tbuckley/cabot-search huggingface dataset:
Immunization with the Gly<sup>1127</sup>-Cys<sup>1140</sup> amino acid sequence of the LRP1 receptor reduces atherosclerosis in rabbits. Molecular, immunohistochemical and nuclear imaging studies
Authors: Olga Bornachea, Aleyda Benitez-Amaro, Angela Vea, Laura Nasarre, David de Gonzalo-Calvo, Juan Carlos Escola-Gil, Lidia Cedo, Antoni Iborra, Laura Martínez-Martínez, Candido Juarez, Juan Antonio Camara, Carina Espinet, Maria Borrell-Pages, Lina Badimon, Joan Castell, Vicenta Llorente-Cortés
Journal: Theranostics (2020)

Background:The LRP1 (CR9) domain and, in particular, the sequence Gly 1127 -Cys 1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL).We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis.Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier.IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group.Anti-P3 antibody levels were determined by ELISA.Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography).Studies treating human macrophages (hMΦ) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells.Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile.HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hMΦ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression.These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hMΦ and hcVSMC exposed to the P3 rabbit serums.Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta.PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group.Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits.The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature.
Abstract P1-20-21: The use of intraoperative ultrasound and guidewire placement to obtain low re-excision rates and increased accuracy of excision in impalpable breast lesions at the Cambridge Breast Unit
Authors: Primeera Wignarajah, Vasiliki Papalouka, Parto Forouhi
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Increasingly we are dealing with more and more impalpable breast lesions thanks to screening programmes, chemotherapy and in situ disease. There are various techniques already employed for assisting in surgery for impalpable lesions such as radioactive and magnetic markers. All of these have limitations and are only useful in surgery. Ultrasound can be used in clinic and theatre to locate tumours and sonographically visible markers. In our experience in the Cambridge breast unit we have found it is more satisfactory to use guidewires that are intraoperatively or preoperatively placed using ultrasound guidance. This allows for direct approach to the lesion at the same time limiting the dissection and volume of resection. The guidewire allows tactile feedback and helps with precision and accuracy of the excision as reflected in the specimen weights. In this study we look at the outcomes of intraoperatively and preoperatively placed guidewires using ultrasound for impalpable breast lesions between 2015 -2018 in the Cambridge Breast Unit. The primary outcomes are re-excision rate and average specimen weights. METHODS: Patients undergoing breast conservation surgery for impalpable lesions from 01/01/2015 to 30/07/2018 were included. Data was collected retrospectively from our electronic records system EPIC and analysed. RESULTS The results were divided into intraoperative localisations and preoperative localisations. A total of 441 lesions in 415 patients were included in this study. Preoperative localisationIntraoperative localisationNumber of patients193222Number of lesions210231*Re-excision rate per patient %19.2%14.0%Specimen weight per patient (grams)39.4g24.2g*Fishers exact 0.24 (NS) CONCLUSION: Impalpable lesions can be successfully localised using ultrasound guidance and a guidewire both intraoperatively and preoperatively with good outcomes. Intraoperative localisation has lower re-excision rates and specimen weights in our study as well as many other benefits for the patient and surgeon. We have looked into how easily and quickly we can train ultrasound naïve trainees in this technique and have achieved good results. Citation Format: Primeera Wignarajah, Vasiliki Papalouka, Parto Forouhi. The use of intraoperative ultrasound and guidewire placement to obtain low re-excision rates and increased accuracy of excision in impalpable breast lesions at the Cambridge Breast Unit [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-21.
Abstract P6-07-03: The prognostic impact of HECTD1 E3 ubiquitin ligase expression in breast cancer patients
Authors: Yasuaki Uemoto, Naoto Kondo, Yumi Wanifuchi-Endo, Tomoko Asano, Tomoka Hisada, Sayaka Nishikawa, Yusuke Katagiri, Mitsuo Terada, Akiko Kato, Yu Dong, Hiroyuki Kato, Satoru Takahashi, Tatsuya Toyama
Journal: Cancer Research (2020)

Abstract Background: The epithelial-to-mesenchymal transition (EMT) is fundamental and is required for cancer cells to metastasize. A E3 ubiquitin ligase, HECTD1,wasidentified as a potent regulator of EMT in breast cancer patients. Depletion of HECTD1 was reported to enhance EMT and migration. Here, we investigated the correlation of HECTD1 mRNA expression with prognosis in early breast cancer patients during long-term follow-up. Materials and methods: A total of 627 invasive breast cancer tissues were analyzed for HECTD1 mRNA expression using a TaqMan PCR system. We also examined correlations between HECTD1 mRNA levels and clinicopathological factors in these samples. The median follow-up period was 10.2 years. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards regression analysis was used for univariate and multivariate analyses of prognostic values. Results: We identified positive correlations between low HECTD1 mRNA levels and shorter disease-free survival (DFS) and overall survival (OS) in breast cancer patients (P=0.02 and P=0.03, respectively). Low HECTD1 mRNA levels were positively correlated with high tumor grade, ERα and PgR negativity, HER2 positivity, and type of adjuvant therapy. Univariate analysis indicated that low HECTD1 mRNA levels was a factor for poor DFS and OS in breast cancer patients (hazard ratio (HR), 1.43; 95% confidence interval (CI), 1.06-1.95 and HR, 1.49; 95% CI, 1.03-2.17, respectively) (Table 1). Conclusion: We showed that low HECTD1 mRNA expression may be a predictive factor of poor prognosis in breast cancer patients. HECTD1 could therefore be a candidate biomarker and therapeutic target in breast cancer patients. Table 1. Univariate Cox regression analysis of HECTD1 mRNA expression associated with prognosis.Patients (n=617)UnivariateDisease-free survivalOverall survivalp valueHR (95%CI)p valueHR (95%CI)HectD1 mRNA expressionhigh3130.021(Reference)0.031(Reference)low3141.43(1.06-1.95)1.49(1.03-2.17) Citation Format: Yasuaki Uemoto, Naoto Kondo, Yumi Wanifuchi-Endo, Tomoko Asano, Tomoka Hisada, Sayaka Nishikawa, Yusuke Katagiri, Mitsuo Terada, Akiko Kato, Yu Dong, Hiroyuki Kato, Satoru Takahashi, Tatsuya Toyama. The prognostic impact of HECTD1 E3 ubiquitin ligase expression in breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-07-03.
Integrative Analysis of Baseline Prognostic Features and Achievement of Minimal Residual Disease Negativity As Predictors of Early Relapse in Transplant-Eligible Multiple Myeloma Patients
Authors: Francesca Gay, Gian Maria Zaccaria, Massimo Offidani, Federico Vozella, Paolo Becco, Angelo Belotti, Andrea Capra, Monica Galli, Fortunato Morabito, Luca Bertamini, Francesco Pisani, Piero Galieni, Rita Rizzi, Alessandro Gozzetti, Norbert Pescosta, Luca De Rosa, Franco Narni, Milena Gilestro, Salvatore Palmieri, Michele Cea, Patrizia Tosi, Nicola Giuliani, Pellegrino Musto, Michele Cavo, Mario Boccadoro
Journal: Blood (2019)
Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients
Authors: Hanne T. Olsen, Helene K. Nedergaard, Thomas Strøm, Jakob Oxlund, Karl-Andre Wian, Lars M. Ytrebø, Bjørn A. Kroken, Michelle Chew, Serkan Korkmaz, Jørgen T. Lauridsen, Palle Toft
Journal: New England Journal of Medicine (2020)

In critically ill, mechanically ventilated patients, daily interruption of sedation has been shown to reduce the time on ventilation and the length of stay in the intensive care unit (ICU). Data on whether a plan of no sedation, as compared with a plan of light sedation, has an effect on mortality are lacking.
A proposal for a new staging system for extranodal natural killer T-cell lymphoma: a multicenter study from China and Asia Lymphoma Study Group
Authors: Huangming Hong, Yexiong Li, Soon Thye Lim, Chaoyong Liang, He Huang, Pingyong Yi, Tao Wu, Xin Du, Mingzhi Zhang, Jinghua Wang, Jun Zhu, Ting Liu, Fanyi Meng, Gang Wu, Ye Guo, Yuan Zhu, Weili Zhao, Jie Jin, Juan Li, Yanming Deng, Kangsheng Gu, Xiangyuan Wu, Xiaoyan Ke, Derong Xie, Daren Lin, Zhigang Peng, Junxin Wu, Qing Liu, Won Seog Kim, Tongyu Lin
Journal: Leukemia (2020)
Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer
Authors: Jessica M. Scott, Samantha M. Thomas, Jeffrey M. Peppercorn, James E. Herndon, Pamela S. Douglas, Michel G. Khouri, Chau T. Dang, Anthony F. Yu, Diane Catalina, Cristi Ciolino, Catherine Capaci, Meghan G. Michalski, Neil D. Eves, Lee W. Jones
Journal: Circulation (2020)

Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer.Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO2peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO2peak (mL O2·kg-1·min-1) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety.No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO2peak increased 0.6±1.7 mL O2·kg-1·min-1 (P=0.05) and 0.8±1.8 mL O2·kg-1·min-1 (P=0.07) in LET and NLET, respectively, compared with attention control. Change in VO2peak ranged from -2.7 to 4.1 mL O2·kg-1·min-1 and from -3.6 to 5.1 mL O2·kg-1·min-1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO2peak responders (ie, Δ ≥1.32 mL O2·kg-1·min-1). NLET improved all patient-reported outcomes compared with attention control.Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.
The effect of surgery type on survival and recurrence in very young women with breast cancer.
Authors: May Lynn Quan, Lawrence Frank Paszat, Kimberley Fernandes, Rinku Sutradhar, David R. McCready, Eileen Rakovitch, Ellen Warner, Frances Catriona Wright, Nicole Hodgson, Muriel Brackstone, Nancy Baxter
Journal: Journal of Clinical Oncology (2013)

1002 Background: Young age has been identified as an independent predictor of recurrence and mortality in women with breast cancer. The equivalence of breast conserving surgery (BCS) with mastectomy remains unclear in this population in an era of multimodal therapy. We sought to determine the effect of surgery type on the risk of recurrence and survival in a large, population based cohort of very young women. Methods: All women diagnosed with breast cancer aged ≤35 between 1994 and 2003 in Ontario were identified from the Ontario Cancer Registry, a population based registry of all incident invasive breast cancers in the province. A retrospective chart review was undertaken to identify patient, tumor and treatment variables, as well as locoregional, distant recurrences and death. Univariable and multivariable Cox proportional hazards regression models were fit to determine the effect of primary surgery type on overall survival while controlling for known confounders. To examine time to recurrence in a multivariable analysis, the proportional subdistribution hazards model (Fine and Gray) was used to account for death being a competing risk. Results: A total of 1,381 patients were identified; the median age was 33 (range 18 – 35), median follow up was 11 years. Primary surgical treatment was BCS in 793 (57%) patients of which 89% had adjuvant radiotherapy. Of the 588 (43%) having mastectomy, 53% underwent post mastectomy radiation. Overall, 38% of patients sustained a recurrence of any type and 31% had died. After controlling for tumor size, margin status, node status, grade, LVI, ER/PR, HER2 and treatment (chemotherapy, radiation, hormones) there was no difference in overall survival (HR 0.99, 95% CI 0.79,1.26) or recurrence (HR 0.96, 95% CI 0.73,1.26) among women treated with BCS or mastectomy. Predictors of recurrence were size ≥2 cm, ≥ 1 positive node, neoadjuvant chemotherapy, and lack of radiation. Predictors of death were similar and included high grade and presence of LVI. Conclusions: Very young women selected for BCS had similar outcomes to those selected for mastectomy after controlling for known prognostic factors for recurrence and death.
Role of Intracellular Ca2+-overload in Cardiac Dysfunction in Heart Disease
Authors: Mohamad Nusier, A Tanju Ozcelikay, Anureet K Shah, Naranjan S Dhalla
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Various heart diseases such as genetically-determined heart failure, acute myocardial infarction, ischemia-reperfusion injury and catecholamine-induced cardiomyopathies are associated with cardiac dysfunction, cellular damage, subcellular derangements and metabolic alterations. Since increase in myocardial Ca2+ is accompanied by these abnormalities, it is generally held that intracellular Ca2+-overload plays an important role in the pathogenesis of cardiac dysfunction as well as cellular and metabolic defects in different cardiovascular diseases. This view is supported by observations in hearts subjected to Ca2+-paradox, where reperfusion of Ca2+-free perfused hearts with Ca2+-containing medium was found to produce a marked increase in myocardial Ca2+-content, cellular damage and cardiac contracture. The intracellular Ca2+-overload in the heart has also been shown to produce mitochondrial Ca2+-overload, depress ATP production, release different toxic substances and induce cardiomyocyte apoptosis. By virtue of its ability to depress cardiac gene expression and increase proteolysis of sarcolemma (SL) sarcoplasmic reticulum (SR) and myofibrils (MF), the intracellular Ca2+-overload has been reported to reduce SL, SR and MF protein content and activities. Such remodeling of subcellular organelles is associated with dramatic alterations in Ca2+ -handling by SL and SR membranes as well as interaction of Ca2+ with MF for the impairment of cardiac function. Thus, it is evident that mitochondrial Ca2+-overload, and subcellular remodeling for Ca2+-handling defects are responsible for the occurrence of cardiac dysfunction, metabolic derangements and cellular damage during the development of heart disease.
Identification of a new aggressive axis driven by ciliogenesis and absence of VDAC1-ΔC in clear cell Renal Cell Carcinoma patients
Authors: Lucilla Fabbri, Maeva Dufies, Sandra Lacas-Gervais, Betty Gardie, Sophie Gad-Lapiteau, Julien Parola, Nicolas Nottet, Monique Meyenberg Cunha de Padua, Julie Contenti, Delphine Borchiellini, Jean-Marc Ferrero, Nathalie Rioux Leclercq, Damien Ambrosetti, Baharia Mograbi, Stéphane Richard, Julien Viotti, Emmanuel Chamorey, Nirvana Sadaghianloo, Matthieu Rouleau, William J. Craigen, Bernard Mari, Stéphan Clavel, Gilles Pagès, Jacques Pouysségur, Frédéric Bost, Nathalie M. Mazure
Journal: Theranostics (2020)

: Renal cell carcinoma (RCC) accounts for about 2% of all adult cancers, and clear cell RCC (ccRCC) is the most common RCC histologic subtype. A hallmark of ccRCC is the loss of the primary cilium, a cellular antenna that senses a wide variety of signals. Loss of this key organelle in ccRCC is associated with the loss of the von Hippel-Lindau protein (VHL). However, not all mechanisms of ciliopathy have been clearly elucidated.
Single-Cell Genomic Characterization Reveals the Cellular Reprogramming of the Gastric Tumor Microenvironment
Authors: Anuja Sathe, Susan M. Grimes, Billy T. Lau, Jiamin Chen, Carlos Suarez, Robert J. Huang, George Poultsides, Hanlee P. Ji
Journal: Clinical Cancer Research (2020)

The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. Its characteristics have an impact on treatments such as immunotherapy. These features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that scRNA-seq analysis of gastric cancer together with paired normal tissue and peripheral blood mononuclear cells (PBMC) would identify critical elements of cellular deregulation not apparent with other approaches.scRNA-seq was conducted on seven patients with gastric cancer and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising gastric cancer (32,407 cells), paired normal tissue (18,657 cells), and PBMCs (5,103 cells). Protein expression was validated by multiplex immunofluorescence.Tumor epithelium had copy number alterations, a distinct gene expression program from normal, with intratumor heterogeneity. Gastric cancer TME was significantly enriched for stromal cells, macrophages, dendritic cells (DC), and Tregs. TME-exclusive stromal cells expressed distinct extracellular matrix components than normal. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Tumor DCs had a unique gene expression program compared to PBMC DCs. TME-specific cytotoxic T cells were exhausted with two heterogenous subsets. Helper, cytotoxic T, Treg, and NK cells expressed multiple immune checkpoint or co-stimulatory molecules. Receptor-ligand analysis revealed TME-exclusive intercellular communication.Single-cell gene expression studies revealed widespread reprogramming across multiple cellular elements in the gastric cancer TME. Cellular remodeling was delineated by changes in cell numbers, transcriptional states, and intercellular interactions. This characterization facilitates understanding of tumor biology and enables identification of novel targets including for immunotherapy.
Identification of the true hyperdiploid multiple myeloma subset by combining conventional karyotyping and FISH analysis
Authors: Gregorio Barilà, Laura Bonaldi, Angela Grassi, Annalisa Martines, Albana Liço, Nadia Macrì, Silvia Nalio, Laura Pavan, Tamara Berno, Antonio Branca, Giulia Calabretto, Marilena Carrino, Antonella Teramo, Sabrina Manni, Francesco Piazza, Gianpietro Semenzato, Renato Zambello
Journal: Blood Cancer Journal (2020)
Activity and functional readiness, not age, are the critical factors for second anterior cruciate ligament injury — the Delaware-Oslo ACL cohort study
Authors: Hege Grindem, Lars Engebretsen, Michael Axe, Lynn Snyder-Mackler, May Arna Risberg
Journal: British Journal of Sports Medicine (2020)

Objective To elucidate the relationships between age, return to level I sport (RTS) within the first postoperative year, passing RTS criteria and second anterior cruciate ligament (ACL) injury. Methods In a prospective cohort study, 213 athletes were followed for 2 years after ACL reconstruction to record second ACL injuries. Independent variables were age, passing RTS criteria and level I RTS within the first postoperative year (vs later or no RTS). We defined passing RTS criteria as ≥90 on the Knee Outcome Survey — Activities of Daily Living Scale, global rating scale of function and quadriceps strength/hop test symmetry. Results The follow-up rate was &gt;87% for all outcomes. In multivariable analysis, level I RTS within the first postoperative year and passing RTS criteria were highly associated with second ACL injury (level I RTS HR: 6.0 (95% CI: 1.6 to 22.6), pass RTS criteria HR: 0.08 (95% CI: 0.01 to 0.6)), while age was not (age HR: 0.96 (95% CI: 0.89 to 1.04)). Athletes &lt;25 years had higher level I RTS rates in the first postoperative year (60.4%) than older athletes (28.0%). Of those who returned to level I sport in the first postoperative year, 38.1% of younger and 59.1% of older athletes passed RTS criteria. Conclusion High rates of second ACL injury in young athletes may be driven by a mismatch between RTS rates and functional readiness to RTS. Passing RTS criteria was independently associated with a lower second ACL rate. Allowing more time prior to RTS, and improving rehabilitation and RTS support, may reduce second ACL injury rates in young athletes with ACL reconstruction.