tbuckley/cabot-search huggingface dataset:
Far reach of <i>Fusobacterium nucleatum</i> in cancer metastasis
Authors: Ye Yang, Christian Jobin
Journal: Gut (2020)

Approximately 8 years ago, two groups independently reported enrichment of Fusobacterium nucleatum (Fn) in human colorectal cancer (CRC) tissues compared with adjacent normal tissues.1 2 Since this discovery, intense research interests have been drawn to the bacterium in the context of CRC. The association between Fn and CRC has been confirmed in numerous studies, and several Fn-driven pro-oncogenic mechanisms have been proposed based on observations from preclinical models.3 Notably, much of our knowledge regarding the involvement of Fn is at the primary CRC development stage. How Fn might impact CRC metastasis—the late stage of carcinogenesis that really determines poor prognosis in patients—is relatively unexplored, despite detection of the bacterium in CRC metastases to the liver and lymph nodes.1 2 4

The first evidence that Fn is important for CRC metastasis emerged in 2017, when it was shown that Fn presence correlated with successful establishment of CRC patients-derived xenografts in mice.4 Yet, the molecular process underlying Fn-dependent metastatic tumour formation was undefined. Earlier this year, three research groups, using a similar in vitro experimental design, reported that Fn infection enhanced migration of human CRC-derived HCT116 cells, although each group proposes distinct mechanisms.5–7 These include induction of interleukin-8 (IL-8) and C-X-C Motif Chemokine Ligand 1 (CXCL1),5 upregulation of caspase …
2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary
Authors: Karen K. Stout, Curt J. Daniels, Jamil A. Aboulhosn, Biykem Bozkurt, Craig S. Broberg, Jack M. Colman, Stephen R. Crumb, Joseph A. Dearani, Stephanie Fuller, Michelle Gurvitz, Paul Khairy, Michael J. Landzberg, Arwa Saidi, Anne Marie Valente, George F. Van Hare
Journal: Journal of the American College of Cardiology (2018)
Role of IgE-FcεR1 in Pathological Cardiac Remodeling and Dysfunction
Authors: Hongmei Zhao, Hongqin Yang, Chi Geng, Yang Chen, Junling Pang, Ting Shu, Meijun Zhao, Yaqin Tang, Zhiwei Li, Baicun Li, Cuiliu Hou, Xiaomin Song, Aoxue Wu, Xiaoxiao Guo, Si Chen, Bin Liu, Chen Yan, Jing Wang
Journal: Circulation (2020)

Immunoglobulin E (IgE) belongs to a class of immunoglobulins involved in immune response to specific allergens. However, the roles of IgE and IgE receptor (FcεR1) in pathological cardiac remodeling and heart failure are unknown.Serum IgE levels and cardiac FcεR1 expression were assessed in diseased hearts from human and mouse. The role of FcεR1 signaling in pathological cardiac remodeling was explored in vivo by FcεR1 genetic depletion, anti-IgE antibodies, and bone marrow transplantation. The roles of the IgE-FcεR1 pathway were further evaluated in vitro in primary cultured rat cardiomyocytes and cardiac fibroblasts (CFs). RNA sequencing and bioinformatic analyses were used to identify biochemical changes and signaling pathways that are regulated by IgE/FcεR1.Serum IgE levels were significantly elevated in patients with heart failure as well as in 2 mouse cardiac disease models induced by chronic pressure overload via transverse aortic constriction and chronic angiotensin II infusion. Interestingly, FcεR1 expression levels were also significantly upregulated in failing hearts from human and mouse. Blockade of the IgE-FcεR1 pathway by FcεR1 knockout alleviated transverse aortic constriction- or angiotensin II-induced pathological cardiac remodeling or dysfunction. Anti-IgE antibodies (including the clinical drug omalizumab) also significantly alleviated angiotensin II-induced cardiac remodeling. Bone marrow transplantation experiments indicated that IgE-induced cardiac remodeling was mediated through non-bone marrow-derived cells. FcεR1 was found to be expressed in both cardiomyocytes and CFs. In cultured rat cardiomyocytes, IgE-induced cardiomyocyte hypertrophy and hypertrophic marker expression were abolished by depleting FcεR1. In cultured rat CFs, IgE-induced CF activation and matrix protein production were also blocked by FcεR1 deficiency. RNA sequencing and signaling pathway analyses revealed that transforming growth factor-β may be a critical mediator, and blocking transforming growth factor-β indeed alleviated IgE-induced cardiomyocyte hypertrophy and cardiac fibroblast activation in vitro.Our findings suggest that IgE induction plays a causative role in pathological cardiac remodeling, at least partially via the activation of IgE-FcεR1 signaling in cardiomyocytes and CFs. Therapeutic strategies targeting the IgE-FcεR1 axis may be effective for managing IgE-mediated cardiac remodeling.
LGG-13. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Julie Bennett, Karen Fang, Javal Sheth, Scott Ryall, Komosa Martin, Nuno Nunes, Liana Nobre, James Perry, Arjun Sahgal, Warren Mason, Sunit Das, Andrew Gao, Derek Tsang, Lananh Nguyen, Normand Laperriere, Julia Keith, David Munoz, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Pediatric low grade gliomas are typically driven by MAPK upregulation with excellent long-term survival. In contrast, adult lower grade gliomas commonly harbor IDH-1 mutations and undergo malignant transformation. Gliomas in adolescents and young adults (AYA) are an orphan group of tumors that have been poorly described. We aim to determine the clinical and molecular landscape of AYA gliomas. METHODS A multi-institutional population based cohort of 839 patients diagnosed with glioma between 15–40 years has been identified. Complete molecular analysis, long term outcome and therapeutic data are being collected. RESULTS Of 364 AYA gliomas analyzed, the prevalence of WHO grade I tumors was highest in those &amp;lt;21 years (54%), while the prevalence of higher grade tumors increased with age. Interestingly, only 38% harbor IDH-1 mutations while 23% harbor pediatric mutations, including 8% with BRAF p.V600E, and 4% with KIAA1549:BRAF fusion. The median age for IDH-1 mutation is 32 years, with highest frequency in WHO grade II and III tumors. In contrast, BRAF alterations were most frequently observed in WHO grade I and II tumors and enriched in those less than 20 years. Five-year progression-free survival for BRAF fusion, p.V600E and IDH-1 p.R132H were 81%, 78% and 26% respectively. No survivors were observed in H3 p.K27M and p.G34R gliomas (p&amp;lt;0.0001). CONCLUSIONS Gliomas in AYA overlap pediatric and adult classification and exhibit enrichment for pediatric alterations. As the latter are associated with improved PFS and are amenable to targeted therapies, this should be considered in the work up of these tumors.
BMA strongly opposes changes to foundation programme applications
Authors: Nikki Nabavi
Journal: BMJ (2020)

The BMA has said it “strongly opposed” the decision to exclude additional degrees and publications from the points system used to allocate foundation training posts, which is set to take effect from 2023.1

A letter to medical schools from the co-chairs of the UK Foundation Programme Office (UKFPO) Tom Lawson and Mike Masding said that the office had decided to make the changes because additional degrees and publications were no longer a useful way of distinguishing between candidates.

“The percentage of applicants seeking points for additional achievements has increased from 30% to 70% in the most recent application round, resulting in less differentiation between application scores,” they said.2 The co-chairs also acknowledged that “the opportunities for students to obtain additional degrees are inconsistent.”

The BMA said that …
Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk
Authors: Deborah A. Silverman, Vena K. Martinez, Patrick M. Dougherty, Jeffrey N. Myers, George A. Calin, Moran Amit
Journal: Cancer Research (2020)

Abstract In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell–derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt–β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.
Early Discontinuation of Endocrine Therapy and Recurrence of Breast Cancer among Premenopausal Women
Authors: Lindsay J. Collin, Deirdre P. Cronin-Fenton, Thomas P. Ahern, Michael Goodman, Lauren E. McCullough, Lance A. Waller, Anders Kjærsgaard, Per Damkier, Peer M. Christiansen, Bent Ejlertsen, Maj-Britt Jensen, Henrik Toft Sørensen, Timothy L. Lash
Journal: Clinical Cancer Research (2021)

Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of endocrine therapy to prevent or delay recurrence. In this study, we evaluated the association between early discontinuation of endocrine therapy and breast cancer recurrence in a cohort of premenopausal women.We identified 4,503 patients with premenopausal ER-positive breast cancer who initiated adjuvant endocrine therapy and were registered in the Danish Breast Cancer Group clinical database (2002-2011). Women were excluded if they had a recurrence or were lost to follow-up less than 1.5 years after breast cancer surgery. Endocrine therapy was considered complete if the patient received at least 4.5 years of treatment or discontinued medication less than 6 months before recurrence. Exposure status was updated annually and modeled as a time-dependent variable. We accounted for baseline and time-varying confounders via time-varying weights, which we calculated from multivariable logistic regression models, and included in regression models to estimate HRs and 95% confidence intervals (CIs) associating early discontinuation with recurrence.Over the study follow-up, 1,001 (22%) women discontinued endocrine therapy. We observed 202 (20%) recurrences among those who discontinued endocrine therapy, and 388 (11%) among those who completed the recommended treatment. The multivariable-adjusted estimated rate of recurrence was higher in women who discontinued endocrine therapy relative to those who completed their treatment (hazard ratio, 1.67; 95% CI, 1.25-2.14).These results highlight the importance of clinical follow-up and behavioral interventions that support persistence of adjuvant endocrine therapy to prevent breast cancer recurrence.
Monitoring eosinophils to guide therapy with biologics in asthma: does the compartment matter?
Authors: Leo Koenderman, Marwan Hassani, Manali Mukherjee, Parameswaran Nair
Journal: Allergy (2020)

Eosinophils, since their initial description by Thomas Wharton Jones in 1846, and staining characteristics by Paul Ehrlich in 1879, have been associated with asthma.1 They are produced in the bone marrow, from pluripotential stem cells, which first differentiate, largely regulated by a transcription factor GATA-1, into a hybrid precursor for both basophils and eosinophils, and then into a separate eosinophil lineage. The eosinophilopoietins IL-3, GM-CSF and notably IL-5 regulate their further expansion and migration out of the bone marrow, and into the circulation. Circulating eosinophils subsequently interact with the endothelium by processes involving rolling, adhesion and diapedesis. Depending on the target organ, eosinophils cross the endothelium into tissues by a regulated process involving the coordinated interaction between networks involving cytokines such as IL-13, the chemokine eotaxin-1, eosinophil adhesion molecules (α4β1, α4β7, αmβ2, αLβ2), and adhesion receptors on the endothelium (MAdCAM-1, VCAM-1 and ICAM-1). Under homeostatic conditions, eosinophils traffic into the thymus, mammary gland, uterus and most prominently into the gastrointestinal tract.2 Thus, in a disease such as asthma, long associated with mobilization of eosinophils from the bone marrow, it is not surprising that eosinophil numbers may be increased in blood and sputum in patients with asthma. The development of biologics targeting IL-5 and IL-13 has provided opportunities to treat patients with asthma whose severity or symptoms are driven by eosinophil biology. Most studies evaluating these biologics were conducted by selecting patients with raised blood eosinophil numbers, and not by enumerating numbers in the airway, as the latter process is cumbersome. There is ongoing controversy as to which would be a better strategy. This commentary examines whether blood eosinophil number is an adequate method to choose those patients who may be good responders to anti-eosinophil biologics and to monitor the response to therapy. Leo Koenderman and Marwan Hassani. Manali Mukherjee and Parameswaran Nair. Dr Nair was supported by the Frederick E. Hargreave Teva Innovation Chair in Airway Diseases. Dr Mukherjee was supported by a Canadian Institutes of Health Research post-doctoral fellowship. The data in the manuscript was supported by a grant from the Canadian Institute of Health Research. LK reports grants from GlaxoSmithKline and non-financial support from Beckman Coulter. MH declares no conflicts of interests. MM reports grants from Methapharm Specialty Pharmaceuticals, Canadian Institute of Health Research, Canadian Asthma Allergy and Immunology Foundation and personal fees from AstraZeneca. PN reports grants and/or personal fees from AZ, Novartis, Teva, Sanofi, Roche, Novartis, Merck and Equillium.
EPID-24. OBESITY IN MALES WITH MENINGIOMA: A U.S. POPULATION-BASED STUDY
Authors: Maryam Shahin, Ali Rae, Christian Lopez Ramos, Jacob Bagley, Stephen Bowden, Carli Bullis, Justin Cetas, Seunggu Han
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The female predominance of meningiomas may reflect a hormonal influence on tumorigenesis. Obesity alters steroid synthesis and chronically exposes men to hyperestrogenemia. OBJECTIVE Identify differences in males undergoing craniotomy for meningioma compared to other tumors or aneurysms. METHODS The National Surgical Quality Improvement Program was retrospectively queried from 2013–2018 for cases of craniotomy for resection of meningioma, other tumor, and aneurysm by CPT code in male patients and confirmed with postoperative ICD-10 code. Height and weight data were used to create body mass index (BMI): underweight (&amp;lt; 18.5), normal (18.5 to&amp;lt; 25), overweight (25 to&amp;lt; 30), class I obesity (30 to&amp;lt; 35), class II obesity (35 to&amp;lt; 40), and class III obesity (40+). RESULTS We identified 2,458 males who underwent craniotomy for meningioma, 9,889 for other tumor, and 386 for aneurysm. Using multivariable logistic regression, age (OR 1.01 per year, 95% CI 1.01-1.01, p&amp;lt; 0.001), diabetes mellitus (OR 1.32, 95% CI 1.17–1.48, p&amp;lt; 0.001), and increasing BMI (overweight: OR 1.55, 95% CI 1.36–1.76, p&amp;lt; 0.001; class I: OR 2.00, 95% CI 1.75–2.30, p&amp;lt; 0.0001; class II: OR 2.05, 95% CI 1.24–1.76, p&amp;lt; 0.001; class III: OR 1.47, 95% CI 1.24–1.76, p&amp;lt; 0.0001) were significantly and independently associated with craniotomy for meningioma compared to other tumor or aneurysm. For other tumor, higher BMI was associated with lower likelihood (overweight: OR 0.70, 95% CI 0.62–0.79, p&amp;lt; 0.001; class I: OR 0.55, 95% CI 0.49–0.63, p&amp;lt; 0.001; class II: OR 0.52, 95% CI 0.44–0.62, p&amp;lt; 0.001; class III: OR 0.74, 95% CI 0.63–0.87, p&amp;lt; 0.001). For aneurysm, there was no significant difference (overweight p=0.70; class I p=0.65; class II p=0.76; class III p=0.57). CONCLUSIONS BMI independently predicts having craniotomy for meningioma when compared to other tumor or aneurysm amongst US male patients.
ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly
Authors: Shayi Wu, Miao Chen, Jiao Huang, Feifei Zhang, Zhaojie Lv, Yongxu Jia, Yu-Zhu Cui, Liang-Zhan Sun, Ying Wang, Ying Tang, Krista R. Verhoeft, Yan Li, Yanru Qin, Xiang Lin, Xin-Yuan Guan, Ka-On Lam
Journal: Cancer Research (2020)

Abstract The ubiquitous second messenger Ca2+ has long been recognized as a key regulator in cell migration. Locally confined Ca2+, in particular, is essential for building front-to-rear Ca2+ gradient, which serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca2+ and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that calcium release–activated calcium modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, predominantly upregulated in the lymph node metastasis of gastric cancer, supports cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in gastric cancer tissues significantly correlated with poor differentiation, invasion, lymph node metastasis, and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation, and metastasis in both gastric cancer cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of gastric cancer cells by inducing FAK-mediated MAPK/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that ORAI2 is a novel gene that plays an important role in the tumorigenicity and metastasis of gastric cancer. Significance: These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway.
COVID-19 Mortality Among American Indian and Alaska Native Persons — 14 States, January–June 2020
Authors: Jessica Arrazola, Matthew M. Masiello, Sujata Joshi, Adrian E. Dominguez, Amy Poel, Crisandra M. Wilkie, Jonathan M. Bressler, Joseph McLaughlin, Jennifer Kraszewski, Kenneth K. Komatsu, Xandy Peterson Pompa, Megan Jespersen, Gillian Richardson, Nicholas Lehnertz, Pamela LeMaster, Britney Rust, Alison Keyser Metobo, Brooke Doman, David Casey, Jessica Kumar, Alyssa L. Rowell, Tracy K. Miller, Mike Mannell, Ozair Naqvi, Aaron M. Wendelboe, Richard Leman, Joshua L. Clayton, Bree Barbeau, Samantha K. Rice, Victoria Warren-Mears, Abigail Echo-Hawk, Andria Apostolou, Michael Landen
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

American Indian/Alaska Native (AI/AN) persons experienced disproportionate mortality during the 2009 influenza A(H1N1) pandemic (1,2).Concerns of a similar trend during the coronavirus disease 2019 (COVID-19) pandemic led to the formation of a workgroup* to assess the prevalence of COVID-19 deaths in the AI/AN population.As of December 2, 2020, CDC has reported 2,689 COVID-19associated deaths among non-Hispanic AI/AN persons in the United States.† A recent analysis found that the cumulative incidence of laboratory-confirmed COVID-19 cases among AI/AN persons was 3.5 times that among White persons (3).Among 14 participating states, the age-adjusted AI/AN COVID-19 mortality rate (55.8 deaths per 100,000; 95% confidence interval [CI] = 52.5-59.3)was 1.8 (95% CI = 1.7-2.0)times that among White persons (30.3 deaths per 100,000; 95% CI = 29.9-30.7).Although COVID-19 mortality rates increased with age among both AI/AN and White persons, the disparity was largest among those aged 20-49 years.Among persons aged 20-29 years, 30-39 years, and 40-49 years, the COVID-19 mortality rates among AI/AN were 10.5, 11.6, and 8.2 times, respectively, those among White persons.Evidence that AI/AN communities might be at increased risk for COVID-19 illness and death demonstrates the importance of documenting and understanding the reasons for these disparities while developing collaborative approaches with federal, state, municipal, and tribal agencies to minimize the impact of COVID-19 on AI/AN communities.Together, public health partners can plan for medical countermeasures and prevention activities for AI/AN communities.During July 22-September 3, 2020, data were collected on confirmed COVID-19-associated deaths that occurred during January 1-June 30, 2020, from 14 participating states.§ These states represent approximately 46.5% of the AI/AN population
SWK-07. A MULTINATIONAL SURVEY OF PAEDIATRIC NEURO-ONCOLOGY SERVICES: A EUROPEAN RESEARCH NETWORK (ERN) PAEDCAN PROJECT
Authors: Katherine Cooper, Barry Pizer, Steven Lane, Stefan Rutkowski
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Brain tumours are clinically and biologically highly diverse and account for 25% of paediatric neoplasms. They carry the highest mortality and morbidity of tumour groups. Their management presents significant challenges with performing modern diagnostic assessments, applying multimodal treatment and establishing interdisciplinary cooperation. Outcomes across Europe differ significantly with varying 5year survival reports of 42–79%. This SIOP-Europe PaedCan survey assessed the structures and facilities for individual states and highlight areas for cooperation and support. DESIGN: An online questionnaire was sent to SIOP-Europe Brain Tumour Group members. This had 55 questions assessing pathology, staging, surgery, radiotherapy and paediatric oncology infrastructure. For analysis of the data we divided countries into lower and higher economic status according to GDP (World Bank 2019) with a cut off of $30,100. RESULTS There were 388 respondents from 44 countries in 181 different institutions. In the lower GDP group we noted decreased access to biological characterisation of tumours and interdisciplinary tumour boards. In this group of nations, patients were less likely to have treatment by a paediatric specialist neurosurgeon, paediatric neuro-oncologist, neuroradiologist, and paediatric radiation oncologist. There was also less availability to perform early MRI (ventilated) and less access to proton beam therapy. This study supports the aim of the ERN to produce a roadmap document with specific standards and publish guidelines for all relevant diagnostic and therapeutic components of care. The ERN also aims to identify a network of institutions to provide patient advice and training to equalise treatment and outcomes for all children across Europe.