tbuckley/cabot-search huggingface dataset:
Epigenetic Regulation of Cancer Stem Cells by the Aryl Hydrocarbon Receptor Pathway
Authors: Sabah Akhtar, Shireen Hourani, Lubna Therachiyil, Abdullah Al-Dhfyan, Abdelali Agouni, Asad Zeidan, Shahab Uddin, Hesham M. Korashy
Journal: Seminars in Cancer Biology (2020)

Compelling evidence has demonstrated that tumor bulk comprises distinctive subset of cells generally referred as cancer stem cells (CSCs) that have been proposed as a strong sustainer and promoter of tumorigenesis and therapeutic resistance. These distinguished properties of CSCs have raised interest in understanding the molecular mechanisms that govern the maintenance of these cells. Numerous experimental and epidemiological studies have demonstrated that exposure to environmental toxins such as the polycyclic aromatic hydrocarbons (PAHs) is strongly involved in cancer initiation and progression. The PAH-induced carcinogenesis is shown to be mediated through the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR)/Cytochrome P4501A pathway, suggesting a possible direct link between AhR and CSCs. Several recent studies have investigated the role of AhR in CSCs self-renewal and maintenance, however the molecular mechanisms and particularly the epigenetic regulations of CSCs by the AhR/CYP1A pathway have not been reviewed before. In this review, we first summarize the crosstalk between AhR and cancer genetics, with a particular emphasis on the mechanisms relevant to CSCs such as Wnt/β-catenin, Notch, NF-κB, and PTEN-PI3K/Akt signaling pathways. The second part of this review discusses the recent advances and studies highlighting the epigenetic mechanisms mediated by the AhR/CYP1A pathway that control CSC gene expression, self-renewal, and chemoresistance in various human cancers. Furthermore, the review also sheds light on the importance of targeting the epigenetic pathways as a novel therapeutic approach against CSCs.
Norman Hugh Moore McKinney
Authors: Miles Rucklidge
Journal: BMJ (2020)

Although born in Belfast, Norman Hugh Moore McKinney (“Hugh”) was to spend most of his life as a general practitioner in Morecambe. He was following in the footsteps of his father, William, who had graduated in medicine at Queen’s University Belfast before settling in Morecambe and setting up in practice there. Hugh’s mother, Edna, was a nurse, so it’s not surprising that he chose medicine as his career.

Hugh was educated at Lancaster Royal Grammar School, a school with which he was to retain a lifelong association. In 1951 he came up to Pembroke, one of the four medical students at that time. His tutor was Percy O’Brien, a man who inspired enormous allegiance among his students, through his taking such a personal interest in their life …
Use of Natural Language Processing to Assess Frequency of Functional Status Documentation for Patients Newly Diagnosed With Colorectal Cancer
Authors: Nicole Agaronnik, Charlotta Lindvall, Areej El-Jawahri, Wei He, Lisa Iezzoni
Journal: JAMA Oncology (2020)

This cross-sectional study applies natural language processing to electronic health records from a large health care delivery system to examine performance status documentation among patients newly diagnosed with colorectal cancer.
Enhanced antitumor efficacy of bile acid-lipid complex-anchored docetaxel nanoemulsion via oral metronomic scheduling
Authors: Saurav Kumar Jha, Jee Young Chung, Rudra Pangeni, Hyeong Seok Choi, Laxman Subedi, Seho Kweon, Jeong Uk Choi, Youngro Byun, Yong-Hee Kim, Jin Woo Park
Journal: Journal of Controlled Release (2020)
Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC
Authors: Aaron C. Tan, Amanda O.L. Seet, Gillianne G.Y. Lai, Tse Hui Lim, Alvin S.T. Lim, Gek San Tan, Angela Takano, David W.M. Tai, Tira J.Y. Tan, Justina Y.C. Lam, Matthew C.H. Ng, Wan Ling Tan, Mei-Kim Ang, Ravindran Kanesvaran, Quan Sing Ng, Amit Jain, Tanujaa Rajasekaran, Wan-Teck Lim, Eng-Huat Tan, Tony Kiat Hon Lim, Daniel S.W. Tan
Journal: Journal of Thoracic Oncology (2020)

IntroductionRET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes.MethodsThis study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected.ResultsA total of 64 patients were included, with a median age of 62 years (range: 25–85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06–0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53–3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04–0.38, p = 0.009).ConclusionsIn RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.
HP0001 The effects of rheumatoid arthritis on sexual expression
Authors: J Hill, R Thorpe, HA Bird
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Objective</h3> To assess patients' perceptions of the effects of RA on their sexual relationships. <h3>Method</h3> A self report questionnaire was distributed to patients attending rheumatology clinics in Leeds. It was returned by pre-paid post to maintain anonymity. <h3>Results</h3> Fifty-nine (80%) questionnaires were returned: 2 by men, 2 were not completed. Womens ages ranged from 36–75 yrs (mean/median 58), men 38–76 yrs (mean 57: median 60). Median duration of RA for women was 18 yrs (mean 19: range 3–40); men 16 yrs (mean 17; range 5–35). Thirty-three women and 8 men were married (duration 1–47 yrs). Five women were single, 6 (1 man) widowed and 3 (1 man) divorced. Sixteen thought RA had strained their sexual relationship and 30 did not. Eighteen thought their RA had altered their relationship but 23 did not. Twenty-three thought RA limited sexual intercourse. Problems cited included pain (11/23); positioning (6/23) and fatigue (5/23). Sexual ability was of little importance to 20 patients but important/very important to 28. Twenty discussed sexual problems with their partners, 19 did not. Sexual relationships were broached by the nurse practitioner in 19 cases but the remaining patients had not been offered discussion. Twenty said they would consider talking to a health professional if problems arose but 21 would not. <h3>Conclusion</h3> Many patients with RA experience problems with their sexual relationships but few are given the opportunity to discuss the subject. The topic needs to be addressed and further work is necessary to assess the patients' requirements and the way in which sexual problems can be addressed within the context of patient management.
THU0140 Rheumatoid arthritis (ra) in vilnius and oslo: a comparison regarding disease and health measures
Authors: JH Dadoniene, T Uhlig, S Stropuviene, A Venalis, A Boonen, TK Kvien
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> In Bone and Joint Decade comparative studies between countries could contribute to better understanding of disease burden of rheumatic diseases. <h3>Objectives</h3> To compare disease and health status measures in RA patient cohorts from Vilnius, Lithuania and Oslo, Norway. <h3>Methods</h3> For 201 patients from Vilnius RA register, matched cases according to age (mean 55.9 (SD1.0)) and gender (167 female) were identified in Oslo RA register. Study variables included sociodemographic characteristics, health status measures (MHAQ, SF-36, pain VAS), disease process measures (disease activity score (DAS-28)), ESR) and previous/current treatment. <h3>Results</h3> Most disease activity and health status measures were worse in Vilnius patients (Table 1). Rheumatoid factor positivity was observed in 61 vs.49% (p = 0.03) in Vilnius and Oslo, respectively. Methotrexate was currently or previously used by 36 vs.49% (p = 0.05) and azatioprine by 29 vs.13% (p = 0.000) in Vilnius and Oslo. For other DMARDS, including corticosteroids no important differences were observed. <h3>Conclusion</h3> In this two-country comparison RA patients from Lithuania had generally worse health status and higher disease activity. This difference could represent geographic differences in disease severity or unequal access to rheumatology care.
SARS-CoV-2 Infection of Airway Cells
Authors: Camille Ehre
Journal: New England Journal of Medicine (2020)

In a laboratory setting, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was inoculated into human bronchial epithelial cells. This inoculation, which was performed in a biosafety level 3 facility, had a multiplicity of infection (indicating the ratio of virus particles to targeted airway cells) of 3:1. These cells were then examined 96 hours after infection with the use of scanning electron microscopy. An en face image (Panel A) shows an infected ciliated cell with strands of mucus attached to the cilia tips. At higher magnification, an image (Panel B) shows the structure and density of SARS-CoV-2 virions produced by human airway epithelial cells. Virus production was approximately 3×106 plaque-forming units per culture, a finding that is consistent with a high number of virions produced and released per cell. Camille Ehre, Ph.D.Baric and Boucher Laboratories at University of North Carolina School of Medicine, Chapel Hill, NC [email protected]
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer
Authors: Burcu F Darst, Tokhir Dadaev, Ed Saunders, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y Xia, Stephen Chanock, Sonja I Berndt, Susan M Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J Weinstein, Vincent Gnanapragasam, Graham G Giles, Tu Nguyen-Dumont, Roger L Milne, Mark Pomerantz, Julie A Schmidt, Lorelei Mucci, William J Catalona, Kurt N Hetrick, Kimberly F Doheny, Robert J MacInnis, Melissa C Southey, Rosalind A Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, David V Conti, Christopher A Haiman
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. Methods Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency &amp;lt; 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
Abstract 13909: Temporal Association Between Breast Cancer and Heart Failure in Postmenopausal Women
Authors: Phillip H Lam, Ana Barac, Anju Nohria, Kerryn Reding, Gregg C Fonarow, Kathy Pan, Helen Sheriff, Charity Morgan, Samer S Najjar, Rowan Chlebowski, Liviu Klein, Charles B Eaton, Barbara V Howard, Ali Ahmed, Selma Mohammed
Journal: Circulation (2019)

Introduction: Heart failure (HF) and breast cancer are two of the leading causes of death in postmenopausal women. The temporal association between HF and breast cancer in a cohort of postmenopausa...
Preparation of high precision multilayer scaffolds based on Melt Electro-Writing to repair cartilage injury
Authors: Yu Han, Meifei Lian, Binbin Sun, Bo Jia, Qiang Wu, Zhiguang Qiao, Kerong Dai
Journal: Theranostics (2020)

Rationale: Articular cartilage injury is quite common. However, post-injury cartilage repair is challenging and often requires medical intervention, which can be aided by 3D printed tissue engineering scaffolds. Specifically, the high accuracy of Melt Electro-Writing (MEW) technology facilitates the printing of scaffolds that imitate the structure and composition of natural cartilage to promote repair. Methods: MEW and Inkjet printing technology was employed to manufacture a composite scaffold that was then implanted into a cartilage injury site through microfracture surgery. While printing polycaprolactone (PCL) or PCL/hydroxyapatite (HA) scaffolds, cytokine-containing microspheres were sprayed alternately to form multiple layers containing transforming growth factor-β1 and bone morphogenetic protein-7 (surface layer), insulin-like growth factor-1 (middle layer), and HA (deep layer). Results: The composite biological scaffold was conducive to adhesion, proliferation, and differentiation of mesenchymal stem cells recruited from the bone marrow and blood. Meanwhile, the environmental differences between the scaffold's layers contributed to the regional heterogeneity of chondrocytes and secreted proteins to promote functional cartilage regeneration. The biological effect of the composite scaffold was validated both in vitro and in vivo. Conclusion: A cartilage repair scaffold was established with high precision as well as promising mechanical and biological properties. This scaffold can promote the repair of cartilage injury by using, and inducing the differentiation and expression of, autologous bone marrow mesenchymal stem cells.
Measuring mobility to monitor travel and physical distancing interventions: a common framework for mobile phone data analysis
Authors: Nishant Kishore, Mathew V Kiang, Kenth Engø-Monsen, Navin Vembar, Andrew Schroeder, Satchit Balsari, Caroline O Buckee
Journal: The Lancet Digital Health (2020)

A surge of interest has been noted in the use of mobility data from mobile phones to monitor physical distancing and model the spread of severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19. Despite several years of research in this area, standard frameworks for aggregating and making use of different data streams from mobile phones are scarce and difficult to generalise across data providers. Here, we examine aggregation principles and procedures for different mobile phone data streams and describe a common syntax for how aggregated data are used in research and policy. We argue that the principles of privacy and data protection are vital in assessing more technical aspects of aggregation and should be an important central feature to guide partnerships with governments who make use of research products.
Impact of mechanical simulator practice on clinical ERCP performance by novice surgical trainees: a randomized controlled trial
Authors: Wenbo Meng, Ping Yue, Joseph W. Leung, Haiping Wang, Xiyan Wang, Fangzhao Wang, Kexiang Zhu, Lei Zhang, Xiaoliang Zhu, Zhengfeng Wang, Hui Zhang, Wence Zhou, Xun Li
Journal: Endoscopy (2020)

Abstract Background Lack of forward-viewing endoscopy experience impairs training in endoscopic retrograde cholangiopancreatography (ERCP). We evaluated the effect of ERCP mechanical simulator (EMS) practice on ERCP performance by surgical trainees. Patients and methods 12 surgical trainees without endoscopy experience were randomly allocated to non-EMS (n = 6) programs or to EMS (n = 6) programs with coaching and 20 hours of supervised EMS practice. All trainees then received supervised hands-on clinical ERCP training. Trainers provided verbal instructions and hands-on assistance, and took over if cannulation was not achieved by 20 minutes. Blinded trainers rated clinical performance. Results Each group performed 150 clinical ERCPs. Biliary cannulation success was significantly higher in the EMS vs. the non-EMS group (P = 0.006), with shorter mean times (in minutes) for intubation, cannulation, and completion (all P &lt; 0.001). EMS trainees showed a significantly better mean performance score (P = 0.006). In multivariate analysis, after adjusting for case sequence, CBD stone, complexity, and EMS training, the effect of EMS practice on odds for successful cannulation remained highly significant (odds ratio [OR] 2.10 [95 %CI 1.46 – 3.01]). At 6 months EMS trainees still had better cannulation success vs. non-EMS controls (P = 0.045); no difference was observed after 1 year. Conclusions EMS practice shortens the ERCP early learning curve of inexperienced surgical trainees, improves clinical success in selective biliary cannulation, and may reduce complications.
Severe COVID-19 Is a Microvascular Disease
Authors: Charles J. Lowenstein, Scott D. Solomon
Journal: Circulation (2020)

he range of clinical responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely broad.Although most patients with coronavirus disease 2019 (COVID-19) present with a mild upper respiratory tract infection and then recover, some infected patients develop pneumonia, acute respiratory distress syndrome, multi-organ failure, and death.Clues to the pathogenesis of severe COVID-19 may lie in the systemic inflammation and thrombosis observed in infected patients.We propose that severe COVID-19 is a microvascular disease in which coronavirus infection activates endothelial cells, triggering exocytosis, a rapid vascular response that drives microvascular inflammation and thrombosis.Both arterial and venous thromboembolism are common in patients with severe COVID-19.The incidence of venous thromboembolic events in patients with COVID-19 admitted to intensive care units ranges from 20% to 35%, and deep venous thrombosis has been identified in 70% to 100% of patient who died from COVD-19. 1 Furthermore, arterial thrombosis resulting in stroke or myocardial infarction occurs in up to 4% of patients with COVID-19 hospitalized in intensive care units.Patients with severe COVID-19 often have laboratory findings consistent with a hypercoagulable state, suggesting widespread thrombosis and fibrinolysis, as well as elevated levels of D-dimer, von Willebrand factor (VWF), and factor VIII.These patients also manifest a hyperinflammatory state, or "cytokine storm," characterized by elevated levels of inflammatory markers such as C-reactive protein and interleukin-6, which have been linked to severity of pneumonia and mortality.Endothelial injury is an underlying mechanism that might link inflammation and thrombosis in severe COVID-19.Autopsy studies have suggested that both endothelial inflammation and microvascular thrombosis are prominent, with inflammatory cells attached to the endothelium of small vessels in lung, kidney, heart, and liver. 2 Moreover, VWF, which is released from endothelial cells after vascular injury, and P-selectin, which is also released from activated endothelial cells, are both markedly elevated in several series of patients with COVID-19. 3,4The combination of high VWF levels, elevated P-selectin levels, microvascular thrombosis, and microvascular inflammation all suggest that microvascular injury may be a common trigger for both the inflammatory and thrombotic complications of COVID-19. 5 We propose that the coronavirus SARS-CoV-2 triggers a unique endothelial response, endothelial exocytosis, which simultaneously activates 2 parallel pathways, microvascular inflammation and microvascular thrombosis, ultimately leading to hyperinflammation and diffuse thrombosis characteristic of severe COVID-19.Exocytosis is a rapid secretory response to injury in which diverse agonists bind to endothelial cell surface receptors, triggering endothelial granules to fuse with the endothelial membrane and release granule contents into the blood stream.
FRI0099 Causes of death in 56 patients with systemic lupus erythematosus
Authors: EK Li, LS Tam
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To describe the causes of death in a Chinese lupus cohort with SLE. <h3>Methods</h3> We examined mortality in a cohort of 427 Chinese patients with SLE seen between 1985–1997. During a mean ± SD of 5.0 ± 3.8 years of follow-up, 56 patients died. The causes of death were determined. <h3>Results</h3> The mean ± SD disease duration from diagnosis to last visit or death for the 427 patients was 6.7 ± 5.4 years, with a duration of follow-up of 5.0 ± 3.8 years. 53 females and 3 males died. The age at death was 35.3 ± 11.3 years. Among those who died, the duration of disease was 5.2 ± 4.8 years with a follow-up of 3.5 ± 3.3 years. In comparison, patients last seen alive had a longer disease duration of 6.9 ± 5.4 years and a longer follow-up of 5.3 ± 3.9 years. Infection and active SLE were the two leading causes of death, occurring in 17 patients (31%) in both instances. The clinical manifestations amongst the 17 patients with active SLE were as follows: seizure in 2, cerebritis in 1, cardiac tamponade in 2, pneumonitis in 2, pulmonary haemorrhage in 2, pulmonary hypertension in 2, nephritis in 2, vasculitis in 2, pancreatitis in 2. In 12 patients, SLE was a contributing factor of death. Thus, active SLE was present in over half of the cases (28 patients) at the time of deaths. The most common type of infection was pneumonia (41%) followed by bacteremias (35.3%). The most prevalent infections were bacterial infections (23.5%), followed by mixed infections (17.6%), fungal (17.6%) and mycobacterium infections (17.6%). Out of the 17 patients in whom the primary cause of death was due to infection, 9 had active SLE at the time of death. <h3>Conclusion</h3> The majority of patients at the time of death had active SLE. Although the percentage of patients dying from infections and active SLE were the same, active SLE was present in half of those with infections suggesting that active disease remains the most important factor in mortality in SLE.