tbuckley/cabot-search huggingface dataset:
FRI0112 RISK OF MALIGNANCY WITH NON-TNFI BIOLOGIC OR TOFACITINIB THERAPY IN RHEUMATOID ARTHRITIS: A META-ANALYSIS OF OBSERVATIONAL STUDIES
Authors: W. Xie, X. Yang, Z. Zhang
Journal: Annals of the Rheumatic Diseases (2020)

Background: With an increasing usage of non-TNFi biologics and tofacitinib, it is crucial to understand the comparative safety of these agents regarding malignancies risk. Objectives: We aim to assess the risk of developing cancer in patients with RA exposed to non- TNF inhibitors (TNFi) biologics or tofacitinib therapy. Methods: Systematical search of PubMed, EMBASE and Cochrane Library plus a hand search of conference proceedings were performed for observational studies that reported cancer incidence in patients with RA treated with biologics or tofacitinib with active comparator of conventional DMARDs (csDMARDs) or TNFi. The pooled relative risk (RR) and 95% confidence interval (CI) were calculated with fix-effects or random-effects model. Results: Of 2,819 identified articles, a total of 10 studies involving over 323,361 patients and 1,179,263 patient-years of follow-up were included. Pooled analysis showed there was no increased risk of developing cancer in general or specific cancer types in RA patients receiving treatment with rituximab (pooled RR 1.13, 95% CI 0.80-1.59), tocilizumab (pooled RR 0.96, 95% CI 0.83-1.11), or tofacitinib (pooled RR 0.97, 95% CI 0.66-1.43), compared with those receiving csDMARDs or TNFi. However, abatacept usage in RA was associated with a slightly increased overall cancer risk (pooled RR 1.13, 95% CI 1.02-1.24) and non-melanoma skin cancer (pooled RR 1.26, 95% CI 1.09-1.45), relative to csDMARDs or TNFi. Conclusion: Compared with csDMARDs or TNFi, there was no increased risk of malignancies among RA patients treated with non-TNFi biologics or tofacitinib, with exception of abatacept associated with slightly increased total cancer and specific caner types. Extended researches are required to confirm the findings in a real-world context. References: [1]Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960-977. Figure 1. Relative risk of developing cancer between rituximab and csDMARDs. (A) any cancer; (B) all cancer types excluding NMSC; (C) solid tumors; (D) hematological cancer; (E) NMSC; or (F) melanoma. csDMARDs: conventional synthetic disease-modifying antirheumatic drugs. NMSC: non-melanoma skin cancer. Disclosure of Interests: None declared
Platelet Glycoprotein Ib α‐Chain as a Putative Therapeutic Target for Juvenile Idiopathic Arthritis: A Mendelian Randomization Study
Authors: Shan Luo, Sarah L. N. Clarke, Athimalaipet V. Ramanan, Susan D. Thompson, Carl D. Langefeld, Miranda C. Marion, Alexei A. Grom, C. Mary Schooling, Tom R. Gaunt, Shiu Lun Au Yeung, Jie Zheng
Journal: Arthritis & Rheumatology (2020)

To ascertain the role of platelet glycoprotein Ib α-chain (GPIbα) plasma protein levels in cardiovascular, autoimmune, and autoinflammatory diseases and whether its effects are mediated by platelet count.We performed a two-sample Mendelian randomization (MR) study, using both a cis-acting protein quantitative trait locus (cis-pQTL) and trans-pQTL near the GP1BA and BRAP genes as instruments. To assess if platelet count mediated the effect, we then performed a two-step MR study. Putative associations (GPIbα/platelet count/disease) detected by MR analyses were subsequently assessed using multiple-trait colocalization analyses.After correction for multiple testing (Bonferroni-corrected threshold P ≤ 2 × 10-3 ), GPIbα, instrumented by either cis-pQTL or trans-pQTL, was causally implicated with an increased risk of oligoarticular and rheumatoid factor (RF)-negative polyarticular juvenile idiopathic arthritis (JIA). These effects of GPIbα appeared to be mediated by platelet count and were supported by strong evidence of colocalization (probability of all 3 traits sharing a common causal variant ≥0.80). GPIbα instrumented by cis-pQTL did not appear to affect cardiovascular risk, although the GPIbα trans-pQTL was associated with an increased risk of cardiovascular diseases and autoimmune diseases but a decreased risk of autoinflammatory diseases, suggesting that this trans-acting instrument operates through other pathways.The role of platelets in thrombosis is well-established; however, our findings provide some novel genetic evidence that platelets may be causally implicated in the development of oligoarticular and RF-negative polyarticular JIA, and indicate that GPIbα may serve as a putative therapeutic target for these JIA subtypes.
Reverse transformation of multidrug-resistant human neuroblastoma stem cells is associated with up-regulation of CD133 and ABCG2, markers of a less differentiated, less malignant cell phenotype
Authors: Barbara A. Spengler, Chirag Shah, June L. Biedler, Robert A. Ross
Journal: Cancer Research (2006)

1370  Reverse transformation –reduction or loss of malignant potential and resumption of contact inhibition –is one recurring concomitant of acquired high-level multidrug resistance in cultured tumor cell lines. Studies of multidrug-resistant rodent sublines linked reverse transformation with overexpression of P-glycoprotein, encoded in humans by the MDR1 (ABCB1) gene, but left open the possibility that differentiation state could also play a role. Using a series of well characterized multidrug-resistant sublines selected from the malignant human neuroblastoma BE(2)-C stem cell clone, we have analyzed expression of markers of differentiation as well as of other ATP-binding cassette (ABC) transporters. The seven resulting sublines could be divided into two groups based on tumorigenicity in nude mice. Group A sublines, selected with colchicine, form tumors in 100% of animals [as does BE(2)-C]. By contrast, Group B sublines, selected with actinomycin D or vincristine, exhibit a 23 to 80% reduction in tumor formation. Western analyses of two representative sublines from each group for levels of neuroblastic [chromogranin A (CGA), neurofilament 68 (NF68)] and non-neuronal [vimentin (VIM)] marker proteins revealed that Group B sublines contain 3- to 4-fold less CGA and NF68 and 20-fold less VIM than Group A sublines –expression patterns suggestive of a less differentiated, earlier stem cell type. Cell morphology also appears less differentiated and the Group B sublines no longer respond to common morphogens. Semi-quantitative RT-PCR analyses for mRNAs encoding proteins expressed in normal stem cells revealed expression patterns likewise consistent with an earlier differentiation stage: 4-fold higher levels of CD133 mRNA and activation of transcription of BCRP1 (ABCG2) in Group B cells compared to Group A. Expression levels of the developmentally earlier stem cell markers, the intermediate filaments cytokeratin 8 and 18, were similar between the groups. Of interest in neuroblastoma, MRP1 (ABCC1) increased in the tumorigenic, more neuroblastic Group A cells whereas MRP4 (ABCC4) decreased. Thus, reverse transformation related to high-level drug resistance correlates with –and may be the consequence of –expression of a less differentiated, intrinsically less malignant, stem cell phenotype.
BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression
Authors: Barbara A. Konkle, Christopher E. Walsh, Miguel A. Escobar, Neil C. Josephson, Guy Young, Annette von Drygalski, Scott W. J. McPhee, R. Jude Samulski, Ivan Bilic, Maurus de la Rosa, Birgit M. Reipert, Hanspeter Rottensteiner, Friedrich Scheiflinger, John C. Chapin, Bruce Ewenstein, Paul E. Monahan
Journal: Blood (2020)
Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity
Authors: Tae Hee Hong, Hongui Cha, Joon Ho Shim, Boram Lee, Jongsuk Chung, Chung Lee, Nayoung K D Kim, Yoon-La Choi, Soohyun Hwang, Yoomi Lee, Sehhoon Park, Hyun Ae Jung, Ji-Yeon Kim, Yeon Hee Park, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Se-Hoon Lee, Woong-Yang Park
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored. Methods We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156). Results Low tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p&lt;0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016). Conclusions Our data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
In ACS, ticagrelor and prasugrel each reduce some ischemic events but increase major bleeding vs. clopidogrel
Authors: Michael G. Nanna, Christopher B. Granger
Journal: Annals of Internal Medicine (2020)

Navarese EP, Khan SU, Kolodziejczak M, et al. Comparative efficacy and safety of oral P2Y12inhibitors in acute coronary syndrome: network meta-analysis of 52 816 patients from 12 randomized trials. Circulation. 2020;142:150-60. 32468837.
Associations of meningioma molecular subgroup and tumor recurrence
Authors: Mark W Youngblood, Danielle F Miyagishima, Lan Jin, Trisha Gupte, Chang Li, Daniel Duran, Julio D Montejo, Amy Zhao, Amar Sheth, Evgeniya Tyrtova, Koray Özduman, Francesco Iacoangeli, Matthieu Peyre, Julien Boetto, Matthew Pease, Timuçin Avşar, Anita Huttner, Kaya Bilguvar, Türker Kilic, M Necmettin Pamir, Nduka Amankulor, Michel Kalamarides, E Zeynep Erson-Omay, Murat Günel, Jennifer Moliterno
Journal: Neuro-Oncology (2020)

We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients.We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling.Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence.We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.
AB0196 The frequency of popliteal cyst in ra patients – ultrasonographic assessment
Authors: MR Kowalski
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The goal of the study was to assess the frequency of Baker's cyst in rheumatoid arthritis patients in comparison to other groups of patients and healthy persons. <h3>Methods</h3> With the real time ultrasonographic device with 7,5 MHz linear probe we examined knee joints of a group of 60 RA patients; 30 health persons served as a control group; the second control group were 60 perimenopausal women. <h3>Results</h3> We found Bakre's cysts in 25 out of 60 RA patients (in 5 cases located in both knees). Among healthy persons there was one person with diagnosed popliteal cyst. In a group of perimenopausal women there were two patients with the cyst. <h3>Conclusion</h3> This study shows the frequency of Bakre's cyst in RA patients in comparison with other groups of patients. Although the study was conducted on a limited number of patients it can give us an estimated data on Bakre's cyst frequency in RA patients.
An MDS Specific Frailty Index Based on Cumulative Deficits Adds Independent Prognostic Value to Established Clinical Prognostic Scoring Systems
Authors: Rebecca Starkman, Richard A. Wells, Lisa Chodirker, Ken Rockwood, Michelle Geddes, Nancy Zhu, Jill Fulcher, Mitchell Sabloff, Mary-Margaret Keating, Brian Leber, Heather A. Leitch, Karen W.L. Yee, Eve St-Hilaire, Nicholas G. Finn, John Storring, Thomas J Nevill, April Shamy, Rajat Kumar, Mohamed Elemary, Robert Delage, Martha Lenis, Alexandre Mamedov, Liying Zhang, Rena Buckstein
Journal: Blood (2017)
The Prehistory of Psychiatric Genetics: 1780–1910
Authors: Kenneth S. Kendler
Journal: American Journal of Psychiatry (2020)

While psychiatric genetics has emerged as one of our most dynamic research fields, the historical context in which we view these developments is limited. To provide such a perspective, the author reviews 48 representative texts, published from 1780 to 1910, examining the inheritance of insanity. Six main conclusions emerge. First, most authors viewed heredity as among the strongest risk factors for insanity. Second, most writers concluded that a predisposition to illness rather than the illness itself was transmitted in families. Third, the probabilistic nature of the transmission was noted, as insanity often skipped generations or affected only a few of many siblings. Fourth, authors discussed the homogeneity versus heterogeneity of familial transmission of the various forms of insanities. Heterogeneous transmission was usually seen as the rule-with relatives of insane patients affected with a wide variety of psychiatric, and sometimes neurological, illnesses. Homogeneous transmission ("like begets like") was the exception. Fifth, writers noted that odd and eccentric personality features were common in the relatives of their insane patients. Finally, inheritance was commonly understood to include prior environmental parental experiences, and some authors noted that parent-offspring transmission of insanity could arise from psychological or intrauterine effects. Many of these conclusions, arising solely from clinical experience and without an understanding of biological mechanisms, statistical analyses, or necessary controls, are supported by later, more rigorous methods. Rather than entirely rejecting its value, we might view this literature as a complementary resource, likely more biased, but suffused with the extensive clinical knowledge of our forebears.
ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer
Authors: Maria Gebre-Medhin, Eva Brun, Per Engström, Hedda Haugen Cange, Lalle Hammarstedt-Nordenvall, Johan Reizenstein, Jan Nyman, Edvard Abel, Signe Friesland, Helena Sjödin, Henrik Carlsson, Karin Söderkvist, Marcus Thomasson, Björn Zackrisson, Per Nilsson
Journal: Journal of Clinical Oncology (2020)

We performed an open-label randomized controlled phase III study comparing treatment outcome and toxicity between radiotherapy (RT) with concomitant cisplatin versus concomitant cetuximab in patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC; stage III-IV according to the Union for International Cancer Control TNM classification, 7th edition).Eligible patients were randomly assigned 1:1 to receive either intravenous cetuximab 400 mg/m2 1 week before start of RT followed by 250 mg/m2/wk, or weekly intravenous cisplatin 40 mg/m2, during RT. RT was conventionally fractionated. Patients with T3-T4 tumors underwent a second random assignment 1:1 between standard RT dose 68.0 Gy to the primary tumor or dose escalation to 73.1 Gy. Primary end point was overall survival (OS) evaluated using adjusted Cox regression analysis. Secondary end points were locoregional control, local control with dose-escalated RT, pattern of failure, and adverse effects.Study inclusion was prematurely closed after an unplanned interim analysis when 298 patients had been randomly assigned. At 3 years, OS was 88% (95% CI, 83% to 94%) and 78% (95% CI, 71% to 85%) in the cisplatin and cetuximab groups, respectively (adjusted hazard ratio, 1.63; 95% CI, 0.93 to 2.86; P = .086). The cumulative incidence of locoregional failures at 3 years was 23% (95% CI, 16% to 31%) compared with 9% (95% CI, 4% to 14%) in the cetuximab versus the cisplatin group (Gray's test P = .0036). The cumulative incidence of distant failures did not differ between the treatment groups. Dose escalation in T3-T4 tumors did not increase local control.Cetuximab is inferior to cisplatin regarding locoregional control for concomitant treatment with RT in patients with locoregionally advanced HNSCC. Additional studies are needed to identify possible subgroups that still may benefit from concomitant cetuximab treatment.
Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension
Authors: Emilia M. Swietlik, Pavandeep Ghataorhe, Kasia I. Zalewska, John Wharton, Luke S. Howard, Dolores Taboada, John E. Cannon, Nicholas W. Morrell, Martin R. Wilkins, Mark Toshner, Joanna Pepke-Zaba, Christopher J. Rhodes
Journal: European Respiratory Journal (2020)

Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception, with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations. We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated. We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by receiver operating characteristic analysis to distinguish CTEPH and both healthy (area under the curve (AUC) 0.64–0.94, all p&lt;2×10 −5 ) and disease controls (AUC 0.58–0.77, all p&lt;0.05). Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15–100% of perturbation) in response to PEA were observed in some, but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine and Krebs cycle metabolites. In addition, metabolites associated with CTEPH and gradients showed significant associations with clinical measures of disease severity. We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with pulmonary hypertension and metabolites that respond to PEA surgery could be a suitable noninvasive marker for evaluating future targeted therapeutic interventions.
High frequency of clonal hematopoiesis in Erdheim-Chester disease
Authors: Fleur Cohen Aubart, Damien Roos-Weil, Marine Armand, Alice Marceau-Renaut, Jean-François Emile, Nicolas Duployez, Frédéric Charlotte, Stéphanie Poulain, Raphael Lhote, Zofia Hélias-Rodzewicz, Véronique Della-Valle, Olivier Bernard, Karim Maloum, Florence Nguyen-Khac, Jean Donadieu, Zahir Amoura, Omar Abdel-Wahab, Julien Haroche
Journal: Blood (2020)
OC-059 Whole transcriptome analysis of colon cancer lymph node metastases reveals metastasis driver genes, signatures and effect of lymphoid ecological niche immune profile
Authors: L Lee, LFreeman Mills, S Irshad, LM Wang, I Tomlinson
Journal: Gut (2017)

Introduction  Metastasis is a key hallmark of cancer and the principal cause of death of patients with colorectal cancer (CRC). The analysis of human CRC biospecimens is important to gain a greater understanding of the molecular drivers. Lymph node metastatic (LNM) tumour deposits are particularly interesting as the presence of lymphatic invasion is a histological feature of paramount importance, defining colorectal cancer stage and an important feature determining patient survival.  Method  The novel technique of 3’ RNA sequencing was utilised to generate the GEP from 188 biospecimens from 69 patients with metastatic stage III CRC. Ribonucleic acid (RNA) was extracted from the primary tissue, lymph node metastatic tumour deposit (LNMTD) from each patient (n=69), and an area of normal Lymph node stroma adjacent (n=50), but separate to the LNM.  Results  69 patients were included in this analysis with a mean age of 69.2 years (sd 10.4) and 52.2% of patients were male. 218 genes were differentially expressed between the LNM and primary tumour at p  Conclusion  A thorough understanding of the biological alterations involved in metastasis is important to improve and develop new therapies for patients with CRC. We have put together the largest cancer cohort of paired tumour-metastatic patients. LNM are more aggressive than the primary tumour and the KRAS signalling pathway is preferentially activated. The degree of activation of this pathway is in turn associated with higher risk of disease relapse/death and use and validation of these biomarkers, particularly LNMS classifications may help predict outcomes for stage III CRCs.  Disclosure of Interest  None Declared