tbuckley/cabot-search huggingface dataset:
Iron, Hepcidin, and Death in Human AKI
Authors: David E. Leaf, Mohan Rajapurkar, Suhas S. Lele, Banibrata Mukhopadhyay, Emily A.S. Boerger, Finnian R. Mc Causland, Michele F. Eisenga, Karandeep Singh, Jodie L. Babitt, John A. Kellum, Paul M. Palevsky, Marta Christov, Sushrut S. Waikar
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Dysregulated iron metabolism plays an important pathogenic role in AKI in animal models, but limited data are available on circulating iron parameters in human AKI. To assess the association of plasma catalytic iron, total iron, transferrin, TSAT, ferritin, free hemoglobin, and hepcidin with 60-day mortality, the authors examined observations in a cohort study of 807 critically ill patients with AKI (all requiring RRT) who were enrolled the ARF Trial Network study. They found that higher concentrations of catalytic iron and lower concentrations of hepcidin are each monotonically and independently associated with increased mortality. These findings identify plasma catalytic iron and hepcidin as potentially useful prognostic markers or therapeutic targets in patients with AKI requiring RRT. Background Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. Methods We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. Results Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. Conclusions These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population.
Reporting of <i>R</i><sup>2</sup> Statistics for Mixed-Effects Regression Models
Authors: Elias S. Sotirchos, Kathryn C. Fitzgerald, Ciprian M. Crainiceanu
Journal: JAMA Neurology (2019)

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Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC).
Authors: Lene Alifrangis, Rik Schoemacker, Niels Jorgen Ostergaard Skartved, Rikke Hald, Maria Düring, Clara Montagut, Guillem Argiles, Scott Kopetz, Ivan David Horak, Michael Kragh, Janet R Wade
Journal: Journal of Clinical Oncology (2019)

496 Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2 nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, V max , V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, V max and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.
Comparison of Th1 and Th2 Immune Responses in Chlamydia pneumoniae-infected Peripheral Blood Mononuclear Cells (PBMC) of Adult and Pediatric Asthmatics
Authors: Sue L. Dong, Tamar A. Smith-Norowitz, Margaret R. Hammerschlag, Rauno Joks, Stephan A. Kohlhoff
Journal: Journal of Allergy and Clinical Immunology (2019)
Development and Validation of an <sup>18</sup>F‐Fluorodeoxyglucose–Positron Emission Tomography With Computed Tomography–Based Tool for the Evaluation of Joint Counts and Disease Activity in Patients With Rheumatoid Arthritis
Authors: Sang Jin Lee, Ju Hye Jeong, Chang‐Hee Lee, Byeong‐Cheol Ahn, Jung Su Eun, Na Ri Kim, Jong Whan Kang, Eon Jeong Nam, Young Mo Kang
Journal: Arthritis & Rheumatology (2019)

Objective Clinical joint count assessment is important for detecting synovitis but its reliability is a subject of controversy. This study was undertaken to assess the correlation of positron emission tomography ( PET )–derived parameters in 68 joints with disease activity and to compare the reliability of joint counts between PET with computed tomography ( CT ) and clinical assessment in patients with rheumatoid arthritis ( RA ). Methods We enrolled 91 patients with active RA (69 in a development group and 22 in a validation group) who underwent concurrent 18 F‐fluorodeoxyglucose ( 18 F‐ FDG )– PET ‐ CT and clinical disease activity evaluation. PET ‐derived parameters were compared with disease activity assessed using clinical joint count parameters. A Disease Activity Score ( DAS ) using counts of PET ‐positive joints was developed, and then validation studies were performed in an independent group. Results The number of PET ‐positive joints (of 28 and 68 joints) was significantly correlated with the swollen joint count ( SJC ) and tender joint count ( TJC ) and the DAS in 28 joints using the erythrocyte sedimentation rate ( DAS 28‐ ESR ). Intraobserver and interobserver reliability of PET for the affected joint counts were excellent. Interobserver reliability between nuclear medicine physicians and rheumatologists was good for the SJC and TJC in both 28 joints and 68 joints. After multivariate analyses, including ESR and patient's global assessment of disease activity (Pt GA ) in addition to PET ‐derived parameters, the PET / DAS was derived as (0.063 × number of PET ‐positive joints in 28 joints) + (0.011 × ESR ) + (0.030 × Pt GA ). A significant correlation between the PET / DAS and the DAS 28‐ ESR was confirmed in the validation group ( P &lt; 0.001). Conclusion PET ‐ CT could serve as a sensitive and reliable method in the evaluation of disease activity in RA patients, and may be applicable as a research tool, particularly in clinical trials.
Limb fractures: hospitals are told to check that correct fixation plates were used in surgery
Authors: Jacqui Wise
Journal: BMJ (2019)

Hospitals in England have been told to review all x rays of patients who had metal plates fitted for limb fractures in the past year, in case the wrong type of fixation plate was used.

NHS Improvement and the British Orthopaedic Association issued the patient safety alert after a systematic review of patient records at one NHS trust found seven cases where the wrong type of fixation plate had been used. The plate failed in two cases: the first after a fall and the second after rehabilitation physiotherapy. The cases involved different surgeons, scrub teams, and theatres, and …
Gemcitabine, docetaxel, and capecitabine (GTX) as a first-line regimen in metastatic pancreatic adenocarcinomas (mPAC): A single institution experience.
Authors: Vikas Singh, Vivek R. Sharma
Journal: Journal of Clinical Oncology (2019)

385 Background: After decades of minimal to no therapeutic options, Gemcitabine emerged as the only safe &amp; effective frontline regimen for mPAC. A 3-drug combination regimen, GTX, first optimized by Fine et al in 2009 showed improved progression free (PFS) &amp; median overall survival (mOS) based on a multicentric prospective phase II study. It didn’t receive much wider acceptance likely due to lack of phase III data and emergence of newer regimens such as Gemcitabine plus nab-Paclitaxel (GA) and FOLFIRINOX (FFX). We reviewed our institutions experience with GTX and other regimens in mPAC patients. Methods: We performed a retrospective review of clinical outcomes in patients diagnosed with mPAC between January 2005 and December 2015 and treated at our institution. Attempts were made to include all eligible patients to reduce any selection bias. Results: Fifty patients with mPAC were analyzed for mOS and toxicities with different regimens. 50% patients received GTX while remaining received – FFX (22%), Gemcitabine (14%), GA (4%), FOLFOX (4%) &amp; other (6%) regimens. The mOS for all the patients was 7.67 months (95% CI 5.98-10.81). The mOS was significantly improved in patients who received GTX as first line regimen compared to patients who received non-GTX regimens (9.45 vs 6.08 months; P-0.0157). GTX also showed non-statistically significant improvement in mOS compared to FFX (9.45 vs 6.08 months; P-0.1436). Compared with FFX, GTX was associated with fewer severe GI (40 vs 45.5%; p – 1.00) and hematologic (20 vs 36.4%; p – 0.40) toxicities. Conclusions: GTX significantly improved mOS and had fewer severe toxicities compared to non-GTX regimens. Limitations include the retrospective and non-randomized nature of the study and the small sample size. However, GTX may be considered an alternative first line regimen in mPAC patients who are unable to tolerate aggressive regimens such as FFX and in whom the need to balance quality of life with efficacy is particularly important.
Pharmacokinetics and pharmacodynamics of liposomal chemophototherapy with short drug-light intervals
Authors: Dandan Luo, Kevin A. Carter, Emilie A.G. Molins, Ninfa L. Straubinger, Jumin Geng, Shuai Shao, William J. Jusko, Robert M. Straubinger, Jonathan F. Lovell
Journal: Journal of Controlled Release (2019)
Abstract 16378: Oral Anticoagulation Post Transcatheter Aortic Valve Replacement in Patients With Atrial Fibrillation
Authors: M Chadi Alraies, Homam Moussa Pacha, Kyle Buchanan, Edward Koifman, Arie Steinvil, Toby Rogers, Rebecca Torguson, Linzhi Xu, Itsik Ben-Dor, Augusto Pichard, Lowell Satler, Ron Waksman
Journal: Circulation (2017)

Background: Oral anticoagulation (OAC) management for atrial fibrillation (AF) patients vary following transcatheter aortic valve replacement (TAVR). Warfarin is standard of care for AF patients po...
Effects of a synbiotic on the fecal microbiome and metabolomic profiles of healthy research cats administered clindamycin: a randomized, controlled trial
Authors: Jacqueline C. Whittemore, Jennifer E. Stokes, Joshua M. Price, Jan S. Suchodolski
Journal: Gut Microbes (2019)

Reduction in antibiotic-associated gastrointestinal signs (AAGS) in people co-administered probiotics is believed to result from shifts in the microbiome and metabolome. Amelioration of AAGS in cats secondary to synbiotic administration has recently been demonstrated. Thus, the aim of this randomized, double-blinded, placebo-controlled trial was to characterize associated changes in the fecal microbiome and metabolome. Sixteen healthy research cats received clindamycin with food, followed 1 h later by either a placebo or synbiotic, daily for 21 days. Fecal samples were collected during baseline, antibiotic administration, and 6 weeks after antibiotic discontinuation. Sequencing of 16S rRNA genes was performed, and mass spectrometry was used to determine fecal metabolomic profiles. Results were compared using mixed-model analyses, with P < 0.05 considered significant. Alpha and beta diversity were altered significantly during treatment, with persistent changes in the Shannon and dysbiosis indices. The relative abundance of Actinobacteria (Adlercreutzia, Bifidobacterium, Collinsella, Slackia), Bacteroidia (Bacteroides, Prevotella), Ruminococcaceae (Faecalibacterium, Ruminococcus), Veillonellaceae (Megamonas, Megasphaera, Phascolarctobacterium) and Erysipelotrichaceae ([Eubacterium]) decreased and relative abundance of Clostridiaceae (Clostridium) and Proteobacteria (Enterobacteriaceae) increased during treatment, followed by variable return to baseline relative abundances. Derangements in short-chain fatty acid (SCFA), bile acid, tryptophan, sphingolipid, polyamine, benzoic acid, and cinnaminic acid pathways occurred with significant group by time, group, and time interactions for 10, 5, and 106 metabolites, respectively. Of particular note were changes related to polyamine synthesis. Further investigation is warranted to elucidate the role of these alterations in prevention of AAGS in cats, people, and other animals treated with synbiotics.
Identification of a ‘Safe Haven’ for RT-qPCR Responses in CML: Can We Reduce the Frequency of Molecular Monitoring?
Authors: Simone Claudiani, Aoife Gatenby, Richard Szydlo, Dragana Milojkovic, Emily Ching, George Nesr, Renuka Palanicawander, George Nteliopoulos, Mary Alikian, Jamshid S Khorashad, Letizia Foroni, Jane F. Apperley
Journal: Blood (2017)
Abstract 18902: Reduced Expression of Microrna-146b Contributes to Impair Ischemia-induced Neovascularization in Hypercholesterolemic Conditions
Authors: Michel Desjarlais, Sylvie Dussault, Sharon Harel, Veronica Sanchez, Sabah Hussain, Alain Rivard
Journal: Circulation (2017)

Background: Hypercholesterolemia is an atherosclerotic condition associated with endothelial dysfunction and impaired neovascularization in response to ischemia. This study sought to define the role of the anti-inflammatory microRNA-146b (miR-146b) in that pathophysiology. Methods and results: qRT-PCR analyses showed that the expression of miR-146b is significantly reduced in the ischemic muscles of hypercholesterolemic ApoE-deficient (ApoE-/-) mice, and in HUVECs exposed to oxLDL. Inhibition of miR-146b (antimiR-146b) in native HUVECs impairs angiogenesis in vitro. On the other hand, forced expression of miR-146b using a miR mimic can rescue oxLDL-mediated impairment of endothelial cell migration and tubule formation. Using a mouse model of hindlimb ischemia, we found that intramuscular injection of miR-146b mimic restores blood flow recuperation, increases vascular densities in ischemic muscles, and reduces ischemic damages in hypercholesterolemic ApoE-/- mice. In addition, miR-146b treatment also incre...
Phase II study of avelumab in combination with cetuximab in pre-treated RAS wild-type metastatic colorectal cancer patients: CAVE (cetuximab-avelumab) Colon.
Authors: Teresa Troiani, Erika Martinelli, Davide Ciardiello, Nicoletta Zanaletti, Claudia Cardone, Carola Borrelli, Antonio Avallone, Alfredo Falcone, Evaristo Maiello, Roberto Bordonaro, Daniele Santini, Carlo Garufi, Filippo G. De Braud, Carmine Pinto, Cesare Gridelli, Fortunato Ciardiello
Journal: Journal of Clinical Oncology (2019)

TPS731 Background: The immune system plays a crucial role in modulating response to monoclonal antibodies therapy in cancer. Novel immunecheckpoint inhibitors have demonstrated potent efficacy alone and in combinations with cytotoxic agents in several cancers. In this regard, avelumab in combination with cetuximab might be a relevant rechallenge strategy in RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients treated in first-line with chemotherapy (CT) in combination with anti-EGFR drugs and who achieved a complete or partial response. Methods: CAVE Colon is a single arm, multi-center phase II study designed to evaluate the efficacy of avelumab and cetuximab in pre-treated RAS WT mCRC patients. Eligible patients: pathologically confirmed RAS WT mCRC treated with a first-line CT in combination with an anti-EGFR agent with a major response achieved (complete or partial), who have progressed to a second line therapy, and received no prior immunotherapy. Primary endpoint is overall survival, secondary endpoint are overall response rate according to RECIST 1.1, progression free survival and safety profile. The current study seeks to demonstrate a median OS of 11 months (alternative hypothesis) by the experimental combination for comparison with historical median OS 8.0 (null hypothesis) with standard third line treatments, which correspond to an improvement of OS at six months from 40% to 57%. It was estimated that it would be needed to enroll 66 patients to achieve a 80% power with a one-sided 5% level test. The accrual period will be 18 months and the total duration of the study will be 36 months. Considering a potential drop-out of approximately 15% of patients, a total of 75 patients will be recruited. Seven patients have been enrolled and started treatment to date (September 15, 2018) with avelumab 10 mg/kg q14 as a one-hour i.v. infusion and cetuximab at 400 mg/m 2 over two-hour and subsequently 250 mg/m 2 q 14 as one-hour i.v. infusion until disease progression or unacceptable toxicity. EudraCT number: 2017-004392-32. This study is partially supported by Merck KgA, Darmstadt, Germany. Results: N/A. Conclusions: N/A. Clinical trial information: EudraCT number: 2017-004392-32.
Piecing Together the IgE-Reactivity Profile of Cannabis sativa in a North-Western European Region
Authors: Ine I. Decuyper, Hans-Peter Rihs, Christel Mertens, Athina L. Van Gasse, Margaretha A. Faber, Margo M. Hagendorens, Vito Sabato, Chris H. Bridts, Didier G. Ebo
Journal: Journal of Allergy and Clinical Immunology (2019)
Marrow-Infiltrating Lymphocytes (MILs) Provide a Robust Platform for CAR-T Cell Therapy
Authors: Eric R. Lutz, Valentina Hoyos, Lakshmi Rudraraju, Elizabeth DeOliveira, Srikanta Jana, Ido Weiss, Ivan M. Borrello, Kimberly Noonan
Journal: Blood (2018)
A blood-based assay for diagnosis of early-stage pancreatic cancer.
Authors: Thomas Jens Ettrich, Andreas Wolfgang Berger, Daniel Schwerdel, Anke C. Reinacher-Schick, Waldemar Uhl, Hana Alguel, Helmut Friess, Alexander Koenig, Michael Ghadimi, Eike Gallmeier, Detlef K. Bartsch, Michael Geissler, Ludger Staib, Andrea Tannapfel, Alexander Kleger, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2019)

234 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Biomarker are needed to facilitate early and preferably noninvasive detection of PDAC, which directly may influence patients’ prognosis. Here we aimed to test a new biomarker combination for early PDAC, consisting of thrombospondin-2 (THBS2), CA19-9 and circulating tumor DNA (ctDNA) analysis. Methods: Thirty-nine patients with histologically proven and clearly resectable PDAC (recruited from the NEONAX trial, NCT02047513) were enrolled. Fifteen patients with benign pancreatic disease (intraductal papillary-mucinous neoplasms, IPMN) served as controls. Blood samples were collected prior treatment. KRAS genotyping was performed after isolation of ctDNA from plasma (QIAamp MinElute ccfDNA Kit, Qiagen) by digital droplet PCR ( KRAS Screening Multiplex Kit; QX200 system, both: Bio-Rad). Clinical data and CA 19-9 levels were assessed by ELISA (Roche); THBS2 values were determined by Quantikine ELISA Human Thrombospondin-2 (R&amp;D Systems). Statistical analyses were done by using GraphPad Prism Version 7.00, GraphPad Software, Inc. Results: THBS2 had a c-statistic of 0.73 for all PDAC stages which was comparable to that of CA 19-9 (0.78). The c-statistic was improved to 0.94 by combining CA 19-9, THBS2 and total cfDNA amount. This marker combination performed best for all stages. C-statistics of defined PDAC stages was 0.93, 1.00 and 0.92 for stage I, stage II and stage III, respectively. Of note, the biggest improvement in sensitivity and specificity was seen for stage I PDAC. Here, c-statistic improved from 0.69 or 0.85 for CA 19-9 alone or the combination of CA 19-9 and THBS2, respectively, to 0.93 for the three-marker combination. Conclusions: These data underscore that CA 19-9, THBS2 and cfDNA marker combination constitutes a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC with a remarkable specificity. Larger studies are needed to examine the power of this approach.