tbuckley/cabot-search huggingface dataset:
CCL21 as a potential biomarker for pulmonary arterial hypertension in systemic sclerosis
Authors: Anna-Maria Hoffmann-Vold, Øyvind Molberg
Journal: Arthritis & Rheumatology (2018)

We thank Zhou and co-workers for their interest regarding our newly published manuscript on the role of CCL21 in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc). Here, we want to respond to their concerns. Genome-wide association studies (GWASs) have been foreshadowed to be a major advance in biomedical discovery, with many robust associations to complex diseases. However, although there are found polymorphisms with SSc, there are, to date, no existing genetic loci for SSc-PAH. Secondly, despite this success, GWAS studies have met considerable skepticism regarding their clinical applicability; mainly arising from their unclear functional consequences. This article is protected by copyright. All rights reserved.
Impact of pretransplant CMV-specific T-cell immune response in the control of CMV infection after solid organ transplantation: a prospective cohort study
Authors: A. Molina-Ortega, C. Martín-Gandul, J.D. Mena-Romo, M.J. Rodríguez-Hernández, M. Suñer, C. Bernal, M. Sánchez, J. Sánchez-Céspedes, P. Pérez Romero, E. Cordero
Journal: Clinical Microbiology and Infection (2018)

IntroductionAlthough solid organ transplant (SOT) recipients with pretransplant serology for cytomegalovirus (CMV-R+) are considered at intermediate risk for CMV infection post transplantation, CMV infection remains a major cause of morbidity in this population. We prospectively characterized whether having pretransplant CMV-specific cellular immunity is independently associated with controlling infection after transplantation in R + SOT recipients.MethodsA prospective cohort of consecutive R + SOT recipients that received pre-emptive treatment for CMV infection was monitored after transplantation and variables were recorded during the follow-up. The cytomegalovirus-specific T-cell immune response was characterized by intracellular cytokine staining and viral loads determined using real-time PCR.ResultsOne hundred and thirty-five R + SOT recipients were included (67 kidney, 64 liver, four liver–kidney). Only one-third of the patients (42; 31.85%) had CMV-specific T-cell immunity (CD8+CD69+INF-γ+ T cells >0.25%) before transplantation. Patients with negative pretransplant immunity had more CMV infection (49, 52.7% vs. 15, 35.7%; p 0.07) and received more antiviral therapy than those with immunity (32, 34.4% vs. 6, 14.3%, p 0.016). Having CMV specific immunity was an independent factor for protection from developing viraemia ≥2000 IU/mL (OR 0.276, 95% CI 0.105–0.725, p < 0.01) and lower administration of treatment (OR 0.398, 95% CI 0.175–0.905, p 0.028). Only patients with no pretransplant CMV-specific T-cell response were diagnosed with CMV-disease (8, 8.6% vs. 0, 0%, p 0.05).Discussion.Our results show that having a pretransplant CMV specific T-cell response may be associated with a lower rate of CMV viraemia and less antiviral treatment after transplantation; however, more prospective studies are needed to confirm these findings.
Adiposity, Blood Pressure, and Incidence of Stroke Subtypes Among 0.5 Million Adult Chinese With 7 Years of Follow-Up
Authors: Z Chen, A Iona, Y Guo, M Smith, R Clarke, S Lewington, Y Chen, L Millwood, Z Bian, R Walters, Y Tang, S Parish, R Collins, J Chen, R Peto, L Li
Journal: Circulation (2014)
Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease
Authors: Katelyn Paz, Ryan Flynn, Jing Du, Jun Qi, Leo Luznik, Ivan Maillard, Kelli P. MacDonald, Geoffrey R. Hill, Jonathan S. Serody, William J. Murphy, Peter T. Sage, Arlene H. Sharpe, David Miklos, Corey S. Cutler, John Koreth, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, James E. Bradner, Ari M. Melnick, Bruce R. Blazar
Journal: Blood (2018)
Long-term Survival and Value of Chimeric Antigen Receptor T-Cell Therapy for Pediatric Patients With Relapsed or Refractory Leukemia
Authors: Melanie D. Whittington, R. Brett McQueen, Daniel A. Ollendorf, Varun M. Kumar, Richard H. Chapman, Jeffrey A. Tice, Steven D. Pearson, Jonathan D. Campbell
Journal: JAMA Pediatrics (2018)

Among children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, the rate of 5-year disease-free survival is 10% to 20%. Approval of tisagenlecleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option. However, tisagenlecleucel is expensive, with a current list price of $475 000 per one-time administration.
Cochrane centre based in Spain calls for investigation into director’s dismissal
Authors: Nigel Hawkes
Journal: BMJ (2018)

Members of Cochrane in Spanish speaking countries have called for an independent investigation into Peter Gotzsche’s expulsion as a member and as director of the Cochrane Nordic Centre.1

A statement agreed by a large majority of the members of Cochrane Iberoamerica said that what was at stake was to clarify how an organisation that wants to be inclusive and transparent resolved a serious conflict with one of its members.

“We doubt that …
First, do “nothing”… and listen
Authors: Nicol van Dyk, Ron Martoia, Kieran O’Sullivan
Journal: British Journal of Sports Medicine (2018)

The oath—‘do no harm’—ensures the health and well-being of the patient are protected, respected and hopefully improved. However, it implies that ‘something’ will be done where a definitive answer or diagnosis will be generated and a specific treatment plan generated. While the latter aligns with common practice and meets the expectations of athletes and clinicians alike,1 it presents a temptation to rush into a specific treatment path that is difficult to resist. Even pain science education (‘explain pain’) as a recognised treatment of common musculoskeletal disorders might still underestimate the initial interaction between the practitioner and the patient.2 It seems that listening, or the opportunity to discuss problems, might be as important as specifically targeted education.2 

In this editorial, we explore a key component of assessment that might aid practitioners in their clinical care of patients—doing ‘nothing’ (translation—really listening). Specifically, how generative listening might improve the outcome for the individual.

In sports medicine, as with other fields of healthcare, athletes seeking consultation are equipped with …
Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling
Authors: Geyan Wu, Lixue Cao, Jinrong Zhu, Zhanyao Tan, Miaoling Tang, Ziwen Li, Yameng Hu, Ruyuan Yu, Shuxia Zhang, Libing Song, Jun Li
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). Experimental Design: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/β-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism by which RBMS3 loss sustained activation of miR-126-5p/β-catenin/CBP signaling and the effects of RBMS3 and miR-126-5p competitively regulating DKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. Results: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited β-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p–mediated repression of these transcripts. Importantly, cotherapy of CBP/β-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. Conclusions: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.
Abstract 15847: Identifying the Symptomatic Middle-aged Subject at Imminent Risk of Sudden Cardiac Arrest
Authors: Audrey Uy-Evanado, Kyndaron Reinier, Aapo Aro, Eric C Stecker, Carmen Teodorescu, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2016)

Introduction: We have recently reported a high rate of warning symptoms in the four weeks preceding sudden cardiac arrest (SCA), that are ignored by the majority of victims. Importantly, an immedia...
“Familial venoms”: a thallium intoxication cluster
Authors: Francesco Ratti, Alberto Facchini, Eduardo Beck, Sara Cazzaniga, Silvia Francesconi, Cecilia Tedesco, Alessandro Terrani, Gabriella Ciceri, Roberto Colombo, Maurizio Saini, Valeria Margherita Petrolini, Giuseppe Citerio
Journal: Intensive Care Medicine (2018)
Doctor who changed patient consent form to cover up mistake is struck off
Authors: Clare Dyer
Journal: BMJ (2018)

A specialist registrar in neurosurgery who changed a patient’s surgical consent form to cover up a mistake and who failed to disclose his disciplinary problems when seeking a hospital post has been struck off the UK medical register for persistent dishonesty.

In August 2015 Ibrahim Hafez attempted to perform a burr hole evacuation of a subdural haematoma but inserted the drain into the patient’s brain instead of into the subdural space, a medical practitioners tribunal heard. He was suspended and excluded by his employer, Imperial College Healthcare NHS Trust.

Imperial told Hafez in several letters that he must notify any prospective employers of his exclusion. But when he applied for a post as clinical fellow in neurosurgery at Hull and East Yorkshire NHS Trust in …
Recent developments and highlights in biomarkers in allergic diseases and asthma
Authors: Ibon Eguiluz‐Gracia, Tunn Ren Tay, Mark Hew, Maria M. Escribese, Domingo Barber, Robyn E. O'Hehir, Maria J. Torres
Journal: Allergy (2018)

Abstract The potential of precision medicine in allergy and asthma has only started to be explored. A significant clarification in the pathophysiology of rhinitis, chronic rhinosinusitis, asthma, food allergy and drug hypersensitivity was made in the last decade. This improved understanding led to a better classification of the distinct phenotypes and to the discovery of new drugs such as biologicals, targeting phenotype‐specific mechanisms. Nevertheless, many conditions remain poorly understood such as non‐eosinophilic airway diseases or non‐IgE–mediated food allergy. Moreover, there is a need to predict the response to specific therapies and the outcome of drug and food provocations. The identification of patients at risk of progression towards severity is also an unmet need in order to establish adequate preventive or therapeutic measures. The implementation of precision medicine in the clinical practice requires the identification of phenotype‐specific markers measurable in biological matrices. To become useful, these biomarkers need to be quantifiable by reliable systems, and in samples obtained in an easy, rapid and cost‐efficient way. In the last years, significant research resources have been put in the identification of valid biomarkers for asthma and allergic diseases. This review summarizes these recent advances with focus on the biomarkers with higher clinical applicability.
Sorafenib, a multi-target inhibitor, and OSU-03012, a phosphoinositide- dependent kinase-1 inhibitor, are synergistic in cytotoxicity against nasopharyngeal carcinoma cells
Authors: Chih-Hung Hsu, Yi-Wei Chao, Wen-Chi Feng, Pei-Yen Yeh, Ching-Shih Chen, Ann-Lii Cheng
Journal: Cancer Research (2008)

1331  Sorafenib, a multi-target kinase inhibitor against Raf kinase and vascular endothelial growth factor receptor, has recently shown clinical benefit in patients with renal cell carcinoma and hepatocellular carcinoma. However, other cancer types and other mechanisms of action may need to be pursued. This study sought to evaluate the role of Mcl-1 in the cytotoxic effect of sorafenib in nasopharyngeal carcinoma (NPC). TW01, TW04, and HONE1 were cell-lines derived from NPC patients. Sorafenib induced a dose-dependent anti-proliferative effect in NPC cells, with IC50s between 3.9 and 9.7 μM by MTT assay. Sorafenib decreased the expression levels of p-MEK and p-ERK, induced apoptosis, and down-regulated Mcl-1 in HONE1 cells. siRNA knock-down of Mcl-1 enhanced the cytotoxic effect of sorafenib in HONE1 cells. OSU-03012, a novel phosphoinositide-dependent kinase-1 (PDK1) inhibitor which could induce apoptosis and anti-tumor effect in a variety of cancer cells, also down-regulated Mcl-1 in NPC cells dose-dependently. The Mcl-1 down-regulation induced by OSU-03012 was prevented by MG-132 but not by cycloheximide, indicating that OSU-03012 mainly affected the degradation pathway of Mcl-1 protein. Further, Mcl-1 down-regulation induced by OSU-03012 was abolished by lithium, suggesting that GSK-3β, which is downstream to PDK1/AKT, might be involved. The combination of sorafenib and OSU-03012 induced profound downregulation of Mcl-1 and synergistic cytotoxicity in HONE1 cells. Our data indicate that OSU-03012 may synergize the anti-tumor effect of sorafenib in NPC cells, and the mechanism of synergisticity is at least partly due to the enhanced suppression of Mcl-1. (The study was supported by the grant NSC-94-2314-B-002-156-, the grant 95R0066-BM01-02, and the grant DOH94-TD-B-111-001 for NCTRC of NTUH from Department of Health, Executive Yuan, R.O.C.)
Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer Patients: Secondary Findings From the Prospective Randomized Phase 3 CONVERT Trial
Authors: Antonin Levy, Cécile Le Péchoux, Hitesh Mistry, Isabelle Martel-Lafay, Andrea Bezjak, Delphine Lerouge, Laetitia Padovani, Paul Taylor, Corinne Faivre-Finn
Journal: Journal of Thoracic Oncology (2018)

The impact of the dose and fractionation of thoracic radiotherapy on the risk of developing brain metastasis (BM) has not been evaluated prospectively in limited stage SCLC patients receiving prophylactic cerebral irradiation (PCI).Data from patients treated with PCI from the CONVERT trial were analyzed.Four hundred forty-nine of 547 patients (82%) received PCI after completion of chemoradiotherapy. Baseline brain imaging consisted of computed tomographic scans in 356 of 449 patients (79%) and magnetic resonance imaging in 83 of 449 (18%) patients. PCI was delivered to 220 of 273 participants (81%) in the twice-daily (BD) group and 229 of 270 in the once-daily (OD) group (85%; p = 0.49). Total median PCI dose was 25 Gy in both the BD and OD groups (p = 0.74). In patients who received PCI, 75 (17%) developed BM (35 [8%] in OD and 40 [9%] in BD) and 173 (39%) other extracranial progression. In the univariate analysis, gross tumor volume (GTV) was associated with an increased risk of BM (p = 0.007) or other radiological progression events (p = 0.006), whereas in a multivariate analysis both thoracic GTV (tGTV) and ECOG performance score were associated with either progression type. The median overall survival (OS) of patients treated with PCI was 29 months. In the univariate analysis of OS, PCI timing from end of chemotherapy, weight loss of more than 10%, and tGTV were prognostic factors associated with OS. In the multivariate analysis, only tGTV was associated with OS. Delay between end of chemotherapy and PCI was not associated with OS.Patients receiving OD or BD thoracic radiotherapy have the same risk of developing BM. Larger tumors are associated with a higher risk of BM.
Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia
Authors: Bowen Yan, Qinwei Chen, Koji Shimada, Ming Tang, Haoli Li, Aishwarya Gurumurthy, Joseph D. Khoury, Bing Xu, Suming Huang, Yi Qiu
Journal: Leukemia (2018)
Abstract #4473: Global proteome comparison of DNA mismatch repair proficient and deficient colorectal cancer cell lines.
Authors: Patrick Halvey, Robbert Slebos, Sheryl Stamer, Daniel Liebler
Journal: Cancer Research (2009)

Deficiencies in DNA mismatch repair (MMR) systems occur in hereditary non-polyposis colorectal cancer (HNPCC) and in 10-15% of sporadic colorectal cancers (CRC). Loss of function mutations in MMR proteins such as MLH1 and MSH2 lead to genetic instability, which contributes to tumor formation. Widespread mutations at the genome level presumably give rise to alterations in protein expression profiles; however, little is known about the effects of MMR deficiency on the proteome. We carried out global shotgun proteomic analysis of four MMR proficient (MMR+) CRC cell lines (HT-29, COLO-205, CaCo2, SW480) and four MMR deficient (MMR-) CRC cell lines ( HCT-116, LS174T, LoVo, RKO). Tryptic peptides from whole cell lysates were separated by isoelectric focusing (IEF) and analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS) on a linear ion trap quadrupole (LTQ) mass spectrometer. Resulting spectra were searched against protein databases using the Myrimatch search algorithms and proteins were identified using parsimonious assembly with IDpicker. When data from all cell lines were assembled together, 5047 protein groups were identified (4.8% protein FDR). Statistical analysis of group-wise differences identified a small number of proteins that differentiated MMR+ and MMR- cell lines, with notably increased spectral counts for DNA repair proteins in MMR+ cell lines (MSH2, RAD50B, MRE11 and others). We further examined protein expression levels for genes known to be mutated in these cell lines. These genes include the KRAS, p53, APC, BAX and the mismatch repair proteins MSH2 and MSH6. KRAS was detected in both wildtype KRAS-expressing cells and mutant KRAS- expressing cells. Likewise, APC was detected in wildtype APC-expressing cells and truncated APC in cells carrying mutant APC, while p53 was only detected in mutant p53-expressing cells. BAX was not detected in MMR- deficient cell lines, LoVo or LS174T cells, which are known to possess a BAX frameshift mutation, but was detected in all wildtype BAX-expressing cells. Furthermore, MSH2 and MSH6 were not detected in LoVo cells, which express mutant forms of these genes. Our results demonstrate that shotgun proteomics can be used to identify broad differences in protein expression profiles between MMR+ and MMR- cell lines and is sensitive enough to pick up subtle changes at the individual protein level. The data suggest that global shotgun proteomic analyses can map individual protein expression patterns to corresponding genetic profiles and distinct cancer-related phenotypes.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4473.
Mapping of the axilla: Lymph node involvement in level 1, 2, and 3 of the axilla and in the interpectoral region in early breast cancer.
Authors: Andreas Jakob, Matthias Frank, Nicole Kuderer, Gary H. Lyman, Jan Willem Siebers
Journal: Journal of Clinical Oncology (2014)

1102 Background: Axillary clearance provides important information for prognosis and staging. The aim of this study was to determine the involvement of the different regions of the axilla in node positve primary breast cancer (PBC). Methods: We conducted a retrospective analysis of data from a single-center, unselected cohort of women with PBC. Between 1997 and 2001 axillary lymph node (LN) dissection comprised of clearance of level 1, 2, and 3 and since 2002 the interpectoral region was also routinely dissected. In all patients level 1 was dissected, level 2 in 98,8%, level 3 in 94,9% and the interpectoral (ip) region in 63,9% of the women. Results: We analysed data of 1,868 women with PBC treated at our institution between 1997 and 2009. 740 (39,6%) of the patients had node pos. disease. Out of these patients 267 (36,1%) had only one LN involved. The other patients (63,9%) had more than one pos. LN. The involvement of the different axilla regions dependent on the number of positive LN referring to the dissection frequency was: 1 pos LN: level 1 96,6%; level 2 0,8%; level 3 1,6% ip 1,7%. 3 pos LN: level 1 100%; level 2 8,9%; level 3 7,9%; ip 7,4%; ≥ 1 pos LN: level 198,8%; level 2 29,4%; level 3 18,9%; ip 9,2%. The involvement of level 2,3 and ip region in relation to the number of pos. LN in level 1:1 pos LN: level2 6,4%; level 3 3,3%; ip 2,6%. 3 pos LN: level 2 19,5%; level 3 10,3%; ip 8,9%. 4-9 pos LN: level 2 52%, level 3 27,8%; ip 12,9%. The frequency of stage pN0 was dependent on the number of removed lymph nodes: in patients with less than 10 LN removed, stage pN0 was diagnosed in 77,5% and in patients with more than 23 resected LNs in only 56% Conclusions: In 64% of patients with node positive PBC, there are more than one LNs involved. Patients with one positive LN in level 1 will have positive nodes in the other regions in over 10%; with two positive nodes in level 1 in 20%; and with three positive nodes in level 1 in 40%, respectively. In patients with 4-9 positive LNs in level 1, level 3 will be involved in 28%. There is an increased risk of metstatic spread to regions, which are not routinely dissected, dependent on the number of positive LNs in level 1. This could have implications on accurate staging and surgical procedures.
Incidental Detection of Skeletal Metastases on 99mTc-DTPA Renography
Authors: Nikhil Seniaray, Ritu Verma, Ethel S. Belho, Harsh Mahajan
Journal: Clinical Nuclear Medicine (2018)

Abstract We present the case of a 53-year-old man with left hydroureteronephrosis who underwent 99m Tc-DTPA renography for functional assessment of bilateral kidneys. 99m Tc-DTPA renography of the patient showed diffusely increased extrarenal 99m Tc-DTPA uptake in the visualized lumbosacral vertebrae and in the pelvic bones, on the blood flow and functional phase of the renography, which was suggestive of disseminated skeletal disease. Subsequent MRI lumbosacral spine and 18 F-FDG PET/CT revealed extensive skeletal metastases corresponding to the increased extrarenal 99m Tc-DTPA uptake in the lumbosacral vertebrae and the pelvic bones from primary left lung mitotic lesion.
Prevalence of Sexual Harassment in Academic Medicine
Authors: Sabine Jenner, Pia Djermester, Judith Prügl, Christine Kurmeyer, Sabine Oertelt-Prigione
Journal: JAMA Internal Medicine (2018)

Rebecca C. Thurston, PhD; Yuefang Chang, PhD; Karen A. Matthews, PhD; Roland von Känel, MD; Karestan Koenen, PhD
Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Children Aged 6–18 Years with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP)
Authors: Nancy M. Bennett, Tamara Pilishvili, Cynthia G. Whitney, Matthew Moore, Ryan Gierke, Aaron M. Harris
Journal: MMWR Morbidity and Mortality Weekly Report (2013)