tbuckley/cabot-search huggingface dataset:
The Promoter-Associated Noncoding RNA <i>pncCCND1_B</i> Assembles a Protein–RNA Complex to Regulate Cyclin D1 Transcription in Ewing Sarcoma
Authors: Ramona Palombo, Paola Frisone, Marco Fidaleo, Neri Mercatelli, Claudio Sette, Maria Paola Paronetto
Journal: Cancer Research (2019)

Most Ewing sarcomas are characterized by the in-frame chromosomal translocation t(11;22) generating the EWS-FLI1 oncogene. EWS-FLI1 protein interacts with the RNA helicase DHX9 and affects transcription and processing of genes involved in neoplastic transformation, including CCND1 (the cyclin D1 gene), which contributes to cell-cycle dysregulation in cancer. In this study, we found that CCND1 expression is significantly higher in patients with Ewing sarcoma compared with other sarcomas and that the pncCCND1_B RNA, a previously uncharacterized CCND1 promoter-associated noncoding (pnc) transcript, is expressed in Ewing sarcoma cells. PncCCND1_B interacted with the RNA-binding protein Sam68 and repressed CCND1 expression. Notably, knockdown of Sam68 affected pncCCND1_B subcellular localization and cyclin D1 expression. Pharmacologic impairment of DHX9/EWS-FLI1 interaction promoted RNA-dependent association of Sam68 with DHX9 and recruitment of Sam68 to the CCND1 promoter, thus repressing it. Conversely, mitogenic stimulation of Ewing sarcoma cells with IGF1 impaired Sam68/DHX9 interaction and positively regulated CCND1 expression. These studies uncover a fine-tuned modulation of the proto-oncogene CCND1 in Ewing sarcoma cells via alternative complexes formed by DHX9 with either EWS-FLI1 or pncCCND1_B-Sam68. SIGNIFICANCE: A pncRNA-based mechanism represses expression of CCND1 through the formation of a protein-RNA complex and provides new therapeutic opportunities for patients with Ewing sarcoma.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/14/3570/F1.large.jpg.
Observation doesn’t mean we can’t improve patient care
Authors: Hannah Tobiss
Journal: BMJ (2014)

Have you ever been in a clinic or on a ward round and found yourself thinking, “If I were that patient, I would have no idea what this doctor is talking about”? Or sometimes you might think: “If I have no idea what the doctor is talking about, how on earth is the patient expected to understand?” I have found myself in this situation several times, and it often crops up in conversation with other medical students.

In these circumstances, there is not a lot that I can do to help patients. Sometimes if the doctor leaves the room and I think I have understood the situation correctly, I will try to give them more information. But, more often than not, these types of consultation end unsatisfactorily, with patients politely accepting an explanation they are not …
Abstract B58: The effect of differential miRNA expression in glioblastoma multiforme molecular subtypes
Authors: Livia Ferreira Silva Verzola, Thiago Vidotto, Jeremy Andrew Squire
Journal: Clinical Cancer Research (2018)

Abstract Glioblastoma multiforme (GBM) is characterized by a distinct profile of specific miRNAs that regulate pathways of therapeutic importance, such as cell proliferation, apoptosis, cell cycle regulation, migration, invasion, and angiogenesis. Recently, the molecular classification of gliomas was updated, and three methylation clusters with distinct prognostic values for GBM were characterized. The aim of this research is to evaluate the expression, the functional roles, and the target genes of the miRNAs that have potential value for diagnosis, prognosis, and treatment in patients within the newest molecular subgroup classification of GBM. First, we performed an in silico analysis 606 GBM samples from the Genome Data Commons (GDC) cohort. Based on the methylation subgroups of gliomas recently published (Cecarelli et al., 2016), we performed a comparison of the miRNA expression between LGm4, LGm5, and LGm6 subgroups through Nexus Expression 3.0 (Biodiscovery). The comparison between LGm4 x LGm6 indicated that eight miRNAs were upregulated, while 17 were downregulated. The LGm5 x LGm4 comparison showed two downregulated miRNAs, and the LGm5 x LGm6 comparison showed one upregulated miRNA. By comparing the differentially expressed miRNAs found in our analysis with two other in silico studies, we found an overlap of 54% of the differentially expressed miRNAs. We will now evaluate the expression levels of the upregulated miRNAs obtained through the in silico analysis of samples of the Hospital of Clinics - Faculty of Medicine of Ribeirão Preto (HCFMRP/USP) through a customized nCounter NanoString panel of 24 miRNA. We will also evaluate the plasma exosomal miRNAs from the same patients using the same 24 miRNA nCounter NanoString panel. By identifying the most significant miRNAs regulating cell proliferation and invasive behavior in this tumor, we will be able to use expression levels of the most informative miRNA to both guide the molecular diagnosis of GBM and facilitate future targeted therapeutics for this aggressive disease. Citation Format: Livia Ferreira Silva Verzola, Thiago Vidotto, Jeremy Andrew Squire. The effect of differential miRNA expression in glioblastoma multiforme molecular subtypes [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B58.
How to conduct a newborn examination
Authors: Emma Parish, Rakesh Tailor, Rashmi Gandhi
Journal: BMJ (2018)

emma.parish2@nhs.net The procedure, what to look for, and how to assess your findings A neonatal examination can help to identify any health problems that haven’t been evident during pregnancy. It can also reassure parents about any concerns that they have after the birth, and provide an opportunity to share health promotion advice with them. The examination is most commonly performed by paediatricians, general practitioners (GPs), or midwives. It might also form the basis of a clinical objective structured clinical examination (OSCE) or a work place assessment during paediatric rotations. On any paediatric placement, you should familiarise yourself with the components of the examination by observing and performing it under supervision. Here we provide a guide on how to perform the examination and some of the common findings it might reveal. Ideally, the first examination should take place 24-72 hours after birth. This allows time for the neonate to adapt physiologically from fetal to neonatal life, increasing the chances of detecting any abnormalities.1 A follow-up examination should be conducted at around 6-8 weeks, usually by the child’s GP. ### Review notes and relevant history #### Maternal notes
Abstract P3-09-06: CXCL1 chemokine stimulates migration and invasion in ER-negative breast cancer through activation of the ERK/MMP-2/9 signaling axis
Authors: S Liu, C Yang, S Guo, R Chen
Journal: Cancer Research (2019)

Abstract Chemokine (C-X-C motif) ligand 1 (CXCL1), a member of the CXC chemokine family, has been reported to be a critical factor in inflammatory diseases and tumor progression. However, its functions and molecular mechanism in estrogen receptor α (ER) negative breast cancer (BC) has little been known. In this study, we discovered that CXCL1 is overexpression in ER-negative breast cancer tissues and cell lines compared with ER-positive patient tissues and cell lines. Treatment with recombinant human CXCL1 protein promotes ER-negative BC cell migration and invasion in dose-dependent manner and stimulates the activation of p-ERK1/2, but not p-STAT3 or p-AKT. Whereas, knockdown of CXCL1 in BC cells attenuates these effects. Moreover, CXCL1 induces the expression of MMP2/9 via ERK1/2 pathway. The blockage of ERK by its antagonists (U0126) can abolish the effect of CXCL1 on MMP2/9 expression. Furthermore, immunohistochemical (IHC) analysis revealsa strong positive correlation between CXCL1 and p-ERK1/2 expressions in BC tissues. In conclusion, our study illustrates that CXCL1 is highly expressed in ER-negative BC and stimulates cell migration and invasion through ERK/MMP2/9 pathway, which may serve as a potential therapeutictarget in ER-negative breast cancer. Citation Format: Liu S, Yang C, Guo S, Chen R. CXCL1 chemokine stimulates migration and invasion in ER-negative breast cancer through activation of the ERK/MMP-2/9 signaling axis [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 P3-09-06.
Abstract ES10-2: Mining noncoding mutations for drivers of development in ER alpha-positive breast cancer
Authors: M Lupien
Journal: Cancer Research (2019)

Abstract Large-scale analysis of whole genome sequencing of breast tumors has identified thousands of genetic alterations, such as single-nucleotide variants (SNVs), outside of gene coding sequences. Delineating the functional impact of these noncoding SNVs is challenging, limiting their inclusion in precision genomics medicine pipelines. Pan-cancer attempts to detect evidence for positive selection within individual CREs identified promoters of a limited number of genes such as TERT. By considering the enrichment of noncoding mutations in cistromes as opposed to individual CREs, we identify the enrichment of noncoding SNVs in cistromes of breast cancer driver transcription factors, including FOXA1. This parallels enrichment of breast cancer genetic predispositions over these transcription factor cistromes. Furthermore, somatic SNVs accumulate in the regulatory plexus of some of these driver transcription factors providing evidence for a multi-targeted approach to disrupt their activity in breast cancer. In conclusion, our results support a functional impact of somatic SNVs converging on the cistrome of driver transcription factors in breast cancer. Altogether, we show how to interrogate noncoding SNVs to delineate the oncogenic determinants of breast cancer to be considered for therapeutic intervention. Citation Format: Lupien M. Mining noncoding mutations for drivers of development in ER alpha-positive breast cancer [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 ES10-2.
Consideration of breast cancer subtype in targeting the androgen receptor
Authors: Clasina M. Venema, Rico D. Bense, Tessa G. Steenbruggen, Hilde H. Nienhuis, Si-Qi Qiu, Michel van Kruchten, Myles Brown, Rulla M. Tamimi, Geke A.P. Hospers, Carolina P. Schröder, Rudolf S.N. Fehrmann, Elisabeth G.E. de Vries
Journal: Pharmacology & Therapeutics (2019)

The androgen receptor (AR) is a drug target in breast cancer, and AR-targeted therapies have induced tumor responses in breast cancer patients. In this review, we summarized the role of AR in breast cancer based on preclinical and clinical data. Response to AR-targeted therapies in unselected breast cancer populations is relatively low. Preclinical and clinical data show that AR antagonists might have a role in estrogen receptor (ER)-negative/AR-positive tumors. The prognostic value of AR for patients remains uncertain due to the use of various antibodies and cut-off values for immunohistochemical assessment. To get more insight into the role of AR in breast cancer, we additionally performed a retrospective pooled analysis to determine the prognostic value of the AR using mRNA profiles of 7270 primary breast tumors. Our analysis shows that a higher AR mRNA level is associated with improved disease outcome in patients with ER-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, but with worse disease outcome in HER2-positive subgroups. In conclusion, next to AR expression, incorporation of additional tumor characteristics will potentially make AR targeting a more valuable therapeutic strategy in breast cancer.
Optical Pacing of Human‐Induced Pluripotent Stem Cell‐Derived Cardiomyocytes Mediated by a Conjugated Polymer Interface
Authors: Francesco Lodola, Vito Vurro, Silvia Crasto, Elisa Di Pasquale, Guglielmo Lanzani
Journal: Advanced Healthcare Materials (2019)

The use of light for triggering skeletal and cardiac muscles allows lower invasiveness higher selectivity and unprecedented possibility to target individual cells or even subcellular compartments in a temporally and spatially precise manner. Because cells are in general transparent, this requires the development of suitable interfaces that bestow light sensitivity to living matter. In the present work, successfully demonstrated is the use of conjugated polymer films as transducer to optically enhance the contraction rate of a human and patient-specific cardiac in vitro cell model. By different experimental approaches, the coupling mechanism to the photothermal effect is assigned. This work extends the range of application of the polymer-mediated cell photostimulation phenomenon to cardiac muscle cells, opening up possible applications in cardiac therapy and for implementation of in vitro studies.
Omental patch for closure of a cecal perforation during endoscopic resection of a laterally spreading tumor
Authors: Piera Alessia Galtieri, Francesco Auriemma, Roberta Maselli, Alessandro Fugazza, Benedetto Mangiavillano, Paul James Belletrutti, Alessandro Repici
Journal: Endoscopy (2019)

We present the case of a 65-year-old man with long-standing ulcerative colitis referred to the Digestive Endoscopy Unit of Humanitas Research Hospital (Milan, Italy) to undergo endoscopic removal of a 45-mm granular laterally spreading tumor of the cecum ([Fig. 1]) [1].
Increased PSMA Expression in Castration-Resistant Prostate Cancer Metastases 3 Months After Initiation of Enzalutamide Indicated by 18F-DCFPyL PET/CT
Authors: Maurits Wondergem, Friso van der Zant, Wouter Broos, Remco Knol
Journal: Clinical Nuclear Medicine (2019)

Abstract Radioisotope-labeled prostate-specific membrane antigen PET/CT is increasingly used for detection of prostate cancer most often in the setting of biochemical recurrence or in primary staging. This report shows increased PSMA expression in lymph node metastases 3 months after initiation of enzalutamide for castration-resistant prostate cancer, whereas lymph node volume and serum prostate-specific antigen decreases over time. This case demonstrates that increasing 18 F-DCFPyL uptake after initiation of androgen deprivation therapy should not be confused with disease progression.
Some things never change
Authors: Isobel Weinberg
Journal: BMJ (2012)

Medical students consider themselves special. We like to think that we are set apart from other students by our onerous course and the responsibilities that lie ahead. Has becoming a doctor always been like this? In his feature, Toby Pitts-Tucker takes a look at the history of medical education (p 12), starting with students who learnt from Hippocrates in ancient Greece, and progressing through to the medieval universities—in which students endured three hour lectures. 

Much has changed since then, starting with the curriculum. Medical students in ancient …
A Neural Circuit Encoding the Experience of Copulation in Female Drosophila
Authors: Lisha Shao, Phuong Chung, Allan Wong, Igor Siwanowicz, Clement F. Kent, Xi Long, Ulrike Heberlein
Journal: Neuron (2019)

Female behavior changes profoundly after mating. In Drosophila, the mechanisms underlying the long-term changes led by seminal products have been extensively studied. However, the effect of the sensory component of copulation on the female's internal state and behavior remains elusive. We pursued this question by dissociating the effect of coital sensory inputs from those of male ejaculate. We found that the sensory inputs of copulation cause a reduction of post-coital receptivity in females, referred to as the "copulation effect." We identified three layers of a neural circuit underlying this phenomenon. Abdominal neurons expressing the mechanosensory channel Piezo convey the signal of copulation to female-specific ascending neurons, LSANs, in the ventral nerve cord. LSANs relay this information to neurons expressing myoinhibitory peptides in the brain. We hereby provide a neural mechanism by which the experience of copulation facilitates females encoding their mating status, thus adjusting behavior to optimize reproduction.
A 53 year old man with blurred vision
Authors: Nicholas Cai-Zhi Chua, Simon Whittingham-Jones, Karl Metcalfe
Journal: BMJ (2012)

A 53 year old man presented to the emergency department complaining of a two week history of blurry vision, particularly while reading the newspaper and television text. He felt well and denied associated headaches, limb weakness, or slurred speech. His medical history was uneventful and he was not currently taking medication.

On examination his respiratory rate was 14 breaths per minute, oxygen saturation was 100% on room air, and vesicular breath sounds on chest auscultation. He had a regular pulse of 80 beats per minute, a hyperdynamic apex beat on palpation, and normal heart sounds were auscultated. The average of several repeated blood pressure measurements were 271/179 mm Hg in the left arm, and 265/183 mm Hg in the right. Electrocardiography showed a combined S wave in lead V1 and R wave in lead V6 of >35 mm, suggestive of left ventricular hypertrophy on voltage criteria. His abdomen was soft, non-tender, and his body mass index measured 30.

Visual acuity (pinhole corrected) was 6/36 in the left eye and 6/18 in the right eye. There was a full range of …
Abstract P3-03-15: Patient reported outcomes in women undergoing sentinel lymph node biopsy in the SUNrISE randomized trial evaluating different doses of superparamagnetic iron oxide
Authors: IT Rubio, A Esgueva, M Espinosa-Bravo, R Rodriguez-Revuelto, C Siso, J Rivero
Journal: Cancer Research (2019)

Abstract Background. Sentinel lymph node biopsy (SLNB) with 2 mL of superparamagnetic iron oxide (SPIO) tracer has shown to be non-inferior to the standard radioisotope technique in several studies. The SUNrISE randomized trial has shown non inferiority of 1mL vs. 1.5 mL vs. 2 mL dose of SPIO with the standard use of radioisotope 99m Tc. We present patient reported outcomes from this randomized trial. Material and methods. Patients with stage I breast cancer who underwent breast conservative surgery and sentinel lymph node biopsy were assigned consecutively (1:1:1) to one of the three groups defined by the different SPIO dose, group 1 (1mL), group 2 (1.5 mL) and group 3 (2 mL). Patients filled a questionnaire related to the presence of skin staining, staining intensity ( mild, moderate, intense) and whether the stain worried them. Patient also completed a quality of life (QoL) EORTC C30 questionnaire at 1 month postoperative visit, at 6 months and at 12 months. First analysis from the 1 month postoperative outcomes are reported here. Follow up on the 6 months will be available for the meeting. Results. One hundred and thirty five patients were included in the trial, 45 in each group. Median age in group 1 was 58 years old, 63 y/o in group 2 and 65 y/o in group 3. (p=0.03) At 1 month follow up, patients in group 1 had less skin tattoo when compared with patients in group 2 and 3 (p= 0.02). There were no significant differences related to skin staining intensity by doses. Seventy percent of patients felt no concern about the tattoo. On the multivariate analysis including age, SPIO dose, body mass index and breast density, only younger age (p = 0.037), and higher SPIO doses (p= 0.029) were significantly associated with increased skin staining. There were no statistically significant differences in responses in the QoL questionnaire at 1 month postoperative visit. There were no severe reactions to the procedure or complications in any patient. Conclusions. SLN with 1mL dose of SPIO has shown non-inferiority in the detection of SLN when compared to 1.5 and 2 mL. Being young and the use of 1.5 and 2 mL increased the risk of developing skin staining. Even though, most of the patients were not concern about the skin staining. Rates of discontinuation of skin discoloration will be assessed at 6 months follow up. Citation Format: Rubio IT, Esgueva A, Espinosa-Bravo M, Rodriguez-Revuelto R, Siso C, Rivero J. Patient reported outcomes in women undergoing sentinel lymph node biopsy in the SUNrISE randomized trial evaluating different doses of superparamagnetic iron oxide [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 P3-03-15.
Proteasomal Degradation of Enhancer of Zeste Homologue 2 in Cholangiocytes Promotes Biliary Fibrosis
Authors: Nidhi Jalan‐Sakrikar, Thiago M. De Assuncao, Guang Shi, Sayed Obaidullah Aseem, Cheng Chi, Vijay H. Shah, Robert C. Huebert
Journal: Hepatology (2019)

During biliary disease, cholangiocytes become activated by various pathological stimuli, including transforming growth factor β (TGF‐β). The result is an epigenetically regulated transcriptional program leading to a pro‐fibrogenic microenvironment, activation of hepatic stellate cells (HSCs), and progression of biliary fibrosis. This study evaluated how TGF‐β signaling intersects with epigenetic machinery in cholangiocytes to support fibrogenic gene transcription. We performed RNA sequencing in cholangiocytes with or without TGF‐β. Ingenuity pathway analysis identified “HSC Activation” as the highly up‐regulated pathway, including overexpression of fibronectin 1 (FN), connective tissue growth factor, and other genes. Bioinformatics identified enhancer of zeste homologue 2 (EZH2) as an epigenetic regulator of the cholangiocyte TGF‐β response. EZH2 overexpression suppressed TGF‐β‐induced FN protein in vitro , suggesting FN as a direct target of EZH2‐based repression. Chromatin immunoprecipitation assays identified an FN promoter element in which EZH2‐mediated tri‐methylation of lysine 27 on histone 3 is diminished by TGF‐β. TGF‐β also caused a 50% reduction in EZH2 protein levels. Proteasome inhibition rescued EZH2 protein and led to reduced FN production. Immunoprecipitation followed by mass spectrometry identified ubiquitin protein ligase E3 component N‐recognin 4 in complex with EZH2, which was validated by western blotting in vitro . Ubiquitin mutation studies suggested K63‐based ubiquitin linkage and chain elongation on EZH2 in response to TGF‐β. A deletion mutant of EZH2, lacking its N‐terminal domain, abrogates both TGF‐β‐stimulated EZH2 degradation and FN release. In vivo , cholangiocyte‐selective knockout of EZH2 exacerbates bile duct ligation–induced fibrosis whereas MDR2 ‐/‐ mice are protected from fibrosis by the proteasome inhibitor bortezomib. Conclusion: TGF‐β regulates proteasomal degradation of EZH2 through N‐terminal, K63‐linked ubiquitination in cholangiocytes and activates transcription of a fibrogenic gene program that supports biliary fibrosis.
Abstract P5-13-01: Not presented
Authors: M Foerster, A Zietsman, M Galakunde, A Anele, C Adisa, J Schuz, I Dos Santos Silva, V McCormack
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Foerster M, Zietsman A, Galakunde M, Anele A, Adisa C, Schuz J, Dos Santos Silva I, McCormack V. Not presented [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 P5-13-01.