tbuckley/cabot-search huggingface dataset:
Effects of Low-Energy Diet or Exercise on Cardiovascular Function in Working-Age Adults With Type 2 Diabetes: A Prospective, Randomized, Open-Label, Blinded End Point Trial
Authors: Gaurav S. Gulsin, Daniel J. Swarbrick, Lavanya Athithan, Emer M. Brady, Joseph Henson, Emma Baldry, Stavroula Argyridou, Nishal B. Jaicim, Gareth Squire, Yvette Walters, Anna-Marie Marsh, John McAdam, Kelly S. Parke, John D. Biglands, Thomas Yates, Kamlesh Khunti, Melanie J. Davies, Gerry P. McCann
Journal: Diabetes Care (2020)

OBJECTIVE To confirm the presence of subclinical cardiovascular dysfunction in working-age adults with type 2 diabetes (T2D) and determine whether this is improved by a low-energy meal replacement diet (MRP) or exercise training. RESEARCH DESIGN AND METHODS This article reports on a prospective, randomized, open-label, blinded end point trial with nested case-control study. Asymptomatic younger adults with T2D were randomized 1:1:1 to a 12-week intervention of 1) routine care, 2) supervised aerobic exercise training, or 3) a low-energy (∼810 kcal/day) MRP. Participants underwent echocardiography, cardiopulmonary exercise testing, and cardiac magnetic resonance (CMR) at baseline and 12 weeks. The primary outcome was change in left ventricular (LV) peak early diastolic strain rate (PEDSR) as measured by CMR. Healthy volunteers were enrolled for baseline case-control comparison. RESULTS Eighty-seven participants with T2D (age 51 ± 7 years, HbA1c 7.3 ± 1.1%) and 36 matched control participants were included. At baseline, those with T2D had evidence of diastolic dysfunction (PEDSR 1.01 ± 0.19 vs. 1.10 ± 0.16 s−1, P = 0.02) compared with control participants. Seventy-six participants with T2D completed the trial (30 routine care, 22 exercise, and 24 MRP). The MRP arm lost 13 kg in weight and had improved blood pressure, glycemia, LV mass/volume, and aortic stiffness. The exercise arm had negligible weight loss but increased exercise capacity. PEDSR increased in the exercise arm versus routine care (β = 0.132, P = 0.002) but did not improve with the MRP (β = 0.016, P = 0.731). CONCLUSIONS In asymptomatic working-age adults with T2D, exercise training improved diastolic function. Despite beneficial effects of weight loss on glycemic control, concentric LV remodeling, and aortic stiffness, a low-energy MRP did not improve diastolic function.
Abstract C60: Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer
Authors: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, Kenneth P. Olive
Journal: Cancer Research (2019)

Abstract Activating mutations of Kras are the main genetic drivers of pancreatic ductal adenocarcinoma (PDA) and are essential for its initiation and maintenance. It was recently shown that suppression of the Kras effectors Raf/Mek/Erk in the context of Kras-mutant pancreatic tumors leads to the increase of autophagic flux, suggesting that this inhibition may be enhancing PDA dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. This discovery, made recently by two independent research teams, led to the development of a two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and in a human PDA patient. Here we present results from an intervention study performed in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice, a highly chemoresistant genetically engineered model of PDA. We found that a two-drug regimen of trametinib (MEK inhibitor) and hydroxychloroquine (autophagy inhibitor) induced frank regressions in all six animals treated to date—an unmatched response in this model. Tumor regressions ranging from 30% to 95% following treatment were sizable, as measured by longitudinal 3D high-resolution ultrasound, and these mice survived significantly longer than historical controls treated with saline under identical conditions. IHC performed on tumor tissues from treated mice showed decreased proliferation and increased apoptosis relative to untreated KPC pancreatic tumors. Some tumors exhibited substantially reduced phospho-ERK expression by IHC. Interestingly, some tumors that underwent large regressions exhibited positive staining for phospho-ERK in the residue tumor tissues, suggesting a mechanism of resistance through the reactivation of this downstream effector. Studies focused on mechanisms of acquired resistance are ongoing. Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, Kenneth P. Olive. Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C60.
The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism
Authors: Nicholas A. Marston, Yared Gurmu, Giorgio E.M. Melloni, Marc Bonaca, Baris Gencer, Peter S. Sever, Terje R. Pedersen, Anthony C. Keech, Carolina Roselli, Steven A. Lubitz, Patrick T. Ellinor, Michelle L. O’Donoghue, Robert P. Giugliano, Christian T. Ruff, Marc S. Sabatine
Journal: Circulation (2020)

The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk.
Is childhood obstructive sleep apnoea an independent risk factor of hypertension in adulthood?
Authors: Rosemary S C Horne, Montida Veeravigrom
Journal: Thorax (2020)

Over a third of children snore when they are asleep and until the last decade this has been considered benign by both parents and health professionals. Snoring was considered something that children would simply grow out of. Snoring is the hallmark symptom of sleep-disordered breathing (SDB), which ranges in severity from simple or primary snoring to obstructive sleep apnoea (OSA) which affects up to 6% of children.1 The incidence of SDB peaks in the preschool years when the size of the adenoids and tonsils—the primary cause of paediatric SDB—peaks in relation to the bony skeleton. In addition, childhood obesity increases the risk of OSA, particularly in older children.

In adults, OSA is recognised as an independent risk factor for hypertension and reduced nocturnal dipping …
Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes
Authors: Kausik K. Ray, Stephen J. Nicholls, Kevin A. Buhr, Henry N. Ginsberg, Jan O. Johansson, Kamyar Kalantar-Zadeh, Ewelina Kulikowski, Peter P. Toth, Norman Wong, Michael Sweeney, Gregory G. Schwartz
Journal: JAMA (2020)

Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes.To test whether apabetalone significantly reduces major adverse cardiovascular events.A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019.Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care.The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke.Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]).Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events.ClinicalTrials.gov Identifier: NCT02586155.
Persistent Diarrhea in Patients With Crohn’s Disease After Mucosal Healing Is Associated With Lower Diversity of the Intestinal Microbiome and Increased Dysbiosis
Authors: Karen Boland, Larbi Bedrani, Williams Turpin, Boyko Kabakchiev, Joanne Stempak, Krzysztof Borowski, Geoffrey Nguyen, A. Hillary Steinhart, Michelle I. Smith, Kenneth Croitoru, Mark S. Silverberg
Journal: Clinical Gastroenterology and Hepatology (2020)
Abstract P3-08-59: High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive breast cancer patients
Authors: Yoshihisa Tokumaru, Masanori Oshi, Mariko Asaoka, Takashi Takeshita, Eriko Katsuta, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe
Journal: Cancer Research (2020)

Abstract Background: MicroRNA-143(miR-143) is known to function as the tumor suppressor in various cancers, including breast cancer. The tumor immune microenvironment such as the balance between the T helper cell type 1 (Th1) and Th2 is reported to associate with the survival of the breast cancer patients. In this study, we hypothesized that the miR-143 has favorable effect to the tumor immune microenvironment. Material and Methods: We obtained the clinicopathological data and survival information of 755 breast cancer patients from The Cancer Genome Atlas (TCGA) database. Survival analysis, Overall survival (OS) and Disease free survival (DFS) was conducted comparing the high and low expression groups. CYT score, CIBERSORT, and other immunological factors were used to evaluate intratumoral immune cell composition within estrogen receptor (ER) positive breast cancer patients. Also, gene set enrichment analysis (GSEA) was performed between miR-143 high and low expression groups within the ER positive group. Results: High expression of miR-143 was significantly associated with prolonged OS only in ER positive breast cancer patients (p=0.014). Expression of miR-143 was not associated with DFS, stage, TNM factors of breast cancer patients. Within ER positive patients, the result of CIBERSORT revealed that high expression of miR-143 was associated with higher percentage of macrophage M1 (p&amp;lt;0.03) and lower percentage of macrophage M2 (p&amp;lt;0.001). There was more Th1 cells in miR-143 high group (p&amp;lt;0.001) whereas Th2 cells were less (p&amp;lt;0.001). This result was strikingly echoed by GSEA, where miR-143 high significantly enriched the genes related to Th1 cells compared with that of Th2 cells. Regulatory T cell, Lymphocyte infiltration signature score, and T cell receptor diversity were higher in the patients with high miR-143 expression (p&amp;lt;0.03, p&amp;lt;0.001, and p&amp;lt;0.001 respectively). CYT score that reflect cytolytic activity was higher in the high miR-143 expression group (p&amp;lt;0.04). Conclusion: High expression of miR-143 was associated with improved OS in ER positive breast cancer patients. Also, miR-143 was found to associate with high Th1 and low Th2 cells as well as enriching the genes relating to Th1 cells, which may explain the favorable role of miR-143 in ER positive breast cancer. Citation Format: Yoshihisa Tokumaru, Masanori Oshi, Mariko Asaoka, Takashi Takeshita, Eriko Katsuta, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe. High expression microRNA-143 is associated with favorable tumor immune microenvironment and better survival of ER positive 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 P3-08-59.
Response by Dikalova and Dikalov to Letter Regarding Article, “Mitochondrial Deacetylase Sirt3 Reduces Vascular Dysfunction and Hypertension While Sirt3 Depletion in Essential Hypertension Is Linked to Vascular Inflammation and Oxidative Stress”
Authors: Anna Dikalova, Sergey Dikalov
Journal: Circulation Research (2020)
Abstract ES10-1: Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells
Authors: C Blanpain
Journal: Cancer Research (2020)

Abstract Stem cells ensure tissue development, homeostasis and repair. We have recently developed new methods to study by lineage tracing the cellular hierarchy and clonal dynamics that govern the development and homeostasis of the mammary gland. I will present new studies combining lineage tracing, clonal analysis, lineage ablation, single cell RNA sequencing, chromatin profiling, and functional experiments in vivo to investigate the cellular and molecular mechanisms regulating multipotency and lineage restriction during mammary gland development and the cellular reprograming occurring after oncogene expression. Defining the mechanisms regulating tissue expansion and cell fate during development and adult regeneration and understanding how these mechanisms are corrupted during tumorigenesis will have important implications for regenerative medicine and cancer therapy. This work is supported by the ERC, WELBIO, FNRS, TELEVIE, and the Fondation Baillet-Latour. Citation Format: C Blanpain. Cellular Plasticity, Fate, Potential and Lineage Commitment of Mammary Gland Stem Cells [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 ES10-1.
Covid-19: local implementation of tracing and testing programmes could enable some schools to reopen
Authors: Allyson M Pollock
Journal: BMJ (2020)

As a public health physician, I am increasingly concerned about the apparent failure to implement fundamental public health measures to tackle the covid-19 outbreak—specifically, community contact tracing, clinical observation, and testing—and about what seems to be one of the knock-on effects of this failure—the blanket closure of schools.

Tracing and clinical observation of contacts, isolation, and quarantine are the classic tools in public health to deal with infectious diseases.1 The World Health Organization reports that these have been painstakingly adopted in China in response to covid-19, with a high percentage of identified close contacts completing medical observation2; and they have been strongly recommended by WHO for other countries.

We lack data in England—contact tracing seems to have been adopted only initially. Modelling conducted by Keeling and colleagues (the authors of one of the papers published by the …
Trainee involvement in ERCP: safe under close surveillance
Authors: Paraskevas Gkolfakis, Marianna Arvanitakis
Journal: Endoscopy (2020)

See also: Impact of trainee involvement on the outcome of ERCP procedures: results of a prospective multicenter observational trialEndoscopy 2020; 52(02): 115-122DOI: 10.1055/a-1049-0359 See also: Reply to Arvanitakis et al.Endoscopy 2020; 52(04): 319-319DOI: 10.1055/a-1089-9302
Risk factors, patterns and long-term prognosis of early and late recurrence in patients with hepatitis B virus-associated hepatocellular carcinoma
Authors: Ming-da Wang, Chao Li, Lei Liang, Li-yang Sun, Hao Xing, Bing Quan, Han Wu, Timothy M. Pawlik, Wan Yee Lau, Feng Shen, Tian Yang
Journal: International Journal of Surgery (2020)
Abstract ML: What would Bill think?
Authors: JA Sparano
Journal: Cancer Research (2020)

Abstract Since the untimely passing of Bill McGuire in 1992, breast cancer mortality rates have declined by approximately 40% despite stable incidence rates, largely due to mammographic screening and broader application of systemic adjuvant therapy in early stage disease. Continued progress is likely given recently reported clinical trials demonstrating improved survival in metastatic disease, including immune checkpoint blockade in triple negative disease, CDK4/6 inhibitors in ER-positive disease, and second-generation immunconjugates in HER2-positive disease. This remarkable progress in reducing breast cancer mortality has come with a price - broader use of adjuvant chemotherapy in patients with early stage disease who might have been adequately treated and perhaps cured without chemotherapy, and the short and long term side effects that may accompany it - which raises the question - what would Bill think of our progress? How would he challenge us to do better?This lecture will focus on three distinct topics that address some potential challenges: (1) How can gene expression profiles and other diagnostic tests be used to guide the use of adjuvant systemic therapy? (2) is time for reappraisal of active surveillance to detect impending recurrence and prevent it? (3) Are there diagnostic and therapeutic strategies that can be used to identify tumors at highest risk of systemic dissemination, and novel therapeutic strategies that block dissemination? Citation Format: JA Sparano. What would Bill think? [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 ML.
Abstract P4-12-13: Correlation of radiotherapy with the prognosis of elderly patients with hormone receptor-positive breast cancer according to immunohistochemical subtyping
Authors: Jin Zhang
Journal: Cancer Research (2020)

Abstract Objective:The present study examined the effect of radiotherapy on recurrence and survival in elderly patients with hormone-receptor-positive early breast cancer. Methods:A retrospective analysis of 327 patients aged ≥65 years with stage I-II, hormone receptor positive breast cancer who underwent breast conserving surgery and received endocrine therapy (ET) or radiotherapy plus endocrine therapy (ET+RT) was performed. Both groups were divided into luminal A type and luminal B type subgroups. Evaluation criteria were 5-year disease free survival (DFS), local relapse rate (LRR), overall survival (OS), and distant metastasis rate (DMR). Results:There were significant differences in 5-year DFS (HR 1.59, 95% CI 1.15-2.19, P=0.005) and LRR (HR 3.33, 95% CI 1.51-7.34, P=0.003), whereas there were no significant differences in OS and DMR between the two groups. In luminal A type, there was no significant difference in 5-year DFS, LRR, OS, and DMR between the ET group and the ET+RT group. In luminal B type, there were statistically significant differences in 5-year DFS (HR 2.188, 95% CI 1.37-3.49, P=0.001), LRR (HR 5.447, 95% CI 1.65-17.98, P=0.005), and OS (HR 1.752, 95% CI 1.01-3.054, P=0.048) between the two groups. In the ET group, there were significant differences between luminal A type and luminal B type in 5-year DFS (HR 1.841, 95% CI 1.23-2.75, P=0.003) and OS (HR 1.763, 95% CI 1.07-2.91, P=0.026). Conclusions:After breast conserving surgery, radiotherapy can reduce the LRR and improve the DFS and OS of luminal B type elderly patients, whereas luminal A type elderly patients do not benefit from radiotherapy. Without radiotherapy, luminal A type patients have better DFS and OS than luminal B type patients. Keywords: disease-free survival (DFS), distant metastasis rate (DMR), endocrine therapy, local relapse rate (LRR), overall survival (OS), radiotherapy Citation Format: Jin Zhang. Correlation of radiotherapy with the prognosis of elderly patients with hormone receptor-positive breast cancer according to immunohistochemical subtyping [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 P4-12-13.
Abstract P4-01-06: Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations
Authors: Taronish Dorab Dubash, Aditya Bardia, Brittany A Reeves, Brian Chirn, Annamaria Szabolcs, Ben S Wittner, John Iafrate, David Ting, Hitisha K Patel, Teeru Bihani, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran
Journal: Cancer Research (2020)

Abstract Women with metastatic hormone receptor positive (HR+) breast cancer benefit from therapies targeting the Estrogen Receptor (ER), but the tumors eventually acquire resistance leading to disease progression. Endocrine resistance involves multiple mechanisms, including deregulation of ER signaling due to activating mutations in the ligand-binding domain of the ESR1 gene. In addition, recent reports describe specific contexts of ESR1 mutations in the preclinical setting where tamoxifen and fulvestrant have demonstrated limited activity. These data together with the frequency of ESR1 mutations (~20-60%) observed in mBC patients in the clinic suggest a need for more effective agents. The activity of elacestrant (RAD1901), an oral selective estrogen receptor degrader (SERD) with demonstrated activity against tumors harboring ESR1 mutations, both in preclinical models and in patients with previously treated advanced breast cancer, was assessed in ex vivo cultures of circulating tumor cells (CTCs) derived from women with metastatic HR+ breast cancer who had received multiple prior hormone therapies. Cultured breast CTCs underwent apoptosis following exposure to elacestrant, and CTCs harboring mutant ESR1 were significantly growth inhibited (IC50: 17.65 ± 3.32 nM) by elacestrant compared to the standard-of-care (SOC) agent fulvestrant. Furthermore, elacestrant eliminated the fulvestrant-resistant CTC populations in vitro. Elacestrant treatment led to significant suppression of ER target genes, PGR and GREB1. Elacestrant is currently being investigated versus standard of care endocrine monotherapy in a Phase 3 clinical trial (EMERALD) in patients with ER+/HER2- advanced/metastatic breast cancer. A co-primary endpoint of the EMERALD trial is evaluation of progression-free survival in patients whose tumors harbor ESR1 mutations. Citation Format: Taronish Dorab Dubash, Aditya Bardia, Brittany A Reeves, Brian Chirn, Annamaria Szabolcs, Ben S Wittner, John Iafrate, David Ting, Hitisha K Patel, Teeru Bihani, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran. Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations [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 P4-01-06.