). Higher uncertainty scores among children were associated with absence of chest pain (p = .04) and lower number of echocardiograms (p = .01). Parents’ uncertainty was associated with missed diagnosis (p = .002), higher education (p = .03 [mother]), and higher income levels (p = .01). Self efficacy was assessed among children &gt;10yrs. While 3 subscales (academic, social, emotional) were analyzed, the overall self-efficacy scores increased with the presence of chest pain (p = .003) and increased aneurysms z-score (p =.03). Qualitative analysis revealed 3 main themes: 1) staying normal while hyper-vigilant; 2) optimism amid relentless worry; and 3) healthy present for a hopeful future. The themes involved contrasting sentiments, each of which was held by the child or the parent but with varied levels of expression. Summary: Negative illness impact is associated with a more intense medical experience. Both children and parents have concerns about future outcomes and management. Coping with uncertainty involves achieving a balance between anxieties and a present and forward focus.
Sedentary time in older men and women: an international consensus statement and research priorities
Authors: Shilpa Dogra, Maureen C Ashe, Stuart J H Biddle, Wendy J Brown, Matthew P Buman, Sebastien Chastin, Paul A Gardiner, Shigeru Inoue, Barbara J Jefferis, Koichiro Oka, Neville Owen, Luís B Sardinha, Dawn A Skelton, Takemi Sugiyama, Jennifer L Copeland
Journal: British Journal of Sports Medicine (2017)

Sedentary time is a modifiable determinant of poor health, and in older adults, reducing sedentary time may be an important first step in adopting and maintaining a more active lifestyle. The primary purpose of this consensus statement is to provide an integrated perspective on current knowledge and expert opinion pertaining to sedentary behaviour in older adults on the topics of measurement, associations with health outcomes, and interventions. A secondary yet equally important purpose is to suggest priorities for future research and knowledge translation based on gaps identified. A five-step Delphi consensus process was used. Experts in the area of sedentary behaviour and older adults (n=15) participated in three surveys, an in-person consensus meeting, and a validation process. The surveys specifically probed measurement, health outcomes, interventions, and research priorities. The meeting was informed by a literature review and conference symposium, and it was used to create statements on each of the areas addressed in this document. Knowledge users (n=3) also participated in the consensus meeting. Statements were then sent to the experts for validation. It was agreed that self-report tools need to be developed for understanding the context in which sedentary time is accumulated. For health outcomes , it was agreed that the focus of sedentary time research in older adults needs to include geriatric-relevant health outcomes, that there is insufficient evidence to quantify the dose–response relationship, that there is a lack of evidence on sedentary time from older adults in assisted facilities, and that evidence on the association between sedentary time and sleep is lacking. For interventions, research is needed to assess the impact that reducing sedentary time, or breaking up prolonged bouts of sedentary time has on geriatric-relevant health outcomes. Research priorities listed for each of these areas should be considered by researchers and funding agencies. This consensus statement has been endorsed by the following societies: Academy of Geriatric Physical Therapy, Exercise &amp; Sports Science Australia, Canadian Centre for Activity and Aging, Society of Behavioral Medicine, and the National Centre for Sport and Exercise Medicine.
The Complex Landscape of Rearrangements in Smoldering and Symptomatic Multiple Myeloma Revealed By Whole-Genome Sequencing
Authors: Raphael Szalat, Niccolo Bolli, Francesco Maura, Stephane Minvielle, Dominik Gloznik, Florence Magrangeas, Philippe Moreau, Anthony Fullam, Mehmet K. Samur, Patrick Tarpey, Nicholas Anthony DaSilva, Helen Davies, Inigo Martincorena, Kevin J. Dawson, Jose Tubio, Jorge Zamora, Yu-Tzu Tai, Kenneth C. Anderson, David Wedge, Herve Avet-Loiseau, Peter J Campbell, Nikhil C Munshi
Journal: Blood (2016)
Two thirds of unfilled consultant posts have no applicants, shows census
Authors: Abi Rimmer
Journal: BMJ (2017)

The proportion of unfilled consultant vacancies that are due to a lack of applicants has doubled in eight years, reaching 65% in 2016, a census has found.

The survey,1 conducted on behalf of the Royal College of Physicians of Edinburgh, the Royal College of Physicians and Surgeons of Glasgow, and the Royal College of Physicians, was sent to all UK consultants and higher specialty trainees on 30 September 2016.

It found that 45% of advertised consultant posts …
Review: The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases
Authors: Joshua M. Thurman, Ashley Frazer‐Abel, V. Michael Holers
Journal: Arthritis & Rheumatology (2017)

The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway-modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement-dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.
80P Expression of Hormad1, A Cancer/Testis Antigen, In Triple-Negative Breast Cancers with High Genomic Instability
Authors: A. Grigoriadis, P. Gazinska, M. Rasmussen, A. Isaksson, E. de Rinaldis, S. Mathew, P. Marra, C. Gillett, S. Pinder, A. Tutt
Journal: Annals of Oncology (2012)
Efficacy and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC) and brain metastases: Preliminary results from the GETUG-AFU 26 (Nivoren) study.
Authors: Bernard J. Escudier, Sylvie Chabaud, Delphine Borchiellini, Gwenaelle Gravis, Christine Chevreau, Pierre Emmanuel Brachet, Lionnel Geoffrois, Brigitte Laguerre, Hakim Mahammedi, Sylvie Negrier, Frederic Rolland, Marine Gross Goupil, Muriel Habibian, Laurence Albiges
Journal: Journal of Clinical Oncology (2017)

4563 Background: Nivolumab (N) has been shown active in patients (pts) with mRCC after failure of 1 or 2 TKIs. Efficacy and safety of N in pts with brain metastases (BM) from RCC is still unknown. The aim of this study is to report preliminary data of the Nivoren study in pts with BM. Methods: GETUG-AFU 26 (Nivoren) is a prospective phase 2 study assessing safety and efficacy of N in a broader mRCC patient population than those recruited in the pivotal phase 3, including pts with BM (previously treated or not, but not requiring steroids), with previous mTOR inhibitor, with PS 2 as well as in previously highly pretreated pts. N was given every 2 weeks at 3mg/kg, until disease progression or unacceptable toxicity. Treatment was allowed beyond progression in case of clinical benefit. All pts had brain CT scan or MRI at baseline. Results: Up to December 2016 , 588 pts have been enrolled including 55 pts with BM (35 (67%) ,6 (12%) and 11 (21%) with 1, 2 or &gt; 2 BM, respectively. Of those 55 pts, 10 pts (23%) were PS 2 and 25 (58%) PS 1, and 16 patients (29%) had received more that 2 lines of therapy. No previous treatment for BM was performed in 67% (n = 37), while 9% had previous brain surgery (n = 5 ;) or brain radiation (n = 17 (31%). 2/55 pts never received N. Median duration of therapy in BM pts was 2.4 months (varying from 0 to 9) with a 3-months PFS of 60% (IC95% = 45 – 73). Median OS is not reached at the time of this analysis. Among 44 pts with assessment of response on BM, 10 (23%) had objective response while 21 (48%) had local progressive disease. Neurologic deterioration requiring steroids was observed in 15 pts (32%) . Updated data will be presented at the meeting. Conclusions: This is the first large study to report preliminary safety and efficacy of N in RCC pts with BM. Safety of N in this pt population appears to be acceptable, although some pts do require steroids because of brain progressive disease. Objective response in the brain was observed in 23% of pts. Further follow up is required to determine the real benefit of N in this group of mRCC pts. Clinical trial information: NCT03013335.