tbuckley/cabot-search huggingface dataset:
Association between Early Life Exposure to Air Pollution and Working Memory and Attention
Authors: Ioar Rivas, Xavier Basagaña, Marta Cirach, Mónica López-Vicente, Elisabet Suades-González, Raquel Garcia-Esteban, Mar Álvarez-Pedrerol, Payam Dadvand, Jordi Sunyer
Journal: Environmental Health Perspectives (2019)

Although previous studies have reported negative associations between exposure to air pollution and cognition, studies of the effects of prenatal and postnatal exposures in early childhood have been limited.We sought to assess the role exposure to fine particulate matter ([Formula: see text]) during different prenatal and postnatal windows may play in children's cognitive development at school age.Within the Brain Development and Air Pollution Ultrafine Particles in School Children (BREATHE) Project, we estimated residential [Formula: see text] exposures by land use regression for the prenatal period and first seven postnatal years of 2,221 children from Barcelona, Spain. The participants ([Formula: see text]) completed computerized tests assessing working memory, attentiveness, and conflict network during four visits in 2012–2013. We used linear mixed effects and distributed lag models to assess the period of exposure to [Formula: see text] in association with cognitive development.Inverse associations were identified between [Formula: see text] exposure during the fifth and sixth postnatal years and working memory, with boys showing much higher vulnerability. Regarding attention functions, exposure to higher [Formula: see text] levels during the prenatal period and from the fourth postnatal year were associated with a reduction in conflict network performance, though we found no association with attentiveness. The overall estimated cumulative effect of a [Formula: see text] increase in [Formula: see text] resulted in a reduction in the working memory [Formula: see text] score of [Formula: see text] [95% confidence interval (CI): [Formula: see text], [Formula: see text]] points and an increase in the conflict attentional network of 11.31 (95% CI: 6.05, 16.57) milliseconds, indicating a poorer performance.Early life exposure to [Formula: see text] was associated with a reduction in fundamental cognitive abilities, including working memory and conflict attentional network. https://doi.org/10.1289/EHP3169.
Abstract B49: Epithelial-mesenchymal plasticity primes inherent resistance to targeted therapies
Authors: Wells S. Brown, Michael Wendt
Journal: Cancer Research (2016)

Abstract The metastasis and acquisition of drug resistance in breast cancer cells has been linked to epithelial-mesenchymal transition (EMT). Directed therapies using kinase inhibitors and antibodies to target human epidermal growth factor receptor 2 (Her2) have served as a testament to the potential of molecular-targeted therapies in this breast cancer subtype. However, Her2-targeted therapies are plagued by the pitfalls of intrinsic and acquired resistance, particularly in the metastatic setting. To address these questions we conducted long-term treatments of Her2-transformed cells with TGF-β. This treatment regime resulted in a robust and plastic EMT phenotype as characterized by their CD44/CD24 profile. Following removal of stimuli, cells that had undergone TGF-β-induced EMT enter into a highly heterogeneous state, the importance of which is evidenced by their increased in vivo tumor growth metastatic capability. Importantly, the Lapatinib resistant cell population that arises following TGF-β-induced EMT can be readily eliminated via treatment with recently developed covalent inhibitors of fibroblast growth receptor (FGFR). Overall our data demonstrate that the EMT processes induced by physiologic cytokine stimulation are not only critical drivers of metastatic progression but they also are key events in producing secondary tumors that are poised to be inherently resistant to clinically used targeted molecular therapies. Citation Format: Wells S. Brown, Michael Wendt. Epithelial-mesenchymal plasticity primes inherent resistance to targeted therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B49.
Abstract P4-06-22: Transcription factor T-bet and PD-L1 expression in tumor microenvironment of triple-negative breast cancer
Authors: H Mori, M Kubo, M Kai, K Kurata, H Kawaji, K Kaneshiro, Y Motoyama, R Kuroki, M Yamada, R Nishimura, M Okido, Y Oda, M Nakamura
Journal: Cancer Research (2019)

Abstract Background: Many analyzes regarding immunotherapies using checkpoint blockade has made it clear that tumor infiltrating lymphocytes (TILs) plays an important role in treating cancers with high levels of somatic mutations such as triple-negative breast cancer (TNBC). We reported the relationship between TILs and PD-L1 expression, and revealed that high-TILs/positive-PD-L1 expression population in TNBC was associated with better prognosis (Oncotarget 2017). However, its molecular mechanism is still unclear. Meanwhile, T-box transcription factor 21 (T-bet) which regulates effecter T-cells activation is derived by stimulation of T-cell receptor and IL-12. Activated T-cells work as antitumor lymphocytes by enhancing the production of cytokines such as INFγ. We focused on T-bet and examined the function of activated T-cells. Patients and Methods: This study included 242 patients with primary TNBC who underwent resection without neoadjuvant chemotherapy at our three hospitals between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on TILs was defined as ≥30 per 0.00625mm2. PD-L1 positivity was defined as ≥1% of tumor cells staining positive for PD-L1. Results: Of the 242 TNBC, CD8 on TILs was expressed as positive in 127 (52.5%) tumors, T-bet on TILs was expressed as positive in 67 (27.7%) tumors, and PD-L1 expression on tumor cells was expressed as positive in 99 (40.9%) tumors. T-bet expression was significantly correlated with CD8 expression (P&amp;lt;0.0001) and PD-L1 expression (P=0.0004). There was no significant difference in recurrence free survival (RFS) and overall survival (OS) regardless of CD8 or PD-L1expression level. Meanwhile, the patients with T-bet-positive tumors had a longer OS, compared to those with T-bet-negative tumors (P = 0.13 in RFS and P = 0.047 in OS). The multivariate analysis revealed that T-bet expression on TILswas an independent and positive prognostic factor for OS(HR = 0.5, 95%CI 0.1-0.9, P = 0.035). Conclusion: OS was significantly longer among patients with high T-bet expressing TNBC. These results may validate the significance of T-bet as a biomarker for various immunotherapies in TNBC. Citation Format: Mori H, Kubo M, Kai M, Kurata K, Kawaji H, Kaneshiro K, Motoyama Y, Kuroki R, Yamada M, Nishimura R, Okido M, Oda Y, Nakamura M. Transcription factor T-bet and PD-L1 expression in tumor microenvironment of triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-22.
Application of PCSK9 Inhibitors in Practice
Authors: Tina M. Kaufman, Bruce A. Warden, Jessica Minnier, Joshua R. Miles, P. Barton Duell, Jonathan Q. Purnell, Cezary Wojcik, Sergio Fazio, Michael D. Shapiro
Journal: Circulation Research (2019)

PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are set to revolutionize the treatment of hypercholesterolemia in the management of atherosclerotic risk, but numerous reports have detailed unprecedented barriers to access for these drugs. To overcome these challenges, our group created a model to facilitate provision of this new therapy for patients who qualify according to Food and Drug Administration criteria. This report details the real-world follow-up experience of PCSK9i use in a large patient cohort structured to ensure rigor in data collection, analysis, and interpretation. The 271 patients approved and actively followed in our PCSK9i clinic between July 2015 and August 2018 represent a 97% approval rate from insurance, with 28% of prescriptions requiring at least one appeal. Over 50% of patients were statin intolerant. On average, there was a median lapse of 15 days between initial visit and insurance approval. PCSK9i therapy was affordable for most patients, with an average monthly out-of-pocket expense of $58.05 (median $0). Only 2.3% of patients were unable to initiate or continue therapy because of cost. Reductions from baseline in LDL (low-density lipoprotein) cholesterol and Lp(a) (lipoprotein [a])were comparable to published reports with median reductions of 60% and 23% at 1 year, respectively. PCSK9i therapy was well-tolerated overall, though 9% of patients reported adverse events, and 5% of patients discontinued due mostly to musculoskeletal and flu-like symptoms. Our practice model demonstrates that PCSK9i therapy can be accessed easily and affordably for the majority of eligible patients, resulting in dramatic improvement in lipid profile results. Moreover, our registry data suggest that results from the prospective clinical trials of PCSK9i on LDL and Lp(a) reduction and on tolerability are applicable to a real-world cohort.
The hidden influence on the Shape of Training
Authors: Benjamin J F Dean
Journal: BMJ (2015)

Medical education and postgraduate medical training in the United Kingdom have undergone much government reorganisation in recent years. The most recent structural upheavals came in the form of Modernising Medical Careers and the Medical Training Application Service, whose rushed introduction in 2007 led to a protest march by doctors, national news headlines, professorial resignations, and ministerial apologies. This personal perspective on the Shape of Training review sits in the context of this history, showing how these past events have quickly been forgotten and important lessons ignored.1

The independent Shape of Training review aimed to look at the current and future healthcare needs of patients in the United Kingdom and how medical training can match these needs. The Shape of Training review steering group (including the four UK health departments, Health Education England, National Education Scotland, and other major professional medical organisations) appointed David Greenaway, professor of economics at the University of Nottingham, as chair in February 2012. The review’s recommendations were published at the end of 2013 and included proposals to train more generalist doctors, introduce shorter training programmes, and change the point of full General Medical Council (GMC) …
Abstract A35: Axl overexpression in a prostate cancer mouse model delays metastasis and may prolong dormancy of disseminated tumor cells
Authors: Haley D. Axelrod, Kenneth C. Valkenburg, Kenneth J. Pienta
Journal: Cancer Research (2016)

Abstract The most common site of metastasis in prostate cancer (PCa) patients is the bone marrow, where disseminated tumor cells (DTCs) preferentially home to the hematopoietic stem cell niche and can undergo a state of dormancy. These PCa cells may lie dormant in the bone marrow for years after prostatectomy, but may eventually re-enter the cell cycle resulting in lethal metastatic disease. Using mouse models of PCa metastasis, our group has previously shown that Gas6/Axl signaling is associated with dormant bone marrow DTCs. In this study we investigated the requirement of Axl in initiating and maintaining the dormant phase. We hypothesized that overexpression of Axl in PCa cells would prolong dormancy. Overexpression of Axl in the bone-homing AR-positive Axl-negative human PCa cell line C42B slows proliferation in vitro. Subcutaneous injection of C42B-Axl cells in a xenograft mouse model resulted in delayed onset of tumor growth relative to WT controls. C42B-WT tumors reached an average volume of 200mm3 at 6.6 weeks, while C42B-Axl tumors reached the same volume at 11 weeks. Regions of the primary tumor with a high percentage of Axl+ cells correlated with a low number of Ki67+ cells, indicating that Axl may inhibit proliferation even in the primary tumor. Surprisingly, C42B-Axl tumors were more vascular as observed by eye, and regions of increased vasculature correlated with a high percentage of Axl+ cancer cells. Metastatic outgrowth in soft tissues reached a lethal burden ~12 weeks following C42B-WT tumor removal, while mice bearing C42B-Axl tumors did not have detectable metastases by eye at the same timepoint post-tumor removal and were apparently healthy. Metastatic outgrowth in the bone was detected by the presence of osteoblastic and osteolytic activity at 5-12 weeks post-tumor removal in the femurs and tibiae of mice bearing C42B-WT tumors. At 8-12 weeks after C42B-Axl tumor removal, however, there was no evidence of metastatic bone disease. While these experiments are still ongoing, we have shown that Axl expression in the primary tumor delayed metastatic burden in both soft tissues and in bone in a mouse model of PCa metastasis. In ongoing studies, we will compare DTC number and time to metastasis in the bone marrow of C42B-WT and C42B-Axl tumor-bearing mice. Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Kenneth J. Pienta. Axl overexpression in a prostate cancer mouse model delays metastasis and may prolong dormancy of disseminated tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A35.
Acute abdominal pain in a boy with cystic fibrosis
Authors: Rélana M Nowacki, Jan W Heynens, Anita M Van den Neucker, Bas H Verhoeven, Jasper Been
Journal: BMJ (2013)

A 10 year old boy presented to the emergency department with a 24 hour history of abdominal pain in a colicky pattern; nausea; and bilious and faecal vomiting. His history included well controlled cystic fibrosis with pancreatic insufficiency and a meconium ileus in the neonatal period, which was treated surgically. He passed his last stools the night before presentation. In the previous days he had passed stools once daily. His drug regimen included pancreatin (pancreatic enzymes), omeprazole, vitamin A, D, E, and K supplements, and hypertonic saline inhalations. On physical examination the boy was uncomfortable and had a distended abdomen with minimal peristalsis. There was tenderness across the whole abdomen and a positive rebound response without guarding or other signs of peritonitis. His body temperature was normal. Laboratory results showed a white blood cell count of 8.8 × 109/L (normal range 4.5-13.0) with normal differential count, platelet count 278 × 109/L (normal range 120-350), C reactive protein 10 mg/L (normal range <10). Serum values for electrolytes, liver and pancreatic enzymes, urea, and creatinine were normal. On ultrasonography an abrupt change in bowel calibre was seen and an upright abdominal radiograph was obtained (fig 1⇓).
Abstract P3-12-15: Withdrawn
Authors: J Yap, M Tamimi, M Griffin, T Stanley, J Steinman, W Chen, F Catalfamo
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Yap J, Tamimi M, Griffin M, Stanley T, Steinman J, Chen W, Catalfamo F. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-15.
Fever Induces a Molecular Homing Response in Immune Cells During Infection
Authors: Tracy Hampton
Journal: JAMA (2019)

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Abstract P1-20-01: Intraoperative ketorolac in high-risk breast cancer patients with and without inflammation. A prospective, randomized, placebo-controlled clinical trial
Authors: M Berliere, G Bouche, F Duhoux, P Coulie, J De Cloedt, A Dekleermaker, J-E Guillaume, M Ledent, J-P Machiels, V Mustin, W Swinnen, L Vander Essen, A Van Maanen, J-C Verougstraete, M De Kock, P Forget
Journal: Cancer Research (2019)

Abstract Introduction: Perioperative events may affect the risk of breast cancer recurrence after surgery. Ketorolac, a non-steroidal anti-inflammatory drug routinely used to improve pain control postoperatively has been associated with better breast cancer outcome in retrospective studies. However, it is still unknown whether a single dose of pre-incisional ketorolac may be sufficient to prolong recurrence-free survival. Patients and methods: The KBCt trial (NCT01806259) is a national, multicenter, prospective, double-blind, placebo-controlled, randomized phase III trial in high risk breast cancer patients. Each patient was assigned to the ketorolac or the placebo group. Patients were given one dose of ketorolac tromethamine (Taradyl®, N.V. Roche S.A., Belgium) or a matching placebo 30 minutes before surgery. Eligible patients were ≥18 and ≤75 years old with histologically or cytologically confirmed, invasive ductal or lobular breast carcinoma planned for curative breast cancer surgery, and with at least one of these 3 criteria: a Neutrophil-to-Lymphocyte Ratio ≥4, node-positive disease (cN1-N3) or a triple-negative histology. The primary endpoint of the study was Disease-Free Survival (DFS). Secondary endpoints included safety, pain assessment and overall survival. Results: Two hundred and three patients were assigned to ketorolac (n=96) or placebo (n=107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD 14) years. Both intra- and post-operative blood losses were not different between groups and there was no difference in pain at day 1 after surgery. There was no difference between the 2 arms for DFS (p=0.52) nor for OS (p=0.88). Discussion and conclusion: This study shows that a single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival is also comparable. No safety concerns were observed in this study. Citation Format: Berliere M, Bouche G, Duhoux F, Coulie P, De Cloedt J, Dekleermaker A, Guillaume J-E, Ledent M, Machiels J-P, Mustin V, Swinnen W, Vander Essen L, Van Maanen A, Verougstraete J-C, De Kock M, Forget P. Intraoperative ketorolac in high-risk breast cancer patients with and without inflammation. A prospective, randomized, placebo-controlled clinical trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-20-01.
Clinical skills in video
Authors: Neil Graham
Journal: BMJ (2010)

Medical schools, print publishers, and good old Google are leading the way by sharing videos of clinical skills to help with life on the wards and preparation for exams.

For basic clinical skills try searching for “cardiovascular examination,” and you’ll find a high quality set of instructional videos from St George’s, London. And if you’re after something more esoteric than cannulation and basic examination, it’s not a bad place to start looking. …
Human lymphoid organ cDC2 and macrophages play complementary roles in T follicular helper responses
Authors: Mélanie Durand, Thomas Walter, Tiphène Pirnay, Thomas Naessens, Paul Gueguen, Christel Goudot, Sonia Lameiras, Qing Chang, Nafiseh Talaei, Olga Ornatsky, Tatiana Vassilevskaia, Sylvain Baulande, Sebastian Amigorena, Elodie Segura
Journal: The Journal of Experimental Medicine (2019)

CD4+ T follicular helper (Tfh) cells are essential for inducing efficient humoral responses. T helper polarization is classically orientated by dendritic cells (DCs), which are composed of several subpopulations with distinct functions. Whether human DC subsets display functional specialization for Tfh polarization remains unclear. Here we find that tonsil cDC2 and CD14+ macrophages are the best inducers of Tfh polarization. This ability is intrinsic to the cDC2 lineage but tissue dependent for macrophages. We further show that human Tfh cells comprise two effector states producing either IL-21 or CXCL13. Distinct mechanisms drive the production of Tfh effector molecules, involving IL-12p70 for IL-21 and activin A and TGFβ for CXCL13. Finally, using imaging mass cytometry, we find that tonsil CD14+ macrophages localize in situ in the B cell follicles, where they can interact with Tfh cells. Our results indicate that human lymphoid organ cDC2 and macrophages play complementary roles in the induction of Tfh responses.
Lecture theatre location: seated to a profession?
Authors: Daniel M Henderson
Journal: BMJ (2010)

Middle to back right: hundreds of lectures at medical school have seen me sit in the same position nearly every time. Why is this? I feel I have changed a lot over the past five years. Psychiatric placements have exposed me to patients with obsessive compulsive disorder, and I’m sure I don’t have that. I’m in control of my own actions, so why have I not experimented with the front row, or even the left hand side? Come to think of it, nearly every medical student I know tends to sit in the same place. Are we all sheep? Are none of us brave enough to buck the trend? I would like to make a huge assumption. I think that where we sit in the lecture theatre reflects our future specialty.

When I began this article, I …