tbuckley/cabot-search huggingface dataset:
Abstract PD2-04: Baseline circulating <i>ESR1</i> mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced hormone receptor positive breast cancer
Authors: N Turner, C Swift, L Kilburn, I Garcia-Murillas, S Johnston, A Budzar, J Robertson, W Gradishar, M Piccart, G Schiavon, S Chia
Journal: Cancer Research (2019)

Abstract Background. ESR1 mutations are acquired frequently in hormone receptor positive breast cancer after treatment with aromatase inhibitors (AI) in the metastatic setting. In prior analysis of the SoFEA phase III randomised trial, we demonstrated the detection of ESR1 mutations in circulating tumor DNA (ctDNA) predicted for greater benefit of fulvestrant compared to exemestane (Fribbens et al JCO 2016). Methods. The phase III EFECT study randomised 693 patients with ER+ metastatic breast cancer who had progressed on a prior non-steroidal AI, between fulvestrant loading dose and then 250mg q28 days and exemestane (Chia S, et al. J Clin Oncol 2008). Baseline serum samples were available from 227 patients in EFECT, and were analysed for the 8 most common ESR1 mutations by multiplex digital PCR. The association between baseline ESR1 status and time to progression (TTP) was analysed using Kaplan-Meier methods. Results. ESR1 mutations were successfully analysed in 98% (222/227) of patients with baseline serum samples, with ESR1 mutations detected in 23.4% (52/222) samples. Overall, detection of ESR1 mutations at baseline was associated with shorter TTP (hazard ratio [HR] 2.03, 95% CI 1.26-3.29, p=0.004). In patients with ESR1 mutation detected, TTP was 2.0 months (95%CI, 1.7-2.4) on exemestane and 3.5 months (95%CI, 1.9-5.0) on fulvestrant (HR 0.67, 95%CI 0.37-1.19, p=0.17). In patients without ESR1 mutations detected, TTP was 4.5 months (95%CI, 3.7-5.6) on exemestane and 3.7 months (95%CI, 3.3-5.2) on fulvestrant (HR 1.05, 95%CI 0.75-1.45, p=0.78). A meta-analysis of SoFEA and EFECT will be presented at the conference. Conclusions. Historical serum samples may be used for ctDNA analysis, illustrating the potential for future research of sample archives. Patients with ESR1 mutation detected in ctDNA have poor outcome when treated with exemestane, replicating prior results from SoFEA and demonstrating clinical utility for ESR1 mutation ctDNA analysis. Citation Format: Turner N, Swift C, Kilburn L, Garcia-Murillas I, Johnston S, Budzar A, Robertson J, Gradishar W, Piccart M, Schiavon G, Chia S. Baseline circulating ESR1 mutation analysis in the randomised phase III EFECT study of fulvestrant versus exemestane in advanced hormone receptor positive 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 PD2-04.
Abstract ES10-3: Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis
Authors: J Conejo-Garcia
Journal: Cancer Research (2019)

Abstract Although the role of estrogen signaling in the progression of a subset of breast tumors has been underscored by the clinical use of Estrogen Receptor antagonists, how estrogens impact protective anti-tumor immunity remains poorly investigated. Here we show that estrogen signaling accelerates the progression of different estrogen insensitive tumor models by contributing to tumor-promoting emergency myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs), and also increases their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens have a profound effect on T-cell-dependent anti-tumor immunity and tumor-promoting inflammation, even independently of the sensitivity of tumor cells to estrogen signaling. Differences in tumor growth in the presence of estrogen-insensitive tumor cells are dependent on blunted anti-tumor immunity and, correspondingly, disappear in immunodeficient hosts and also upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Consequently, selective antagonists of estrogen receptor alpha (but not estrogen receptor beta) could have significant effects in delaying the progression of estrogen-sensitive and estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anti-cancer immunotherapies. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathological, tumor-promoting myelopoiesis. Our work suggests that new anti-estrogen drugs without agonistic effects (different from tamoxifen) could have benefits to boost protective immunity in a wide range of cancers, while augmented estrogenic activity could contribute to tumor initiation and/or malignant progression. Citation Format: Conejo-Garcia J. Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis [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 ES10-3.
Assessment of Gender-Based Linguistic Differences in Physician Trainee Evaluations of Medical Faculty Using Automated Text Mining
Authors: Janae K. Heath, Gary E. Weissman, Caitlin B. Clancy, Haochang Shou, John T. Farrar, C. Jessica Dine
Journal: JAMA Network Open (2019)

Women are underrepresented at higher ranks in academic medicine. However, the factors contributing to this disparity have not been fully elucidated. Implicit bias and unconscious mental attitudes toward a person or group may be factors. Although academic medical centers use physician trainee evaluations of faculty to inform promotion decisions, little is known about gender bias in these evaluations. To date, no studies have examined narrative evaluations of medical faculty by physician trainees for differences based on gender.To characterize gender-associated linguistic differences in narrative evaluations of medical faculty written by physician trainees.This retrospective cohort study included all faculty teaching evaluations completed for the department of medicine faculty by medical students, residents, and fellows at a large academic center in Pennsylvania from July 1, 2015, through June 30, 2016. Data analysis was performed from June 1, 2018, through July 31, 2018.Word use in faculty evaluations was quantified using automated text mining by converting free-text comments into unique 1- and 2-word phrases. Mixed-effects logistic regression analysis was performed to assess associations of faculty gender with frequencies of specific words and phrases present in a physician trainee evaluation.A total of 7326 unique evaluations were collected for 521 faculty (325 men [62.4%] and 196 women [37.6%]). The individual words art (odds ratio [OR], 7.78; 95% CI, 1.01-59.89), trials (OR, 4.43; 95% CI, 1.34-14.69), master (OR, 4.24; 95% CI, 1.69-10.63), and humor (OR, 2.32; 95% CI, 1.44-3.73) were significantly associated with evaluations of male faculty, whereas the words empathetic (OR, 4.34; 95% CI, 1.56-12.07), delight (OR, 4.26; 95% CI, 1.35-13.40), and warm (OR, 3.45; 95% CI, 1.83-6.49) were significantly associated with evaluations of female faculty. Two-word phrases associated with male faculty evaluations included run rounds (OR, 7.78; 95% CI, 1.01-59.84), big picture (OR, 7.15; 95% CI, 1.68-30.42), and master clinician (OR, 4.02; 95% CI, 1.21-13.36), whereas evaluations of female faculty were more likely to be associated with model physician (OR, 7.75; 95% CI, 1.70-35.39), just right (OR, 6.97; 95% CI, 1.51-32.30), and attention (to) detail (OR, 4.26; 95% CI, 1.36-13.40).The data showed quantifiable linguistic differences between free-text comments about male and female faculty in physician trainee evaluations. Further evaluation of these differences, particularly in association with ongoing gender disparities in faculty promotion and retention, may be warranted.
Abstract P4-01-02: Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence
Authors: RC Coombes, A Armstrong, S Ahmed, K Page, RK Hastings, R Salari, H Sethi, A-R Boydell, SV Shchegrova, D Fernandez-Garcia, KL Gleason, K Goddard, DS Guttery, ZJ Assaf, M Balcioglu, DA Moore, L Primrose, SL Navarro, A Aleshin, F Rehman, BJ Toghill, MC Louie, BG Zimmermann, C-HJ Lin, JA Shaw
Journal: Cancer Research (2019)

Abstract Background: Many breast cancer patients relapse after primary treatment but there are no reliable tests to detect distant metastases before they become overt. Here we show earlier identification of recurring patients through a scalable personalised ctDNA analysis. The method is applicable to all patients, and not limited to hot-spot mutations typically detected by gene panels. Methods: Forty-nine non-metastatic breast cancer patients were recruited following surgery and adjuvant therapy. Plasma samples (n=208) were serially collected semi-annually. Using the analytically validated SignateraTM workflow, we determined mutational signatures from primary tumour whole exome data and designed personalised assays targeting 16 variants with high sensitivity by ultra-deep sequencing (average &amp;gt;100,000X). The patient-specific assay was used to detect the presence of the mutational signature in the plasma. Results: In 16 of 18 (89%) clinically-relapsing patients, ctDNA was detected ahead of metastatic relapse being diagnosed by clinical examination, radiological and biochemical (CA15-3) measurements, and remained ctDNA-positive through follow-up. Of the 2 patients not detected by ctDNA, one had a small local recurrence only (now resected) and the other had three primary tumours. None of the 31 non-relapsing patients were ctDNA-positive at any time point (n=142). Metastatic relapse was predicted by Signatera with high accuracy and a lead time of up to 2 years (median=9.5 months). Conclusions: The use of a scalable patient-specific ctDNA-based validated workflow detects breast cancer recurrence ahead of clinical detection. Accurate and earlier prediction by ctDNA analysis could provide a means of monitoring breast cancer patients in need of second-line salvage adjuvant therapy in order to prevent overt life-threatening metastatic progression. Citation Format: Coombes RC, Armstrong A, Ahmed S, Page K, Hastings RK, Salari R, Sethi H, Boydell A-R, Shchegrova SV, Fernandez-Garcia D, Gleason KL, Goddard K, Guttery DS, Assaf ZJ, Balcioglu M, Moore DA, Primrose L, Navarro SL, Aleshin A, Rehman F, Toghill BJ, Louie MC, Zimmermann BG, Lin C-HJ, Shaw JA. Early detection of residual breast cancer through a robust, scalable and personalized analysis of circulating tumour DNA (ctDNA) antedates overt metastatic recurrence [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 P4-01-02.
Abstract OT1-05-03: Efficacy and safety of scalp cooling device for prevention of alopecia in patients with breast cancer
Authors: A Kodera, K Ogura, A Hattori, H Yukawa, S Sakaguchi, A Matsuoka, N Tanaka, M Kamimura, N Jibiki, Y Naritaka, A Hirano
Journal: Cancer Research (2019)

Abstract Background Chemotherapy for breast cancer causes alopecia as a side effect. Some patients refuse chemotherapy because of alopecia, resulting in the omission of a standard therapy. It is believed that a scalp cooling device can prevent alopecia by promoting vasoconstriction of the scalp and reducing exposure of the hair root cells to anticancer agents. There are phenotypic differences of the efficacy of a scalp cooling device for alopecia. In fact, a Dutch scalp cooling registry reported that the success rate of scalp cooling was 51% in European women and 33% in Asian women. Therefore, we aimed to investigate the efficacy of scalp cooling device for chemotherapy-induced alopecia among Asian women with breast cancer. Trial design This is a phase II trialto evaluate the efficacy and safety of scalp cooling device for risk reduction of alopecia in women with stage I/II/III breast cancer treated with adjuvant/neoadjuvant chemotherapy in a single institute. Eligibility criteria Women diagnosed with Stage I to III breast cancer who are scheduled to receive preoperative or postoperative adjuvant chemotherapy containing anthracycline and/or taxanes are enrolled. Patients who have blood malignancies (leukemia, non-Hodgkin lymphoma, other systemic lymphoma), and cold allergy, are excluded. Specific aims The primary endpoint is the proportion of patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 0-1 alopecia after the completion of all cycles of chemotherapy (success rate). Secondary endpoints are safety, quality of life, use of wig or cap, and success rates after the completion of all cycles of chemotherapy distinguished by anthracycline(AC) and taxane. The cooling device is the Paxman scalp cooling system. Scalp cooling was performed from 30 mins before initiation until 90 mins (25 min for taxane) after chemotherapy. Pictures of the scalp were taken at the time of the initiation of each course. Statistical methods Successful treatment was defined as the presence of less than 50% of hair-loss area. The sample size was calculated using the Simon method, with a type I error of 10% (two-sided) and a study power of 80%.The expected success rate is 30%, with a threshold success rate of 10%, and the required number of patients was estimated to be 19. Present and target accrual Patient accrual was started in April 2018 and present accrual is 3. We plan to enroll a total of 20 patients in the trial. Citation Format: Kodera A, Ogura K, Hattori A, Yukawa H, Sakaguchi S, Matsuoka A, Tanaka N, Kamimura M, Jibiki N, Naritaka Y, Hirano A. Efficacy and safety of scalp cooling device for prevention of alopecia in patients with 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 OT1-05-03.
In the Mind's Eye: Perceptual coupling and sensorimotor contingencies
Authors: Julian Hochberg
Journal: Behavioral and Brain Sciences (2001)

The theoretical proposal that perceptual experience be thought of as expectancies about sensorimotor contingencies, rather than as expressions of mental representations, is endorsed; examples that effectively enforce that view are discussed; and one example (of perceptual coupling) that seems to demand a mental representation, with all of the diagnostic value such a tool would have, is raised for consideration.
Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML
Authors: Cihangir Duy, Matt Teater, Francine E. Garrett-Bakelman, Tak C. Lee, Cem Meydan, Jacob L. Glass, Meng Li, Johannes C. Hellmuth, Helai P. Mohammad, Kimberly N. Smitheman, Alan H. Shih, Omar Abdel-Wahab, Martin S. Tallman, Monica L. Guzman, David Muench, H. Leighton Grimes, Gail J. Roboz, Ryan G. Kruger, Caretha L. Creasy, Elisabeth M. Paietta, Ross L. Levine, Martin Carroll, Ari M. Melnick
Journal: Cancer Discovery (2019)

Disruption of epigenetic regulation is a hallmark of acute myeloid leukemia (AML), but epigenetic therapy is complicated by the complexity of the epigenome. Herein, we developed a long-term primary AML ex vivo platform to determine whether targeting different epigenetic layers with 5-azacytidine and LSD1 inhibitors would yield improved efficacy. This combination was most effective in TET2 mut AML, where it extinguished leukemia stem cells and particularly induced genes with both LSD1-bound enhancers and cytosine-methylated promoters. Functional studies indicated that derepression of genes such as GATA2 contributes to drug efficacy. Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the GATA2 locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2 mut AML was associated with dampening of therapeutic GATA2 induction. TET2 knockdown in human hematopoietic stem/progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Our data provide a basis for rational targeting of cooperating aberrant promoter and enhancer epigenetic marks driven by mutant epigenetic modifiers. SIGNIFICANCE: Somatic mutations of genes encoding epigenetic modifiers are a hallmark of AML and potentially disrupt many components of the epigenome. Our study targets two different epigenetic layers at promoters and enhancers that cooperate to aberrant gene silencing, downstream of the actions of a mutant epigenetic regulator.This article is highlighted in the In This Issue feature, p. 813.
Abstract A61: A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion
Authors: Jessica Konen, Bhakti Dwivedi, Jeanne Kowalski, Adam Marcus
Journal: Cancer Research (2016)

Abstract During tumor metastasis, cancer cells invade as a collective pack to navigate the tumor microenvironment. In experimental models, this collective pack is phenotypically heterogenous and contains leader cells which pioneer invasion into the microenvironment and follower cells that immediately attach to and follow the leaders. To dissect the molecular mechanisms underlying this phenotypic heterogeneity, we developed a technique termed spatiotemporal genomic and cellular analysis (SAGA), which uses image-guided genomics to precisely select living, rare cell populations that are maintained within a physiologically relevant environment for downstream genomic and molecular analyses. In this manner, we can select, isolate, and amplify any living cell based upon phenotypic criteria. Using 3-D H1299 lung cancer cell spheroids, we precisely selected as few as 10 leader cells using the SAGA technique and extracted them from the bulk of a multicellular cancer spheroid embedded within a 3-D matrix. These isolated cells were used to create the first leader and follower purified cell cultures. The purified leader cell cultures continually show dynamic invasive patterns over time, while follower cells alone have limited invasive capabilities. Reintroducing limited numbers of leader cells, or even leader cell conditioned media, into follower cell cultures promoted invasion and motility in the follower cells. Genomic analysis comparing leader versus follower cell lines show significant enrichment in cell adhesion and vascular endothelial growth factor (VEGF) signaling pathways in leader cells. This was confirmed by protein analysis showing that leader cells secrete significantly higher levels of VEGF compared to follower cells, and VEGF inhibition abolished leader-follower collective invasion. Overall, our data show that SAGA can precisely select living cells based upon dynamic behaviors for genomic analysis and can amplify rare cell populations for subsequent molecular, cellular, and proteomic analyses. Therefore, this image-guided method has the potential to impact the field of tumor heterogeneity by uncovering genomic signatures of rare yet dynamic subpopulations within a heterogeneous cancer population. Citation Format: Jessica Konen, Bhakti Dwivedi, Jeanne Kowalski, Adam Marcus. A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion. [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 A61.
Common scenarios for MMI stations
Authors: Matthew Billingsley
Journal: BMJ (2015)

What to expect and how to approach stations Multiple mini interviews (MMI) are designed to assess the non-academic qualities of medical school applicants. The type of interview stations a university picks will reflect the characteristics they are looking for in prospective students. While there is some variation across the United Kingdom, MMIs are likely to cover core themes. Some overarching qualities you should show at all interviews are a commitment to a career in medicine, professionalism, integrity, strong communication skills, and the ability to work in a team. Listed below are some examples of scenarios that you could face in your MMI. A good way to practise is to work in groups of two or three and take it in turns being the interviewee, the examiner, and the actor. It is important to remember there is often no right or wrong answer in the MMI and that you are being assessed on your approach and attitude towards a situation. You should view an MMI as an assessment of your thought processes rather than having to arrive at a correct answer. #### Scenario 1—ethical scenario ##### Information sheet for candidate For a station like this, you could be given a list of patients who are waiting for a liver transplant. Two livers have just become available, and you are asked to rank the patients in order of who you believe is most entitled to the available organs. While you do so, you should discuss with the examiner your reasons for choosing this order as well as stating what additional information may be useful to know before you make a decision. The patient details available to you are included below. ###### Patients
Assessment of Airway Driving Pressure and Respiratory System Mechanics during Neurally Adjusted Ventilatory Assist
Authors: Giacomo Grasselli, Luigi Castagna, Chiara Abbruzzese, Nadia Corcione, Sebastiano M. Colombo, Amedeo Guzzardella, Tommaso Mauri, Vittorio Scaravilli, Nicola Bottino, Antonio Pesenti
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Perceptual filling-in and the resonant binding of distributed cortical representations
Authors: Tony Vladusich
Journal: Behavioral and Brain Sciences (2001)

Pessoa et al. (1998a) summarize a wide body of data suggesting that perceptual filling-in phenomena can be attributed to neural filling-in processes. However, they reject, on philosophical grounds, the hypothesis that filled-in representations in the brain are the immediate substrate of visual percepts. It is proposed in this commentary that resonant binding between distributed cortical areas may instead be the crucial ingredient for conscious visual percepts, and that filling-in processes may facilitate the interactions between behaving organisms and object surfaces. These suggestions circumvent some of the philosophical problems associated with the idea of localized visual representations.