tbuckley/cabot-search huggingface dataset:
Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis
Authors: Karin Tran-Lundmark, Phan-Kiet Tran, Gabrielle Paulsson-Berne, Vincent Fridén, Raija Soininen, Karl Tryggvason, Thomas N. Wight, Michael G. Kinsella, Jan Borén, Ulf Hedin
Journal: Circulation Research (2008)

Heparan sulfate (HS) has been proposed to be antiatherogenic through inhibition of lipoprotein retention, inflammation, and smooth muscle cell proliferation. Perlecan is the predominant HS proteoglycan in the artery wall. Here, we investigated the role of perlecan HS chains using apoE null (ApoE0) mice that were cross-bred with mice expressing HS-deficient perlecan ( Hspg2 Δ3/Δ3 ). Morphometry of cross-sections from aortic roots and en face preparations of whole aortas revealed a significant decrease in lesion formation in ApoE0/ Hspg2 Δ3/Δ3 mice at both 15 and 33 weeks. In vitro, binding of labeled mouse triglyceride-rich lipoproteins and human LDL to total extracellular matrix, as well as to purified proteoglycans, prepared from ApoE0/ Hspg2 Δ3/Δ3 smooth muscle cells was reduced. In vivo, at 20 minutes influx of human 125 I-LDL or mouse triglyceride-rich lipoproteins into the aortic wall was increased in ApoE0/ Hspg2 Δ3/Δ3 mice compared to ApoE0 mice. However, at 72 hours accumulation of 125 I-LDL was similar in ApoE0/ Hspg2 Δ3/Δ3 and ApoE0 mice. Immunohistochemistry of lesions from ApoE0/ Hspg2 Δ3/Δ3 mice showed decreased staining for apoB and increased smooth muscle α-actin content, whereas accumulation of CD68-positive inflammatory cells was unchanged. We conclude that the perlecan HS chains are proatherogenic in mice, possibly through increased lipoprotein retention, altered vascular permeability, or other mechanisms. The ability of HS to inhibit smooth muscle cell growth may also influence development as well as instability of lesions.
Blinatumomab + Tyrosine Kinase Inhibitors with No Chemotherapy in BCR-ABL-Positive or IKZF1-Deleted or FLT3-ITD-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia Patients: High Molecular Remission Rate and Toxicity Profile
Authors: Andrey N. Sokolov, Elena N. Parovichnikova, Vera V. Troitskaya, Larisa A. Kuzmina, Irina V. Galtseva, Sergei M. Kulikov, Sergey N. Bondarenko, Julia O. Davidova, Nikolay M. Kapranov, Irina A. Lukyanova, Tatiana I. Lobanova, Ekaterina I. Usikova, Ksenija I. Zarubina, Valeriy G. Savchenko
Journal: Blood (2017)
Similarities and differences between the immunopathogenesis of COVID-19–related pediatric multisystem inflammatory syndrome and Kawasaki disease
Authors: Ana Esteve-Sole, Jordi Anton, Rosa Maria Pino-Ramirez, Judith Sanchez-Manubens, Victoria Fumadó, Claudia Fortuny, María Rios-Barnes, Joan Sanchez-de-Toledo, Mónica Girona-Alarcón, Juan Manuel Mosquera, Silvia Ricart, Cristian Launes, Mariona Fernández de Sevilla, Cristina Jou, Carmen Muñoz-Almagro, Eva González-Roca, Andrea Vergara, Jorge Carrillo, Manel Juan, Daniel Cuadras, Antoni Noguera-Julian, Iolanda Jordan, Laia Alsina
Journal: Journal of Clinical Investigation (2021)

Multisystem inflammatory syndrome associated with the SARS-CoV-2 pandemic has recently been described in children (MIS-C), partially overlapping with Kawasaki disease (KD). We hypothesized that (a) MIS-C and prepandemic KD cytokine profiles may be unique and justify the clinical differences observed, and (b) SARS-CoV-2–specific immune complexes (ICs) may explain the immunopathology of MIS-C. Seventy-four children were included: 14 with MIS-C, 9 patients positive for SARS-CoV-2 by PCR without MIS-C (COVID), 14 with prepandemic KD, and 37 healthy controls (HCs). Thirty-four circulating cytokines were quantified in pretreatment serum or plasma samples and the presence of circulating SARS-CoV-2 ICs was evaluated in MIS-C patients. Compared with HCs, the MIS-C and KD groups showed most cytokines to be significantly elevated, with IFN-γ–induced response markers (including IFN-γ, IL-18, and IP-10) and inflammatory monocyte activation markers (including MCP-1, IL-1α, and IL-1RA) being the main triggers of inflammation. In linear discriminant analysis, MIS-C and KD profiles overlapped; however, a subgroup of MIS-C patients (MIS-Cplus) differentiated from the remaining MIS-C patients in IFN-γ, IL-18, GM-CSF, RANTES, IP-10, IL-1α, and SDF-1 and incipient signs of macrophage activation syndrome. Circulating SARS-CoV-2 ICs were not detected in MIS-C patients. Our findings suggest a major role for IFN-γ in the pathogenesis of MIS-C, which may be relevant for therapeutic management.
Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient
Authors: Hila Milo Rasouly, Vimla Aggarwal, Louise Bier, David B. Goldstein, Ali G. Gharavi
Journal: Annals of Internal Medicine (2021)

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.
Histone deacetylase inhibitors for therapy of retinoblastoma
Authors: Clifton Dalgard, Jon Yang, Kurt van Quill, Joan O'Brien
Journal: Cancer Research (2007)

697  Retinoblastoma is a pediatric cancer and blinding eye disease. Combination chemotherapy is the current firstline therapy for larger RB tumors. Histone deacetylase (HDAC) inhibitors have demonstrated efficacy for the treatment of various human cancers. In this study, we systematically characterized the potential utility of HDAC inhibitors for the treatment of retinoblastoma. Treatment of retinoblastoma cell lines (Y79, WERI-Rb1, Rb143) and human primary retinoblastoma cells (Rb641) with various HDAC inhibitors significantly decreased cell viability in a concentration dependent manner. HDAC inhibitor treatment also resulted in G1 cell cycle arrest and apoptotic cell death as demonstrated by increased caspase-3/7 activity and annexin V binding. In vitro cell viability assays using HDAC inhibitors in combination with one of the standard agents in RB therapy (carboplatin, etoposide, or vincristine) displayed additive or synergistic cytotoxic effects. We also tested the therapeutic effects of the benzamide, MS-275, in a transgenic murine model of retinoblastoma. In a dose escalation study, we observed no retinal toxicity after a single 1 uL intraocular injection of up to 10 umol/L MS-275. A single intraperitoneal injection of up to 4 mg MS-275 was used to study the drug’s ability to cross the blood-retinal barrier. An increase in the level of acetylated histone H3 protein from whole eye extracts confirmed intraocular penetration of MS-275 after systemic treatment. Retinoblastoma tumor burden was significantly reduced in animals treated with 20 mg/kg MS-275 intraperitoneally every other day for 21 days, relative to vehicle treated controls.
Conversion from unresectable to resectable liver metastases in real-world patients with liver-only metastatic colorectal cancer (mCRC) treated with FOLFOXIRI plus bevacizumab: The Conversion trial.
Authors: Shahid Ahmed, Deborah Anderson, Haji I. Chalchal, Lynn Dwernychuk, Dilip Gill, Josh Gitlin, Austin Hammond, Rani Kanthan, Duc Le, June Lim, Rajan Rakheja, Nazmi Sari, Franco Vizeacoumar, Adnan Zaidi, Michael Moser
Journal: Journal of Clinical Oncology (2021)

TPS147 Background: Patients with mCRC generally have a limited life expectancy, however, a small number of patients with liver-only mCRC could be cured following metastasectomy. In highly selected patients with mCRC, FOLFOXIRI (5FU, oxaliplatin, and irinotecan) plus bev results in high response rates. However, very limited evidence is available about efficacy of this regimen in real-world patients with liver-only mCRC. Furthermore, there is paucity of biomarkers that predict liver metastasectomy in such patients. The current study aims a) to evaluate rate of conversion from unresectable to resectable liver metastases in real-world patients with liver-only mCRC following FOLFOXIRI-bev, b) to identify predictive markers including an early PET-FDG response that correlate with curative surgery, &amp; c) to determine disease control rate, overall survival, quality of life, treatment toxicities, and cost-effectiveness of surgery. Methods: In this pragmatic phase 2 study, 37 patients with liver-only unresectable mCRC who are deemed eligible for FOLFOXIRI-bev by their oncologist will be recruited at the two major cancer centers in Saskatchewan. Patients will receive FOLFOXIRI-bev every two weeks for a total of 12 cycles and will undergo periodic imaging tests. The resectability of liver metastases will be determined by a multidisciplinary team. For those patients who are not able to undergo a curative surgery, a doublet chemotherapy regimen ±bev will be continued at the discretion of treating oncologist. . The prognostic and predictive value of mutations in specific genes involved in cell proliferation, cell death resistance, angiogenesis, and invasion in colorectal cancer along with the relationship between the abundance and characteristics of exRNA and conversion rate and survival will be assessed. Logistic regression and Cox proportional analyses will be performed to assess correlation between an eight-week FDG-PET/CT response to chemotherapy and other biomarkers and rate of removal of metastases and survival, respectively. This pragmatic study will help to determine conversion rate in real-world patients with FOLFOXIRI plus bev and role of early FDG-PET/CT scan response and other biomarkers in predicting metastasectomy along with cost-effectiveness of this approach. Clinical trial information: NCT03401294.
Effect of Tidal Volume on Pulmonary Outcomes After Surgery—Reply
Authors: Dharshi Karalapillai, Ary Serpa Neto, Rinaldo Bellomo
Journal: JAMA (2021)

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Risk Stratification Among Survivors of Cardiac Arrest Considered for Coronary Angiography
Authors: Ahmed A. Harhash, Teresa L. May, Chiu-Hsieh Hsu, Sachin Agarwal, David B. Seder, Michael R. Mooney, Nainesh Patel, John McPherson, Paul McMullan, Richard Riker, Eldar Soreide, Karen G. Hirsch, Pascal Stammet, Alison Dupont, Sten Rubertsson, Hans Friberg, Niklas Nielsen, Tanveer Rab, Karl B. Kern
Journal: Journal of the American College of Cardiology (2021)
Prognostic value of KRAS and PI3K pathway mutations for advanced pancreatic ductal adenocarcinoma (PDAC) patients (pts).
Authors: Adam Diehl, Lindsay Marie Hannan, Elena Gabriela Chiorean
Journal: Journal of Clinical Oncology (2021)

424 Background: KRAS mutation (MUT) variants (var) have been associated with differential clinical outcomes in advanced PDAC pts (Hendifar, 2020). Recent data from PDAC cell lines suggests that, unlike KRAS G12D/V, the KRAS G12R var is unable to interact with p110α PI3Kα and relies on KRAS-independent p110γ PI3K activity to support macropinocytosis, a nutrient uptake process necessary for tumor growth (Hobbs, 2020). Methods: We retrospectively reviewed advanced PDAC pts who received at least first-line (1L) systemic therapy and underwent next generation sequencing (NGS) at University of Washington between 2013 and 2020. We analyzed, using Fisher’s exact test, whether KRAS var were associated with PI3K pathway mutations (PI3K MUT). Using multivariate (Cox proportional hazards) analysis, we compared overall survival (OS) and progression-free survival (PFS) from start of 1L therapy for pts whose tumors harbored any KRAS var with and without stratification by PI3K MUT status. Results: 127 pts had NGS (96% tissue, 4% ctDNA). Median OS (mOS) and PFS were 16.8 months (mos) and 8.6 mos, respectively. 111 PDAC were KRAS MUT (87%): 43 (39%) G12D, 35 (32%) G12V, 23 (21%) G12R, 1 (0.9%) G12C, 6 (5%) Q61. 15 PDAC (12%) had 16 PI3K MUT, including 7 PIK3CA, 3 AKT2, 3 RICTOR, 1 PTEN, 1 PIK3C2B, and 1 PIK3R1. PI3K MUT occurred in 26% of tumors with KRAS G12R vs 8% in other KRAS var (p=0.0265). In multivariate analysis controlling for age, performance status, stage at diagnosis, type of 1L chemotherapy, TP53 MUT and GATA6 amplification status, pts with KRAS G12R var PDAC vs other variants had longer mOS (20.4 vs 14.5 mos, HR 0.67 (95% CI 0.47 – 0.93), p=0.0215) and mPFS on 1L therapy (12.2 vs 6.8mos, HR 0.60 (95% CI 0.40 – 0.85), p=0.0040). In pts with KRAS G12R var PDAC, concurrent PI3K MUT vs PI3K WT associated with shorter mOS (19.4 vs 24.2mos, HR 2.79 (95% CI 0.97 – 10.6), p=0.0570). In pts with non-G12R KRAS var tumors, PI3K MUT vs WT did not confer shorter OS (mOS 17.6 vs 14.5 mos, HR 1.20 (95% CI 0.72 – 2.0), p=0.55). Conclusions: KRAS G12R PDAC have a higher incidence of PI3K MUT than other KRAS var. KRAS G12R status may confer improved prognosis vs other KRAS variants, albeit this benefit is offset by the presence of concurrent PI3K MUT.
A phase Ib multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients with advanced recurrent or unresectable gastric and gastroesophageal adenocarcinoma (aGEC) after at least one line of treatment with a fluoropyrimidine and platinum containing regimen.
Authors: Farshid Dayyani, Kit Tam, Edward Kim, Parvin Keshtmand, Samuel Ejadi, Fa Chyi Lee, May Thet Cho
Journal: Journal of Clinical Oncology (2021)

TPS251 Background: In 2L+ aGEC, taxanes +/- ramucirumab or IRI are recommended treatment options. IRI has been tested in multiple single arm and randomized trials in second line (2L)+ aGEC, with reported objective response rates (ORR) in the 15-29% range and median progression-free survival (PFS) of &lt;3 months (mo). Outcomes for aGEC remain poor with a median overall survival (OS) of 9.6 mo and PFS at 6 mo (PFS6) of only 36%. The TAGS trial in third line (3L)+ aGEC showed a significant improvement in OS from 3.6 mo to 5.7 mo with FTD/TPI over placebo. A 2L treatment with taxanes after 1L platinum containing regimens is currently associated with worsening peripheral neuropathy, which often leads to dose reductions, treatment delays, and a reduced quality of life for patients. The feasibility of FTD/TPI combined with IRI (+/- bevacizumab) in a modified 14-day schedule has been published for advanced colon cancer (PMID: 31924737) with no new safety signals while also encouraging activity in a cohort of heavily pretreated patients. Methods: Hypothesis:The combination of FTD/TPI with IRI in 2L+ aGEC is feasible, clinically active, and provides a treatment option which is not associated with development of peripheral neuropathy. Trial Design: 2-center, prospective, open label, non-randomized phase 1b trial. Eligibility: Diagnosis of aGEC, 1+ line of treatment including a fluoropyrimidine/platinum, ECOG 0-2, adequate organ function. Treatment:FTD/TPI 25mg/m2 on days 1-5 and IRI 180mg/m2 on day 1 every 14 days. G-CSF in allowed as needed. Primary objective: Feasibility of the regimen and estimate of efficacy. Primary endpoint: PFS6. Secondary objectives: OS, ORR, adverse events. Total number of pts to be enrolled N=20. Current enrollment (September 2020) N=14. Clinical trial information: NCT04074343.
Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR
Authors: Hervé Avet-Loiseau, Jesus San-Miguel, Tineke Casneuf, Shinsuke Iida, Sagar Lonial, Saad Z. Usmani, Andrew Spencer, Philippe Moreau, Torben Plesner, Katja Weisel, Jon Ukropec, Christopher Chiu, Sonali Trivedi, Himal Amin, Maria Krevvata, Priya Ramaswami, Xiang Qin, Mia Qi, Steven Sun, Ming Qi, Rachel Kobos, Nizar J. Bahlis
Journal: Journal of Clinical Oncology (2021)

In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies.MRD was assessed via next-generation sequencing (10-5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations.The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival.Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.
Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy
Authors: Mark Canney, Sean J. Barbour, Yuyan Zheng, Rosanna Coppo, Hong Zhang, Zhi-Hong Liu, Keiichi Matsuzaki, Yusuke Suzuki, Ritsuko Katafuchi, Heather N. Reich, Daniel Cattran
Journal: Journal of the American Society of Nephrology (2020)

Background On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. Methods In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to &lt;1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). Results During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. Conclusions Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.
Development of a Core Outcome Set for Clinical Trials in Non-infectious Uveitis of the Posterior Segment
Authors: Mohammad O. Tallouzi, Jonathan M. Mathers, David J. Moore, Nicholas Bucknall, Melanie J. Calvert, Philip I. Murray, Alastair K. Denniston, Annabelle Okada, Daniel Vasconcelos-Santos, Douglas A. Jabs, Janet Davis, Justine Smith, Manfred Zierhut, Marc D. de Smet, David Maese, Gaynor M. Hollis, Graham Roberts, Joanna Emerson, Joseph Quigley, Katie Cave, Kenneth Twigge, Maxine McCarthy, Ruth Davis, Eileen Twigge, Helen Roberts, Martin Emerson, Racheal Maese, Bashar Mohammed, Catey Bunce, Erika Damato, Miles Stanford, Natraj Poonit, Richard Lee, Srilakshmi M. Sharma
Journal: Ophthalmology (2021)
AB0168 Psychopathologic study in patients with fibromyalgia
Authors: AR De la Serna, M Serra, J Wulf
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Fibromyalgia is considered a psychosomatic disease. <h3>Objectives</h3> This study was conducted to assess psychopathology changes in patients with fibromyalgia. <h3>Methods</h3> We evaluated sequential outpatients with ACR criteria of fibromyalgia, through interviews by clinical psychologist, a psychiatrist and test for general psychopathology (Golberg), depression (Beck) and anxiety (Stai). <h3>Results</h3> Demographic data: Twenty-nine patients were evaluated (4 men). Twenty-seven were married. Eighteen were immigrants. Twenty-four had children. Eight were unemployed. Thirteen were house wives. Three non qualified professionals. Eleven retailers and two qualified professionals. Psychopathologic results: Eight patients were totally normal. Golberg'test: twelve patients were normal. Five had mild and twelve severe alterations. Beck'test: thirteen patients were normal. Four suffered from mild depression. Four moderate, four severe and four more severe depression. Stai'test: ten patients didnt anxiety. Eighteen were trait anxiety and sixteen state anxiety. Interview: nineteen patients had sleep problems. Twenty-four were fatigued and fifteen had relapse thinking. <h3>Conclusion</h3> The absence of psychopathology in 28% of patients with fibromyalgia, and the mild changes in others, allows us to differentiate between psychogenic rheumatism and fibromyalgia, and obligues us to establish a psychogenic evaluation in these.