tbuckley/cabot-search huggingface dataset:
Disease characteristics and treatment outcomes of young colorectal cancer patients.
Authors: Hiral D. Parekh, Yu Wang, Wissam Hanayneh, Miles Cameron, Sanda Tan, Atif Iqbal, Thomas Read, Carmen Joseph Allegra, Thomas J. George
Journal: Journal of Clinical Oncology (2019)

691 Background: The incidence of colorectal cancer (CRC) in young patients (&lt; 50 years) is increasing but little is known about disease characteristics and treatment outcomes in this patient population. Methods: CRC patients diagnosed at &lt; 50 years of age (UF institutional registry 2000-2017) constituted the IRB approved study cohort. Statistical methods included descriptive statistics, uni-variable cox proportional hazard regression model, Pearson chi-square exact and Wilcoxon rank-sum test. Results: The median age at diagnosis was 45 years (range 17-50, n = 286) with 212 (74%) diagnosed between age 40-50. One third (35.7%) of patients had rectal primary and most common histology was adenocarcinoma (ACa, 84.6%) and 20% of those had poorly differentiated tumor. More than half of patients had an advanced primary (T3/T4, 65%) and 44% had lymph node positive disease. A trend towards increased delivery of perioperative therapy was seen in early staged disease. (See table) Patients who underwent curative resections had better hemoglobin (p = 0.005) and albumin levels (Alb, p &lt; 0.001) and lower CEA level (p &lt; 0.001). Factors associated poor survival were low alb levels ≤ 34 g/l, advanced primary tumor (T3/T4), nodal disease (N1/N2) and presence of diffuse metastasis. For stage 4 disease, the cancer-specific survival (CSS) at 1 year was 77.2%, 3-year CSS was 46.1% and 5-year CSS was 29%; survival was better (HR = 0.4; 95% CI 0.2-0.6, p &lt; 0.001) among patients who underwent metastatectomy. Conclusions: Our data suggests that younger CRC patients were more likely to be managed in an aggressive manner with a higher proportion of early stage patients receiving perioperative therapy. A suggestion of an improved CSS was seen in advanced stage disease even with similar prognostic factors. Review of larger datasets are warranted. [Table: see text]
Access to emergency departments for acute events and identification of sickle cell disease in refugees
Authors: Lucia De Franceschi, Caterina Lux, Frédéric B. Piel, Barbara Gianesin, Federico Bonetti, Maddalena Casale, Giovanna Graziadei, Roberto Lisi, Valeria Pinto, Maria Caterina Putti, Paolo Rigano, Rossellina Rosso, Giovanna Russo, Vincenzo Spadola, Claudio Pulvirenti, Monica Rizzi, Filippo Mazzi, Giovanbattista Ruffo, Gian Luca Forni
Journal: Blood (2019)
Abstract 19924: Circulating Factors in Stable Human HFpEF Induces “Beiging” of White Adipose Tissue In Vitro
Authors: Maria Valero-Munoz, Richard M Wilson, Flora Sam
Journal: Circulation (2016)

Background: Despite the increasing prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) in humans, there are no evidence-based therapies for HFpEF. Clinical studies indicate a relationship between obesity-associated dysfunctional white adipose tissue (AT) and HFpEF. We recently showed that HFpEF is associated with “beiging” in white AT, in hypertension-induced and TAC-induced HFpEF in lean mice. We now seek to investigate the translational implications of these findings. Methods: Sera were collected from chronic, stable HFpEF patients from an ambulatory HF clinic. Patients with HFpEF were enrolled if they were previously admitted with a HFpEF exacerbation within the prior year and had a LVEF >50% within 6 months prior to enrollment. Control samples were obtained from healthy subjects without HF or known cardiac disease. Sera were used to treat visceral adipose tissue samples obtained from wild-type mice and cultured in DMEM medium for various time points (30 min, 6h and 24h). Tissue s...
GARFIELD classifies disease-relevant genomic features through integration of functional annotations with association signals
Authors: Valentina Iotchkova, Graham R. S. Ritchie, Matthias Geihs, Sandro Morganella, Josine L. Min, Klaudia Walter, Nicholas John Timpson, Ian Dunham, Ewan Birney, Nicole Soranzo
Journal: Nature Genetics (2019)
CD276-positive circulating endothelial cells in advanced colorectal cancer.
Authors: Elske C. Gootjes, Jaco Kraan, Tineke Buffart, Cornelis Verhoef, Henk M.W. Verheul, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2019)

572 Background: The value of circulating endothelial cells (CECs) as predictive biomarker in metastatic colorectal cancer (mCRC) may be improved by using tumor-derived CECs. CD276 can discriminate between tumor derived and normal CECs. We evaluated whether CD276+CEC is a clinically relevant biomarker with 100% sensitivity to predict response to first line palliative combination systemic therapy with fluoropyrimidine and oxaliplatin in patients with mCRC. Methods: Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial. At baseline and at first evaluation (after 4 cycles of 5-FU/LV or 3 cycles capecitabine with oxaliplatin ± bevacizumab), CECs were measured by flowcytometry with a previously validated panel (CD34+CD45-CD146+DNA+; and additional CD276+ for tumor derived CECs). A clinically relevant cut-off value of (CD276+) CECs was determined as 100% sensitivity (and 80% specificity in 95% CI) identifying patients with progressive disease within 6 months. Results: There were 182 baseline samples, from which 133 follow up samples were available for analysis. CEC and CD276+CEC counts significantly increased during treatment from 48 to 90 CEC/4 ml (p = 0.00) and from 14 to 33 CD276+CEC/4 ml (p = 0.00) at baseline and at first evaluation, respectively. In patients treated with bevacizumab, CEC counts were lower after three cycles compared to patients treated with chemotherapy alone 75.5 vs 131 CEC/4ml (p = 0.04), 28 vs 41 CD276+CEC/4 ml (p = 0.08). Baseline values nor changes in CEC and CD276+CEC counts were predictive for poor response (progressive disease within 6 months, AUC 0.53 for CEC and AUC 0.52 for CD276+CEC). Conclusions: Despite numerical changes during therapy, CEC and CD276+CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC. (NCT01792934.)
Genomic profile of gastric cancer in the United States versus East Asia.
Authors: Gregory A. Gilmore, Mohamad Barakat, Uzair Bashir Chaudhary, Jeffrey P. Gregg, Amir Fathi
Journal: Journal of Clinical Oncology (2019)

45 Background: Gastric cancer is the fourth most common cancer type and is the third leading cause of cancer deaths worldwide. Much heterogenicity exists in gastric cancer including geographic variation, with significantly higher incidence in Eastern Asia and a well-known but poorly understood relationship with Asian ethnicity. It has thus been hypothesized that differences in incidence and survival between United States and Asia may be related to a difference in the underlying tumor biology. Methods: We sought to compare the mutational frequencies by comparison of proportions of the 25 most frequent mutations between a US and Chinese population. The US population was derived from The Cancer Genome Atlas (TCGA) PanCancer Atlas comprising 440 patients and the Chinese from a University of Hong Kong Study comprising 100 patients. Results: We found there was a statistically significant difference (P ≤ 0.05) in the frequency of recurrent mutations between US and China population in 14 of the 25 most common genes mutations (table). Conclusions: This data suggests an underlying difference in the mutational profile of gastric cancers in the US as compared with Asia. These findings thus may help to describe the differences in incidence, histology, and outcomes that has been well described in the literature between these two regions of the world. [Table: see text]
Abstract P2-06-16: New targets in triple negative breast cancer: Role of Oncostatin M receptor pathway
Authors: I Alvarez, A Araujo, A Abaurrea, R Rezola, A Urruticoechea, C Lawrie, MM Caffarel
Journal: Cancer Research (2019)

Abstract BACKGROUND:Triple negative breast cancer (TNBC) has poor prognosis, lack of targeted therapies and are often refractory to conventional chemotherapy treatments. Therefore, finding new therapeutic targets for those tumours is an unmet need with high clinical impact. In this context, Oncostatin M receptor (OSMR) is a promising therapeutic target as it is over-expressed in this tumour subtype and its activation promotes invasiveness (Guo L, et al. 2013 Oncogene; West NR, et al.2014 Oncogene). We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis (Caffarel MM, et al 2013 Journal of Pathology; Caffarel MM, et al 2014 Journal of Pathology; Kucia-Tran JA, et al. 2016 Brit J Cancer; Kucia-Tran JA, et al 2018 Journal of Pathology). We now investigate the role of OSMR in breast cancer progression. METHODS: To address this issue we use a wide array of tools including in vitro cell cultures and in vivo models. The expression of OSMR pathway was analysed in FFPE samples and large datasets of publicly available breast cancer samples (METABRIC, n=1462; and TCGA, n=547). RESULTS: OSMR and its ligand Oncostatin M (OSM) are over-expressed in basal tumours, where they associate with shorter overall survival (p=0.015). While OSMR is expressed by breast cancer cells and cancer associated fibroblasts, the main source of OSM seems to be primarily macrophages. OSM treatment of breast cancer cells induces the expression of important mediators of angiogenesis and invasion. Importantly, OSMR activation accelerates tumour onset, tumour growth and metastasis in orthotopic xenografts in nude mice. CONCLUSIONS: Our results support that OSMR pathway may have an important role in the initiation and progression of breast cancer and that it could be a promising candidate for therapeutic targeting in TNBC. OSMR could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer. Citation Format: Alvarez I, Araujo A, Abaurrea A, Rezola R, Urruticoechea A, Lawrie C, Caffarel MM. New targets in triple negative breast cancer: Role of Oncostatin M receptor pathway [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-16.
DNA Damage Response/TP53 Pathway Is Activated and Contributes to the Pathogenesis of Dilated Cardiomyopathy Associated With LMNA (Lamin A/C) Mutations
Authors: Suet Nee Chen, Raffaella Lombardi, Jennifer Karmouch, Ju-Yun Tsai, Grace Czernuszewicz, Matthew R.G. Taylor, Luisa Mestroni, Cristian Coarfa, Priyatansh Gurha, Ali J. Marian
Journal: Circulation Research (2019)

Rationale: Mutations in the LMNA gene, encoding LMNA (lamin A/C), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies. Objective: To gain insights into the molecular pathogenesis of DCM in laminopathies. Methods and Results: We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes. LMNA D300N mutation is associated with DCM in progeroid syndromes. Expression of LMNA D300N led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. Administration of doxycycline suppressed LMNA D300N expression and prevented the phenotype. Whole-heart RNA sequencing in 2-week-old WT and LMNA D300N mice led to identification of ≈6000 differentially expressed genes. Gene Set Enrichment and Hallmark Pathway analyses predicted activation of E2F (E2F transcription factor), DNA damage response, TP53 (tumor protein 53), NFκB (nuclear factor κB), and TGFβ (transforming growth factor-β) pathways, which were validated by Western blotting, quantitative polymerase chain reaction of selected targets, and immunofluorescence staining. Differentially expressed genes involved cell death, cell cycle regulation, inflammation, and epithelial-mesenchymal differentiation. RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart. Increased expression of CDKN2A (cyclin-dependent kinase inhibitor 2A)—a downstream target of E2F pathway and an activator of TP53—provided a plausible mechanism for activation of the TP53 pathway. To determine pathogenic role of TP53 pathway in DCM, Tp53 gene was conditionally deleted in cardiac myocytes in mice expressing the LMNA D300N protein. Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival. Conclusions: Cardiac myocyte-specific expression of LMNA D300N , associated with DCM, led to pathogenic activation of the E2F/DNA damage response/TP53 pathway in the heart and induction of myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. The findings denote the E2F/DNA damage response/TP53 axis as a responsible mechanism for DCM in laminopathies and as a potential intervention target.
Outcomes following stereotactic body radiotherapy (SBRT) in locally recurrent rectal cancer (LRRC) in a previously irradiated pelvis.
Authors: Thomas Smith, Sean O'Cathail, Yatman Tsang, Mark Harrison, Maria A Hawkins
Journal: Journal of Clinical Oncology (2019)

640 Background: Management of LRRC is challenging. There is no consensus regarding the best approach for patients not suitable for exenteration. Hyperfractionated re-irradiation is associated with &gt; 10% grade 3 toxicity and it is demanding for patients and department. Here we report initial outcomes of an inoperable cohort treated with SBRT. Methods: A prospective nationally maintained database for SBRT re-irradiation was interrogated. Eligibility criteria were pelvic recurrence in a previously irradiated colorectal cancer, not eligible for exenteration, &gt; 6 mo disease free survival, &gt; 6mo from previous RT, ≤ 3 metastases, PS 0-1. SBRT dose of 30Gy in 5 fractions in &lt; 10 days was specified. Every 3 mo toxicity was assessed using the CTCAE v4.0, QoL using the EQ5D, respectively and imaging was undertaken. Median progression free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 28 patients with 33 separate pelvic lesions were treated between Oct 2015-June 2018. The median age was 64 years (range 36-84). 27/28 had received 45-50.4Gy in 25-28F with concurrent Capecitabine, 1/28 received 25Gy/5F, all followed by surgery. Combining SBRT, the cumulated effective dose received was &gt;100Gy 10 . The median GTV volume was 14.9cc (range 0.47-121.73cc). All completed the SBRT. There were minimal symptoms at baseline pain = 7, urinary = 3, GI = 3, nerve = 1. 48% grade 1 or grade 2 acute toxicity was reported at 6 weeks, with 25% grade 1 or grade 2 late toxicity, but no grade 3 toxicities reported with a median follow up of 10 months (range 2-30). There was an 81% local control rate with a median PFS of 12.2 months (95% CI 4.0-20.5) and a 2-year OS of 70.4% (95% CI 49.0-100). 28% (8/28) solely progressed out of field. Conclusions: Acute toxicity is minimal in this cohort of patients with initial excellent local control. Follow-up is continued. SBRT appears effective and convenient for patients who are non-surgical candidates with pelvic recurrence and offers the opportunity for local and symptom control, whilst deferring systemic treatment.
Headache in Multiple Sclerosis
Journal: BMJ (1969)

Introduction Multiple Sclerosis (MS) is a common neurological disease in young adults with variable clinical symptoms and signs. Many of MS patients experience headache. This study was done to evaluate the prevalence of headache in MS patients. Materials and Methods This descriptive cross-sectional study was carried out in MS clinics affiliated to Isfahan university of Medical Sciences in the first six months of 1380. For each patient a questionnaire was filled according to history and examination, and the data was analyzed by SPSS program. Results From 100 patients, 67 had headache and 86.6 of them were women .Tension headache in 47.7 and migraine headache in 34.3 was reported. Of 100 patients, 23 of them had migraine headache, 36 patients had history of headache before the onset of MS, whom in 52.8 severity of headache was increased. Of patients 10.4 had headache at the onset of MS and in 6.8 headache was the first symptom of MS. The neurological signs and symptoms were presented after headache. Conclusion According to this study different types of headaches are common in MS and the migraine type is more common than in general population.
KRAS mutation is associated with upregulation of integrin beta-4 expression leading to tumor invasion in colorectal cancer.
Authors: Seo-Hyun Choi, Michael Marco, Ching-Tung Chen, Raphael Pelossof, Kevin Patrick O'Rourke, Jesse Joshua Smith, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2019)

576 Background: KRAS mutation ( KRAS mut ) is associated with aggressive biological behavior and resistance to chemoradiotherapy in colorectal cancer (CRC). The tumor microenvironment is a critical component framing the biological behavior of cancers. We have recently shown that a KRAS mut modulates the tumor microenvironment by reducing the expression of extracellular matrix (ECM) genes in CRC. The effect of a KRAS mut on integrins, the epithelial cell receptors for ECM proteins, remains largely unknown. Here, we investigated the impact of KRAS mut on integrin expression in CRC and the effect of integrin beta 4 (ITGB4) expression on CRC phenotype. Methods: The genomic profile of 79 locally advanced rectal cancers (LARC) was characterized by the MSK-IMPACT DNA assay and RNA sequencing by Hi-Seq platform. The transcriptomic changes associated with KRAS in the LARC cohort was validated in the TCGA colon cancer dataset. Expression of ITGB4 was investigated by immunofluorescence (IF) in 39 colon cancer specimens by counting ITGB4-positive cells in an E-cadherin positive epithelial population. The relationship between KRAS and ITGB4 was also explored by manipulating KRAS expression in human cell lines and genetically engineered mouse models (GEMMs). ITGB4 knockout in HCT116 CRC cell lines and organoids from GEMMs were generated with CRISPR/Cas9. ITGB4 expression was confirmed using qRT-PCR and western blotting. Cell proliferation was assessed with the MTT assay. Cell invasion and migration were assessed in a trans-well system. Results: ITGB4 gene expression was increased in KRAS mut compared to KRAS wildtype in LARC and TCGA. Increased ITGB4 expression in KRAS mut colon cancers was also validated by IF (p = 0.0029). Introduction of KRAS mut in HCT116 CRCs and GEMMs increased ITGB4 expression by 1.5 to 2 fold. Knockout of ITGB4 reduced the migration and invasion of HCT116 CRC cells but did not alter proliferation. Conclusions: KRAS mut increases the expression of ITGB4 in CRC. Increased ITGB4 expression is associated with CRC cell invasion and migration. These results inform the biology of tumor progression in KRAS mut CRC tumors.
Neuropsychiatric symptoms in Tanzanian HIV-infected children receiving long-term efavirenz treatment: a multicentre, cross-sectional, observational study
Authors: Lisa Van de Wijer, Deborah N Mchaile, Quirijn de Mast, Blandina T Mmbaga, Nanda N J Rommelse, Ashanti Duinmaijer, André J A M van der Ven, Arnt F A Schellekens, Grace D Kinabo
Journal: The Lancet HIV (2019)
Phosphatidylserine-Exposing Extracellular Vesicles after Splenectomy Are Associated with Increased D-Dimers and Fibrin Generation in Hereditary Hemolytic Anemia
Authors: Stephanie Van Straaten, Chi Hau, Najat Hajji, Jill Verhoeven, Roger Schutgens, Wouter van Solinge, Richard van Wijk, Rienk Nieuwland, Eduard J. van Beers
Journal: Blood (2018)
Sex Differences in Type 2 Innate Lymphoid Cells in Adult Asthmatics
Authors: Michael J. Aw, Parameswaran K. Nair, Brittany Salter, Ruchong Chen, Kentaro Machida, Mark D. Inman, Chynna Huang, Melanie Kjarsgaard, Katherine Radford, Paul M. O'Byrne, Gail M. Gauvreau, Roma Sehmi
Journal: Journal of Allergy and Clinical Immunology (2019)
Examining the effects of BET, HDAC2, and EZH2 inhibition on esophageal adenocarcinoma (EAC) cell line proliferation.
Authors: Kleovoulos Kofonikolas, Alex M Frankell, Elizabeth Catherine Smyth, Rebecca C. Fitzgerald
Journal: Journal of Clinical Oncology (2019)

68 Background: EACs often carry amplifications in MYC (19%) and mutations in the SWI/SNF complex (13%) which act as oncogenic drivers. Targeting of MYC-amplified tumors via BET inhibition, as well as HDAC2 or EZH2 inhibition in SWI/SNF-mutated tumors, show promise in hematological cancers, and solid tumors, respectively. Herein, we investigate the effects of BET, HDAC2, and EZH2 inhibition on EAC cell line proliferation. Methods: MYC-wild type (n = 5), MYC-amplified (n = 2), SWI/SNF-wild type (n = 6) and SWI/SNF-mutant (n = 1) EAC cell lines that have undergone whole genome sequencing (WGS) were plated at 10% confluency and treated with BET (JQ1), pan-HDAC (SAHA), and EZH2 (EPZ-6438) inhibitors at various concentrations. The CellTiter-Glo cell proliferation assay was used to compare the effects of drug treatment on proliferation between different cell lines and drug concentrations before and after treatment. Results: MYC-amplified EAC cell lines were more sensitive to BET inhibition (Table); GI50 concentrations for JQ1 are comparable to those achieved in melanoma and lymphoma cell lines, cancer types in which clinical activity has been demonstrated. ERBB2 amplified or ERBB2 mutant EAC cells were also sensitive to BET inhibition. HDAC2 inhibition reduced proliferation of both SWI/SNF-wild type and mutant cell lines at high concentrations, whilst all cell lines were resistant to EZH2 inhibition, even at the highest concentrations used. Conclusions: MYC amplified EAC tumors appear to be sensitive to BET inhibition; these results warrant further evaluation in pre-clinical models and clinical trials. HDAC2 and EZH2 inhibition were ineffective in both the SWI/SNF-wild type and mutant type EAC cell lines; these therapies are less likely to provide benefit for EAC patients. [Table: see text]
Enumeration of IL-17A/F Producing Innate Lymphoid Cells in Subjects with COPD
Authors: Xiaotian Ju, Takeshi Miromoto, Suzzane Beaudin, Brittany Salter, Jennifer Wattie, Karen J. Howie, Paul M. O'Byrne, Gail M. Gauvreau, Roma Sehmi
Journal: Journal of Allergy and Clinical Immunology (2019)
Chronic Lymphocytic Leukemia Patients with IGH Rearrangements Are Characterized By a Distinct Genetic Landscape with Prognostic Implications
Authors: Claudia Pérez Carretero, Maria Hernandez-Sanchez, Teresa Gonzalez, Miguel Quijada Álamo, Marta Martín Izquierdo, Jesus M Hernández-Sánchez, Sandra Santos-Mínguez, María-Jesús Vidal, Alfonso García de Coca, Carlos Aguilar, Manuel Vargas-Pabón, Sara Alonso, Magdalena Sierra, Araceli Rubio-Martínez, Julio Dávila, José R Díaz-Valdés, Jose Antonio Queizan, Jose Angel Hernandez-Rivas, Maria-Victoria Mateos, Rocio Benito, Ana E. Rodriguez, Jesús-María Hernández-Rivas
Journal: Blood (2018)
Considering selection pressures for identity fusion and self-sacrifice in small-scale societies
Authors: Polly Wiessner
Journal: Behavioral and Brain Sciences (2018)

Abstract Whitehouse's view that our ultrasocial species evolved in small, warring bands is questioned, and alternative social selection pressures for the evolution of identity fusion and self-sacrifice in small-scale societies are proposed. Short durations of states of fusion allow for re-evaluation of risks; the consolidation of episodic memories into collective oral traditions elicits cooperation. Dysmorphic memories may be more powerful in generating identity fusion when followed by euphoric ones, as in “rites of torture” in male initiations.