tbuckley/cabot-search huggingface dataset:
Phosphorylation of SOCS1 Inhibits the SOCS1–p53 Tumor Suppressor Axis
Authors: Emmanuelle Saint-Germain, Lian Mignacca, Geneviève Huot, Mariana Acevedo, Karine Moineau-Vallée, Viviane Calabrese, Véronique Bourdeau, Marie-Camille Rowell, Subburaj Ilangumaran, Frédéric Lessard, Gerardo Ferbeyre
Journal: Cancer Research (2019)

Expression of the suppressor of cytokine signaling-1 (SOCS1) is inactivated in hematopoietic and solid cancers by promoter methylation, miRNA-mediated silencing, and mutations. Paradoxically, SOCS1 is also overexpressed in many human cancers. We report here that the ability of SOCS1 to interact with p53 and regulate cellular senescence depends on a structural motif that includes tyrosine (Y)80 in the SH2 domain of SOCS1. Mutations in this motif are found at low frequency in some human cancers, and substitution of Y80 by a phosphomimetic residue inhibits p53-SOCS1 interaction and its functional consequences, including stimulation of p53 transcriptional activity, growth arrest, and cellular senescence. Mass spectrometry confirmed SOCS1 Y80 phosphorylation in cells, and a new mAb was generated to detect its presence in tissues by IHC. A tyrosine kinase library screen identified the SRC family as Y80-SOCS1 kinases. SRC family kinase inhibitors potentiated the SOCS1-p53 pathway and reinforced SOCS1-induced senescence. Samples from human lymphomas that often overexpress SOCS1 also displayed SRC family kinase activation, constitutive phosphorylation of SOCS1 on Y80, and SOCS1 cytoplasmic localization. Collectively, these results reveal a mechanism that inactivates the SOCS1-p53 senescence pathway and suggest that inhibition of SRC family kinases as personalized treatment in patients with lymphomas may be successful. SIGNIFICANCE: These findings show that SOCS1 phosphorylation by the SRC family inhibits its tumor-suppressive activity, indicating that patients with increased SOCS1 phosphorylation may benefit from SRC family kinase inhibitors.
Scrap 10 minute consultations, RCGP urges
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The standard 10 minute GP consultation should be scrapped by 2030 as part of a major shake-up in the delivery of primary care, the Royal College of General Practitioners has advised.

Extending GP consultations to 15 minutes, or longer for those who need it, would provide more appropriate and effective care to patients with increasingly complex needs, the college said. Its recommendations are included in a new report outlining its vision for the future of general practice,1 which sets out how it would like to see care delivered by 2030.

The report drew on feedback from 3000 GPs, other …
Benign High-Flow Priapism With a Diffuse and Intense 18F-FDG Uptake on 18F-FDG PET/CT Scanning
Authors: Zakieh Nasiri, Soroush Zarehparvar Moghadam, Zahra Kiamanesh, Farshad Emami, Ramin Sadeghi
Journal: Clinical Nuclear Medicine (2019)

Abstract We present benign high-flow priapism with intensive 18 F-FDG uptake as an unusual finding in a case of testicular teratocarcinoma with a history of left orchiectomy and chemotherapy. 18 F-FDG PET/CT scan showed pulmonary metastases, left obturator node involvement, and intense 18 F-FDG uptake in the penis. Upon examination, the patient had a painless erection that lasted for couple of days. Because of pulmonary metastases, second-line chemotherapy regimen was started by his physician. The patient's priapism resolved spontaneously, with no episode of recurrence at 2 years' follow-up.
Evaluation of intraoperative frozen section with final histopathology results for sentinel lymph node biopsy in breast cancer
Authors: A. Kr, S. Sp, R. Kumar
Journal: Annals of Oncology (2019)

Background: Intraoperative assessment of sentinel lymph nodes for patients undergoing surgery for early breast cancer has the potential to reduce the need for delayed axillary lymph node dissection (ALND), significantly reducing patient morbidity, expediting adjuvant therapy, reducing length of hospital stay and cost of hospitalisation. This study aims to evaluate intraoperative frozen section in identifying cancerous involvement of sentinel lymph nodes in early breast cancer. Methods: The frozen section and final histopathology reports of 104 consecutive patients undergoing surgery for early breast cancer with sentinel lymph node biopsy between May 2016 and June 2017 were assessed. Results: Intraoperative frozen section has a sensitivity and specificity of 89.7 (75.8–97.1%, p B 0.05) and 100%, respectively, with a negative predictive value of 94.1 (86.3–97.6%, p B 0.05) in identifying metastasis to sentinel node. Conclusions: The sensitivity of frozen section is lowered by its inability to accurately pick up micrometastasis. However, frozen section is highly accurate in picking up macrometastasis with a sensitivity of 100%. Legal entity responsible for the study: Manipal Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
DIAGNOSE AND DISREGARD POLICY CAN BE IMPLEMENTED IN PATIENTS WITH LYNCH SYNDROME WHEN DONE BY EXPERT COLONOSCOPISTS
Authors: A Gavrić, L Rivero Sanchez, C Arnau, J Herrero, D Remedios, V Alvarez, E Albéniz, P Calvo, J Gordillo, I Puig, J López Vicente, A Huerta, M López-Cerón, I Salces, B Peñas, S Parejo, M Herraiz, A Gimeno, E Saperas, C Alvarez, L Moreno, C Rodriguez de Miguel, M Diaz, T Ocaña, L Moreira, M Cuatrecasas, S Carballal, A Sánchez, G Jung, O Ortiz, J Llach, F Balaguer, M Pellisé
Journal: Endoscopy (2019)

To evaluate the adequacy of a “diagnose and disregard” strategy for rectosigmoid (RS) diminutive polyps in Lynch syndrome patients.
EFFECT OF THE NATIONAL SCREENING PROGRAM ON THE COLORECTAL CANCER INCIDENCE AND MORTALITY REDUCTION IN THE CZECH REPUBLIC
Authors: S Suchanek, O Ngo, T Grega, O Majek, M Zavoral
Journal: Endoscopy (2019)

The organized non-population based National Colorectal Cancer (CRC) Screening Program in the Czech Republic has been running since year 2000. In January 2014, the transition to population-based setting has been implemented. The main target lesions of the CRC screening program are the adenomas and early cancers. Therefore, the relation between number of colonoscopies/endoscopic polypectomies and CRC incidence and mortality decrease was evaluated.
THE OUTCOME OF FCSEMS FOR REFRACTORY MPD STRICTURES: A SYSTEMATIC REVIEW AND POOLED ANALYSIS
Authors: A Tringali, E Stasi, M Cintolo, E Forti, L Dioscoridi, F Pugliese, DG Adler, M Mutignani
Journal: Endoscopy (2019)

Pancreatic duct (PD) stent placement is an effective treatment for symptomatic chronic pancreatitis associated with PD stricture. A subset of patients is refractory then the placement of multiple plastic stents has demonstrated a higher clinical success rate. Self-expandable metal stents (SEMSs) have been used with unsatisfactory results because of migration. However, fully covered SEMSs (FC-SEMSs) have not been extensively studied in this clinical context.
West Nile virus infection in individuals with pre-existing Usutu virus immunity, northern Italy, 2018
Authors: Alessandro Sinigaglia, Monia Pacenti, Thomas Martello, Silvana Pagni, Elisa Franchin, Luisa Barzon
Journal: Eurosurveillance (2019)

In 2018, there was a large West Nile virus (WNV) outbreak in northern Italy. We observed five atypical cases of WNV infection that were characterised by the presence of WNV RNA and WNV IgG at the time of diagnosis, but no IgM response during follow-up. Neutralisation assays demonstrated pre-existing Usutu virus immunity in all patients. Besides challenging diagnosis, the immunological crosstalk between the two viruses warrants further investigation on possible cross-protection or infection enhancement effects.
SAKK 21/12: A stratified, multicenter phase II trial of transdermal CR1447 in endocrine responsive-HER2 negative and triple negative-androgen receptor positive metastatic or locally advanced breast cancer
Authors: M.H.F. Vetter, K. Rothgiesser, Q. Li, H. Hawle, W. Schönfeld, K. Ribi, S. Riniker, R. von Moos, A. Müller, B. Thürlimann
Journal: Annals of Oncology (2019)

Background: CR1447 is a novel transdermal formulation of 4-OH-Testosterone with aromatase inhibiting properties and androgen receptor modulation. Phase I data demonstrated efficacy and a favorable toxicity profile. In this trial efficacy and toxicity cohort A (A) with estrogen-receptor positive disease and cohort B (B) with androgen-receptor positive triple negative metastatic breast cancer was investigated. Methods: Based on the phase I data, a dose of 400 mg was topically administered on both thighs every day. Primary endpoint was disease control rate at week 24 (DC24). The goal is to show that disease control at 24 weeks (DC24) of > 30% (A) and >15 % (B). In (A) patients (pts) with a maximum of one line of endocrine therapy for advanced disease (AD) for at least six months without progression were eligible (N = 21). Eight pts were excluded because they did not fulfill these criteria. In (B) up to two prior lines of chemotherapy for AD were allowed. Results: After registration of 37 pts (A)=29 and (B)=8, accrual was stopped after an interim analysis due to futility in (A) and slow accrual in (B). DC24 was reached in 5 out of 21 eligible pts (24%) in (A) and 0% in (B). In (A) eight pat were ineligible due to amendment of inclusion criteria. In (A) median PFS of eligible pts was 5.1 months (m) (95% CI: 2.5-5.6) and 2.6 months (95% CI: 2.1-2.9) in non-eligible pts. In (B) median PFS was 2.5 m (95% CI 0.7-2.6). Median OS of eligible pts in (A) was 24.6 m (95% CI 22.9-NA) and in (B) 10.8 m (95% CI 3.3-10.9). QoL assessed by FACT-ES questionnaire at baseline, week 4 and 24 showed no deterioration under treatment. CR1447 had a favorable safety profile without treatment related grade 3-5 toxicities in stratum A. Most common treatment related toxicities were: hypertriglyceridemia (60%), aspartate aminotransferase increased (51%) and dry skin (46%). Conclusions: CR1447 is an innovative endocrine therapy with a favorable safety profile. Despite not reaching the primary endpoint (DC24 in 30% of patients), the DC24-rate of 24% in the 2nd-line setting and one patient in prolonged PR are a signal of activity. Further evaluation in a truly endocrine sensitive population is warranted. Clinical trial identification: NCT02067741. Legal entity responsible for the study: SAKK Switzerland. Funding: Curadis, Erlangen, Germany. Disclosure: All authors have declared no conflicts of interest.
USE OF ENDOSCOPIC CLASSIFICATIONS AMONGST TRAINEES IN IRELAND
Authors: G Harkin, N McGettigan, M Hussey, C Moran, G Harewood, D Cheriyan, K Boland, A O'Toole, S Patchett
Journal: Endoscopy (2019)

Use of classifications to describe endoscopic findings in a standardised fashion is recommended. Their use is advocated for both upper and lower endoscopy. Incorporating them into routine practice is advised but requires education and initiative.
The clinical impact of substituting multigene assays: Comparative clinical analysis of PAM50-ROR versus 21-gene assay
Authors: C.J. Markopoulos, L. Hochheiser, J. Hornberger, E. Hytopoulos, M.C. Stoppler, M. Gitlin
Journal: Annals of Oncology (2019)

Background: The National Cooperative Cancer Network Guidelines (v3.2018, Oct 2018) state that 21-gene assay (Oncotype DX Breast Recurrence Score®, Genomic Health, Inc.) is the preferred multigene assay (MGA) to predict chemotherapy (CT) benefit for early stage breast cancer (ESBC). We assessed the potential effects of substituting another MGA, PAM50-ROR (Prosigna®, NanoString), for the 21-gene assay on clinical outcomes. Methods: We conducted a decision analysis using Markov Chain Monte Carlo simulation (rjags package in R) to estimate posterior distributions in a cohort of 100,000 women with ESBC. The discordance of PAM50-ROR with the 21-gene Recurrence Score® result threshold for beneficial effects of CT (Sparano NEJM 2018) was extracted from the only three published discordance studies. Effects of adjuvant CT on distant recurrence, overall survival, and toxicities were based on Chandler et al. (JCO 2018) outcomes over 25-year time horizon. Primary endpoints are incidence of distant recurrence, incidence of chemotoxicities, and overall survival. Results: About 1 in 4 women (25%; IQR 16 - 28) tested with PAM50-ROR have results discordant with 21-gene assay, resulting in an average increase of 2,466 of 100,000 women tested receiving CT (IQR -1,647 – 9,702). PAM50-ROR classifies 7% of women as high risk who have RS ≤ 25 (with chemotoxicities and no chemobenefit), 11% as low/intermediate risk who have RS > 25 (with increased distant recurrence and decreased survival among those not treated with CT), and 25% as intermediate who have RS ≤ 25, of whom >7% are likely to receive CT. The consequent effect of treatment choices based on discordant test is an increased incidence of distant recurrences (3,052; IQR 1,212 – 3,319), increased incidence of toxicities (696; IQR -324 – 2,228), and decreased years of overall survival (34,255 y; IQR 16,586 – 38,118). Conclusions: Use of PAM50 ROR compared with the 21-gene assay may lead to an increase in CT recommendations and potentially less desirable clinical consequences. Implementation of new incentives to create value-based oncology care needs safeguards to focus use towards optimal interventions. Legal entity responsible for the study: Genomic Health, Inc. Funding: Genomic Health, Inc. Disclosure: C.J. Markopoulos: Consultant: Genomic Health Inc.; Educational grants: AstraZeneca, Pfizer, Novartis. L. Hochheiser: Consultant: Abbott (providing guidance and direction as part of a Payor Advisory Board); Manuscript consultant: Genomic Health, Inc. J. Hornberger, E. Hytopoulos, M.C. Stoppler: Employee, owns stock: Genomic Health, Inc. M. Gitlin: Consultant: Genomic Health.
Health secretary promises to overhaul GPs’ IT systems
Authors: Elisabeth Mahase
Journal: BMJ (2019)

Technology companies will be invited to develop new and innovative IT systems for general practice as part of the new GP IT Futures framework, England’s health secretary has said.1

In a speech at the King’s Fund Digital Health and Care Congress on 23 May, Matt Hancock said that companies will be challenged to supply cloud based systems that allow patient information to be shared easily and securely between …
Клініко-патогенетичні особливості перебігу неалкогольної жирової хвороби печінки у хворих на бронхіальну астму та ожиріння
Authors: L.M. Pasiieshvili, N.M. Zhelezniakova, Т.M. Pasiieshvili
Journal: GASTROENTEROLOGY (2020)

Унаслідок коморбідності бронхіальної астми (БА) й ожиріння відбувається формування неалкогольної жирової хвороби печінки (НАЖХП), при наявності якої виникають зміни в патогенетичних ланках захворювання. Мета роботи: підвищення ефективності діагностики НАЖХП у хворих на БА, що перебігає на тлі ожиріння, шляхом встановлення зв’язку між показниками цитокінової ланки імунітету й жирнокислотного спектра крові. При проведенні роботи було обстежено 50 хворих на БА, серед яких у 27 захворювання перебігало на тлі ожиріння. Вивчали показники ліпідного й вуглеводного спектрів крові, вміст інтерлейкінів-1, -2, -4, -6 та сумарне значення насичених, ненасичених і поліненасичених жирних кислот. Було показано, що коморбідність БА і ожиріння, внаслідок якої формується НАЖХП, призводить до змін у ліпідному та вуглеводному спектрах крові, що характеризуються гіперліпідемією й порушенням толерантності до глюкози. Одночасно реєструються зміни в цитокіновій ланці імунітету (ознаки латентного запалення) та жирнокислотному спектрі крові з розвитком нестабільності клітинних мембран та порушенням вироб­лення ейкозаноїдів. Це, у свою чергу, забезпечує безперервність запального процесу (його хронізацію) та ураження інших органів і систем (зокрема, серцево-судинної) за рахунок розвитку ендотеліальної дисфункції. Отже, при поєднаному перебігу БА й ожиріння формується НАЖХП та виникають передумови до прогресування патологічного процесу.
Regulation of MMP9 expression by human arylamine N-acetyltransferase (NAT1) via Hif-1a
Authors: P. Li, R.F. Minchin, N. Butcher
Journal: Annals of Oncology (2019)

Background: Metastatic disease remains a major cause of mortality in breast cancer and previous studies have shown that arylamine N-acetyltransferase 1 (NAT1) is associated with increased cancer spread and poorer outcomes in breast cancer patients. However, the mechanism remains largely unknown. NAT1 alters cancer cell survival and invasive capacity in vitro. Since breast cancer cell invasion has been associated with increased matrix metalloproteinase 9 (MMP9) expression, we investigated the effects of NAT1 on MMP9 expression and activity in a range of cancer cells. Methods: NAT1 gene deleted cell-lines (Breast cancer: MDA-MB-231, T47D; Colon cancer: HT29; Cervical cancer: HeLa; Prostate cancer: 22Rv1) were generated using CRISPR/Cas9 technology. In vitro invasion was determined by fluorescent gelatin degradation assay on coverslips, visualised by confocal microscopy and quantified using ImageJ. Gene expression was quantified by real-time RT-PCR and protein expression in cells and growth medium was determined by Western blot analyses. siRNA was used to silence Hif-1α expression. ChIP-qPCR was performed to measure acetylation level of histones at specific motifs in the MMP9 promoter. Results: NAT1 deletion (KO) resulted in the up-regulation of MMP9 mRNA and protein level in the highly invasive MDA-MB-231 cells as well as T47D cells but not in the poorly invasive lines HT-29, HeLa or 22Rv1. Activity of the MMPs in a gelatin degradation assay showed an 8-fold increase in the MDA-MB-231 KO compared to parent cells. Hif-1α, a transcriptional factor for several MMPs, also increased significantly following NAT1 deletion. These changes were rescued by ectopic expression of NAT1 in the MDA-MB-231 KO cells. Inhibition of Hif-1α with siRNA decreased MMP9 mRNA and protein levels. ChIP-qPCR analyses on the MMP9 promoter region revealed that both acetyl-histone H3 (AcH3) and acetyl-histone H4 lysine12 (AcH4K12) levels increased on the SMYD3 binding site, but not on the proximal or distal AP-1 binding sites. Conclusions: NAT1 negatively regulates MMP9 transcription via HIF1-α and by altering histone acetylation level at the SMYD3 binding site. These observations may, in part, explain the poor outcome of breast cancer patients with low or negligible NAT1 expression. Legal entity responsible for the study: University of Queensland. Funding: National Health and Medical Research Council of Australia. Disclosure: All authors have declared no conflicts of interest.
DIAGNOSTIC YIELD OF UPPER ENDOSCOPY ACCORDING TO APPROPRIATENESS: A SYSTEMATIC REVIEW
Authors: C Hassan, A Zullo
Journal: Endoscopy (2019)

Despite some official guidelines are available, a substantial rate of inappropriateness for upper gastrointestinal (UGI) endoscopies has been reported. This study aimed to estimate the inappropriate rate of UGI in different countries, also including the diagnostic yield.
A Novel View of Umbilical Cord Blood Versus Maternal Peripheral Blood — Evidence for an Increase in the Number of Circulating Stem Cells on Both Sides of the Fetal–Maternal Circulation Barrier.
Authors: Kasia Sielatycka, Agata Poniewierska-Baran, Karolina Nurek, Andrzej Torbe, Mariusz Z Ratajczak
Journal: Blood (2017)
PLACE OF ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY IN THE MANAGEMENT OF ECHINOCCOCAL CYSTS COMMUNICATING WITH BILE DUCTS: A SINGLE CENTER EXPERIENCE
Authors: H Boutallaka, H Seddik, S Mrabti, A Sair, I El Koti, S Sentissi, A Benkirane
Journal: Endoscopy (2019)

The aim of our study is to specify the efficacy of ERCP in the management of hydatid cysts communicating with bile ducts.
Utility of the HEp-2000 antinuclear antibody substrate
Authors: Adrian Y S Lee, Dimitra Beroukas, Peter J Roberts-Thomson
Journal: Annals of the Rheumatic Diseases (2019)

Utility of the HEp-2000 antinuclear antibody substrateWe write with regards to the recently published consensus paper antinuclear antibody (ANA) staining patterns by Damoiseaux et al which was most informative. 1We were surprised, however, that there was no mention or discussion of the HEp-2000 substrate (Immunoconcepts, Sacremento, California, USA) despite the acknowledgement that anti-SS-A/Ro60 is frequently missed on indirect immunofluorescence assay (IIFA). 1 The HEp-2000 substrate is a modified HEp-2 substrate that is transfected with Ro60 cDNA and hence, over-expresses this antigen. 2It produces a bright nuclear/nucleolar staining pattern under IIFA when anti-SS-A/Ro60 antibodies are present (figure 1), and is one of the most commonly detected extractable nuclear antigen antibodies. 3he HEp-2000 substrate is a sensitive way to detect anti-SS-A/ Ro60 antibodies that may be otherwise missed on conventional immunoassays, such as immunoblotting and the standard HEp-2 substrate. 4 5However, it is not a perfect screen as the HEp-2000 substrate may still miss detection of anti-SS-A/Ro60 sera 6 7 indicating that at least a second method for anti-SS-A/Ro60 and other antibody detection is still required. 8For other ANA specificities, HEp-2000 performs similarly to the standard HEp-2 substrate with no significant impact on the detection of other ANA fluorescent patterns 9 10 and in fact, improved sensitivities. 5 It is important to maximise the chances of identifying anti-SS-A/ Ro60, for the antibody, as an example, has significant implications for fertile women for the development of neonatal lupus erythematosus which may have devastating sequelae. 11We therefore recommend others to consider the HEp-2000 substrate if employing the IIFA method for ANA detection.
COLON CLEANSING EFFICACY AND SAFETY OF 1L NER1006 IN PATIENTS WITH MILD TO MODERATE RENAL IMPAIRMENT: POST HOC ANALYSIS OF RANDOMISED PHASE 3 CLINICAL TRIALS
Authors: C Hassan, H Thompson, S Mokashi, J Drenth
Journal: Endoscopy (2019)

Only polyethylene glycol (PEG) bowel preparations are recommended for patients with renal failure. This post hoc analysis of randomised phase 3 clinical trials assessed the colon cleansing efficacy of the first 1L PEG, NER1006, in renally impaired versus non-renally impaired patients.