tbuckley/cabot-search huggingface dataset:
Abstract P3-02-01: Mammographic Screening: Good Prognosis Tumor Biology in Screen-detected Breast Cancers
Authors: CA Drukker, MK Schmidt, EJT Rutgers, F Cardoso, K Kerlikowske, LJ Esserman, L Slaets, J Bogaerts, LJ van't Veer
Journal: Cancer Research (2012)

Abstract Introduction After the introduction of population-based screening breast cancer incidence increased while breast cancer mortality declined. Our previous analyses suggested screen detection might be associated with a higher likelihood of a biologically low risk or even ultralow risk tumor assessed by the 70-gene signature (MammaPrint™). (Ultralow 70-gene signature defined as indexscore &amp;gt; 0.6, no distant metastasis observed at 5 years in the original 78 patients with no adjuvant systemic treatment.) The aim of this study is to determine the proportion of biologically low and ultralow risk tumors among the screen-detected tumors. Second, to evaluate the impact of analog versus the more sensitive digital screening technique on the biology of tumors detected. Methods All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041) accrued 2007–2011, who were invited for the Dutch screening program (biennial, age 50–75), were included (n = 1381). The proportions of 70-gene signature high, low and ultralow risk were calculated for patients with screen detected (n = 694), interval (n = 366), and symptomatic, non-screening (n = 321) carcinomas, taking into account analog vs. digital technology. Co-variants, such as age, tumor size, histological type, ER, progesterone receptor (PgR) and HER2/neu-oncoprotein (ERBB2) will be included in a multinominal logistic regression model to assess both confounding and effect modification by technology type; these data are pending and will be available during SABCS 2012. Results Among the screen-detected tumors, 33% had a high risk 70-gene signature tumor and 67% had a low risk tumor (table 1). A significant difference was seen between the screen-detected carcinomas and interval carcinomas (p X2 test = 0.001) in all 70-gene signature risk groups. Among the screen detected carcinomas, 41.5% was detected using analog mammography and 58.5% was detected using digital mammography. Analog mammography detected 26.4% high risk, 31.9% low risk and 41.7% ultralow risk tumors. This is significantly different using digital mammography (p X2 test = 0.001), which detected 37.7% high risk, 32.8% low risk and 29.6% ultralow risk tumors. Conclusion Screen detection was found to be associated with a higher likelihood of a biologically low risk tumor. Half of all screen-detected low risk tumors had an index score above 0.6, indicating an ultralow risk of distant metastasis. The transition from analog to digital mammography resulted in a decrease in detection of ultralow risk tumors and an increase in the detection of high risk tumors. Screen-detected low risk biology tumors are frequent and comprehension may aid to minimize overtreatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-02-01.
CircDLST promotes the tumorigenesis and metastasis of gastric cancer by sponging miR-502-5p and activating the NRAS/MEK1/ERK1/2 signaling
Authors: Jing Zhang, Lidan Hou, Rui Liang, Xiaoyu Chen, Rui Zhang, Wei Chen, Jinshui Zhu
Journal: Molecular Cancer (2019)

Accumulating evidence shows that, the dysregulation of circular RNAs (circRNAs) is associated with the progression of multiple malignancies. But, the underlying mechanisms by which has_circ_0032627 (circDLST) contributed to gastric cancer (GC) remain undocumented. The expression and cellular localization of circDLST and its association with clinicopathological characteristics and prognosis in patients with GC was analysed by using fluorescence in situ hybridization. Gain- and loss-of-function experiments as well as a subcutaneous xenograft tumor model and a liver metastasis model from orthotopic implantation of GC tissues were conducted to assess the role of circDLST in GC cells. CircDLST specific binding with miR-502-5p was confirmed by dual luciferase gene report, RNA immunoprecipitation (RIP) assays and RIP-miRNA expression profiling. qRT-PCR and Western blot analysis was used to detect the effects of circDLST on miR-502-5p-mediated NRAS/MEK1/ERK1/2 signaling in GC cells. The expression levels of circDLST were dramatically elevated in GC tissues as compared with the adjacent normal tissues, and acted as an independent prognostic factor of poor survival in patients with GC. Knockdown of circDLST inhibited the cell viability, colony formation, DNA synthesis, cell invasion and liver metastasis in vitro and in vivo, whereas overexpression of circDLST had the opposite effects. Furthermore, circDLST was co-localized with miR-502-5p in the cytoplasm of GC cells, and acted as a sponge of miR-502-3p in GC cells, which abrogated the tumor promoting effects of circDLST by inactivating the NRAS/MEK1/ERK1/2 signaling in GC cells. CircDLST promotes the tumorigenesis and metastasis of GC cells by sponging miR-502-5p to activate the NRAS/MEK1/ERK1/2 signaling.
Human T cell repertoire: what happens in thymus does not stay in thymus
Authors: Antonio La Cava
Journal: Journal of Clinical Investigation (2019)

The T cell receptor (TCR) repertoire is diverse, thus allowing recognition of a wide range of pathogens by T cells. In humans, the study of the formation of TCR repertoires is problematic because of the difficulty in performing investigations in vivo. In this issue of the JCI, Khosravi-Maharlooei and colleagues describe a new humanized mouse model that allows direct investigations on this topic. Using high-throughput and single-cell TCR-complementarity-determining region 3 β (TCR-CDR3β) sequencing, the authors were able to demonstrate that human thymic selection is a major driver of TCR sequence sharing, also implicating a preferential selection of shared cross-reactive CDR3βs during repertoire formation.
Abstract P2-02-10: Progesterone receptor membrane component-1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells: Potential mechanism contributing to breast cancer progression
Authors: M Ludescher, N Stamm, D Niederacher, E Ruckhäberle, T Fehm, H Neubauer
Journal: Cancer Research (2019)

Abstract Background: Progesterone Receptor Membrane Component-1 (PGRMC1) is upregulated in breast tumors and elevated expression of PGRMC1 is associated with increased tumor growth, indicating that PGRMC1 plays a role in carcinogenesis of breast cancer. However, the mechanism by which PGRMC1 contributes to breast cancer progression is not understood yet. Here we describe a potential mechanism by which PGRMC1 contributes to progression of breast cancer via deregulation of cholesterol synthesis and metabolization. Methods: PGRMC1 interaction partners were identified by co-immunoprecipitation followed by mass spectrometry and validated using proximity ligation assay (PLA) in various breast cancer cell lines. To study how elevated PGRMC1 expression contributes to cholesterol balance, we generated PGRMC1 overexpressing breast cancer cells and determined levels of cholesterol-, lathosterol- and the cholesterol metabolite 27-hydroxycholesterol. Since 27-hydroxycholesterol is presumed to have estrogenic action, stimulating the growth of ER-positive breast cancer cells and limiting the effectiveness of aromatase inhibitors, we further investigated the activity of ERα in PGRMC1 overexpressing cell lines. Results: Interaction of PGRMC1 with proteins involved in cholesterol synthesis, including Acyl-CoA desaturase (SCD), Squalene synthase (FDFT1) and Lanosterol 14-alpha demethylase (CYP51A1), was detected by mass spectrometry and verified by PLA. Elevated levels of cholesterol and its metabolites were detected in PGRMC1 overexpressing cells, suggesting a contribution of PGRMC1 to cholesterol synthesis and metabolization. Further, increased activity of ERα was found in PGRMC1 overexpressing cells, indicating activation of the receptor by cholesterol metabolites. Conclusion: Cholesterol metabolism is involved in cancer cell proliferation as well as resistance to anti-cancer therapy. Our results indicate that elevated cholesterol metabolism induced by interaction of PGRMC1 with enzymes of the cholesterol biosynthesis pathway might contribute to malignant transformation and promote breast cancer progression. PGRMC1 might therefore present an interesting target for anti-cancer therapy. Citation Format: Ludescher M, Stamm N, Niederacher D, Ruckhäberle E, Fehm T, Neubauer H. Progesterone receptor membrane component-1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells: Potential mechanism contributing to breast cancer progression [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 P2-02-10.
Abstract P4-10-09: The impact of Charlson comorbidity index on survival of triple negative breast cancer
Authors: C Parise, V Caggiano
Journal: Cancer Research (2019)

Abstract Background Patients with cancer and comorbidities have been found to have poorer survival since they may be unable to receive or complete treatments. It is not clear if comorbid conditions impact survival of patients in all stages of disease and all ER/PR/HER2 subtypes. Purpose The purpose of this study was to determine how the Charlson Comorbidity Index (CCI) affected the risk of mortality of triple negative breast cancer (TNBC) within each stage of disease. Methods We accessed 22,503 cases of TNBC and documented CCI from the California Cancer Registry 2000-2015. The CCI is a weighted index based on the presence of certain comorbid conditions twelve months prior through six months following the cancer diagnosis and weighted by the severity of those conditions. A score of 0 is interpreted as no significant comorbidity burden and scores of 3 or more are generally interpreted as a high comorbidity burden. Kaplan-Meier Survival Analysis and the Log Rank test were used to compare differences in breast cancer specific survival between patients with a CCI of 1, 2 or higher (2+) versus a CCI of 0. Cox Regression Analysis was used to estimate risk of mortality of CCI after adjusting for age, race/ethnicity, socioeconomic status, grade, and treatment. Analyses were conducted separately for each stage. Hazard ratios and 95% confidence intervals (CIs) were reported. Results There 16,664 (74.1%) cases with a CCI of 0; 3,915 (17.4%) with a CCI of 1; 1,055 (4.7%) had a CCI of 2, and the remaining 869 (3.9%) cases of TNBC had a CCI of 3 or higher. Unadjusted survival analysis indicated that for stages 2 and 3, there was increased survival with decreasing CCI score. For stages 1 and 4, survival was only better for patients with a CCI of 0 versus a CCI of 2+. Cox regression analysis indicated that the CCI made no difference in risk of mortality for patients with stage 1 disease. Patients with a CCI of 2+ had an increased risk of mortality when compared with a CCI of 0 for stage 2 (HR = 1.48, CI: 1.25-1.77), stage 3 (HR=1.25, CI: 1.03-1.52) and stage 4 (HR = 1.53; CI: 1.22-1.92). Conclusion Comorbidity as measured by the CCI does not increase the risk of mortality for patients with stage 1 TNBC and only increases risk of mortality in higher stages for patients with a CCI score of 2 or higher. Citation Format: Parise C, Caggiano V. The impact of Charlson comorbidity index on survival 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 P4-10-09.
Abstract ES5-2: Clinical and molecular profiles to identify who is at risk?
Authors: M Dowsett
Journal: Cancer Research (2019)

Abstract The persistent risk of recurrence from ER-positive primary breast cancer has been known for many years. It was recently described in detail and in relation to baseline clinicopathologic factors in a meta-analysis by the EBCTCG. This involved nearly 63,000 patients that had been prescribed 5 years of endocrine therapy and had reached the end of that time recurrence-free (Pan et al, NEJM, 2017, 377, 1836). Among other things this revealed that even among patients with T1N0 disease 13% had a distant recurrence between years 5 and 20. Our group have previously created a Clinical Treatment Score (CTS) from nodal status, tumor size, grade, age and type of adjuvant endocrine treatment and validated this for estimating risk of distant recurrence from the time of diagnosis. Drawing on a training dataset of 4,735 patients from the ATAC trial and a validation set of 6,711 patients from the BIG1-98 trial we created the CTS5, a prognostic score of risk from year 5, that features the same factors as CTS other than type of endocrine treatment (Dowsett et al, JCO, 2018, 36, 1941). Of note, only 4/304 patients with one to three positive nodes that were categorized as low risk in the validation set had a distant recurrence between years 5 and 10. The CTS5 calculator can be accessed online at www.cts5-calculator.com. There are several commercially available molecular profiles that estimate the risk of recurrence over years 0-10 after diagnosis in endocrine-treated primary breast cancer. In the TransATAC study some of these, including the EPClin and PAM50-ROR, show similar prognostic information over years 5-10 (after 5 years of endocrine therapy) as they do over years 0-5 (during endocrine therapy). In contrast, while the Oncotype Recurrence Score (RS) showed similar prognostic information to EPClin and PAM50-ROR in years 0-5 its performance in years 5-10 was substantially worse. Examination of the time-dependent prognostic relationship of each of the individual genes and modules in the RS showed that those patients with higher ER signaling had good prognosis before year 5 but poorer after year 5, suggesting that the cessation of endocrine therapy may lead to this poorer post-5 year outcome (Dowsett et al Clin Cancer Res, 2015, 21, 2763). A broad-based assessment of gene expression in the TransATAC sample set found that there was limited potential to identify a prognostic profile that performed substantially better after 5 years (Buus et al, Breast Cancer Res, 2018, 20, 103). One test, the 7-gene Breast Cancer Index, has reported on a relatively small sample set that it can predict the benefit or not from extended adjuvant endocrine therapy. Further validation studies of this are warranted as well as other tests that provide the same predictive information. Citation Format: Dowsett M. Clinical and molecular profiles to identify who is at risk? [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 ES5-2.
Abstract 18289: New Roles of the Interplay Between Endothelin and Insulin-like Growth Factor 1 in the Regulation of Vascular Redox State in Patients With Type 2 Diabetes and Coronary Atherosclerosis
Authors: Ioannis Akoumianakis, Marios Margaritis, Fabio Sanna, Laura Herdman, Constantinos Psarros, Rana Sayeed, George Krasopoulos, Paulus Wohlfart, Keith Channon, Charalambos Antoniades
Journal: Circulation (2015)

Background: Insulin resistance (IR) is associated with increased cardiovascular risk. Given that plasma endothelin (ET) is elevated in IR, we explored whether the variations in ET levels mediate the vascular complications of type 2 diabetes (T2DM), by exploring its links with vascular redox state in human vessels. Methods: The study population consisted of 383 patients undergoing coronary bypass surgery (CABG), 30% with T2DM. Levels of ET, insulin growth factor 1 (IGF1), insulin and glucose (to calculate HOMA-IR as an index of insulin resistance) were measured in plasma, while vascular superoxide (O2) was measured in saphenous vein segments obtained during surgery. Results: Patients with untreated T2DM had elevated plasma ET, contrary to treated patients with T2DM (A). A positive association was observed between plasma endothelin and IGF1 levels in non-T2DM, which was reversed in T2DM (B). Elevated plasma ET was associated with increased NADPH-stimulated O2- (indicative of higher NADPH oxidase activity) and more LNAME inhibitable O2- (suggestive of more eNOS uncoupling) in human vessels (C, D). Conclusions: We demonstrate that circulating ET is elevated in untreated T2DM but its levels are normalised after intensive glycaemic control. We also document a striking effect of DM on the balance between ET and IGF1, and we demonstrate for the first time in humans, that elevated plasma ET is associated with increased O2- generation in the vascular wall through activation of NADPH-oxidase and uncoupling of eNOS. This study shows that ET and its interplay with IGF1 is possibly a key mechanism linking T2DM with its vascular complications in humans
Incidence of opportunistic infections during ibrutinib treatment for B-cell malignancies
Authors: Kerry A. Rogers, Luay Mousa, Qiuhong Zhao, Seema A. Bhat, John C. Byrd, Zeinab El Boghdadly, Tomas Guerrero, Lauren B. Levine, Fabienne Lucas, Polina Shindiapina, Audrey M. Sigmund, Matthew Sullivan, Tracy E. Wiczer, Jennifer A. Woyach, Farrukh T. Awan
Journal: Leukemia (2019)
Beyond the prospectus
Authors: Kate Chapman
Journal: BMJ (2011)

Succeeding in Your Medical Degree has managed to find a gap in the market. In between the “how to get into medical school” handbooks and the “how to pick your specialty” guides is the small space for the “how to understand quite dull bits of your course that you’ll probably need to know about at some point” books, where this slots right in.

Its aim is to help new medical students understand the course they are starting, and it does this very …
A Prospective Registry Study of Peg-G-CSF Prophylaxis for Patients with Diffuse Large B-Cell Lymphoma (CISL 1403)
Authors: Jeong Seong Hyun, Seok Jin Kim, Jung Yong Hong, Youngil Koh, Hye Jin Kang, Yong Park, Gyeong-Won Lee, Won-Sik Lee, Deok-Hwan Yang, Young Rok Do, Jae-Cheol Jo, HyeonSeok Eom, Kwai Han Yoo, Joon-ho Lee, Min Kyoung Kim, Park Byeong Bae, Jae-Yong Kwak, Seong Yoon Lee, Ji-Hyun Kwon, Jong-Ho Won, Byeong Seok Sohn, Hyo Jung Kim, Hwan Jung Yun, Dae-Sik Hong, Hojin Shin, Sung Yong Oh, Cheolwon Suh, Won Seog Kim
Journal: Blood (2017)
FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia
Authors: Kelly J. Norsworthy, Kunthel By, Sriram Subramaniam, Luning Zhuang, Pedro L. Del Valle, Donna Przepiorka, Yuan-Li Shen, Christopher M. Sheth, Chao Liu, Ruby Leong, Kirsten B. Goldberg, Ann T. Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2019)

Abstract On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30–0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval. See related commentary by Fathi, p. 6015
Modulation of CRTh2 expression on allergen‐specific T cells following peptide immunotherapy
Authors: Christopher D. Rudulier, Elena Tonti, Eddie James, William W. Kwok, Mark Larché
Journal: Allergy (2019)

Abstract Background Allergen immunotherapy using synthetic peptide T‐cell epitopes (Cat‐PAD) from the major cat allergen Fel d 1 has been shown, in allergen exposure studies, to significantly reduce symptoms of allergic rhinoconjunctivitis in cat‐allergic subjects. However, the immunological mechanisms underlying clinical benefit remain only partially understood. Since previous studies of whole allergen immunotherapy demonstrated a reduction in the frequency of allergen‐specific (MHC II tetramer + ) CD4 + T cells expressing the chemokine receptor CRTh2, we assessed the impact of Cat‐PAD on the frequency and functional phenotype of Fel d 1‐specific CD4 + T cells. Methods Using before and after treatment samples from subjects enrolled in a randomized, double‐blind, placebo‐controlled trial of Cat‐PAD, we employed Fel d 1 MHC II tetramers and flow cytometry to analyze the expression of chemokine receptors CCR3, CCR4, CCR5, CXCR3, and CRTh2, together with markers of memory phenotype (CD27 and CCR7) on Fel d 1‐specific CD4 + T cells. Results No statistically significant change in the frequency of Fel d 1‐specific CD4 + T cells, nor in their expression of chemokine receptors or memory phenotype, was observed. However, a significant reduction in cell surface expression of CRTh2 was observed between the placebo and active groups ( P = 0.047). Conclusions Peptide immunotherapy with Cat‐PAD does not significantly alter the frequency or phenotype of Fel d 1‐CD4 + T cells, but may decrease their expression of CRTh2.
Abstract P5-08-08: Not presented
Authors: Y Zhao, H Sun, W Jin
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Zhao Y, Sun H, Jin W. Not presented [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 P5-08-08.
Should medical students be required to study the arts? Yes
Authors: Giskin Day, Matthew Rinaldi
Journal: BMJ (2013)

The way medicine is taught and the contents of curriculums are always under scrutiny. Giskin Day and Matthew Rinaldi say students are missing a valuable lesson by not studying the arts, but Jane Macnaughton (doi:10.1136/sbmj.f5056) says including the arts in medical education has failed to meet its objectives