tbuckley/cabot-search huggingface dataset:
Two-year trends of taxane-induced neuropathy in women enrolled in a randomized trial of acetyl-l-carnitine (SWOG S0715).
Authors: Dawn L. Hershman, Joseph M. Unger, Katherine D. Crew, Cyrus Ebnesajjad, Heather Greenlee, Louis Fehrenbacher, Carol Moinpour, Lori M. Minasian, Danika L Lew, Siu-Fun Wong, James Lloyd Wade, Michael Fisch, Kathy S. Albain, Norah Lynn Henry
Journal: Journal of Clinical Oncology (2017)

10093 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and disabling side effect of taxanes that leads to suboptimal treatment and adversely affects quality of life. Acetyl-L-Carnitine (ALC) was unexpectedly found to increase CIPN in a randomized trial. We investigated the long-term patterns of CIPN among patients enrolled in this trial. Methods: S0715 was a randomized, double-blind, multi-center trial comparing ALC (1000 mg TID) versus placebo for 24 weeks in women with stage I-III breast cancer undergoing taxane-based chemotherapy. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale at 12 weeks. Additional assessments were conducted at weeks 24, 36, 52 and 104. We examined the reduction of NTX score over 2 years using linear mixed models for longitudinal data, adjusting for stratification factors and the baseline NTX score. Individual assessment time-points were examined using linear regression. Results: SWOG S0715 registered 437 patients, of whom 409 were eligible and evaluable, including 208 assigned to receive ALC and 201 to placebo. Patterns of evaluability were similar over time by arm. The results for the primary outcome of interest, NTX, show a statistically significant (p = 0.01) average difference of -1.39 (95% CI: -2.47 to -0.31) between treatment groups, with the ALC group having lower scores (worse CIPN) on average than the placebo group. These differences were particularly evident at Weeks 24 (p = 0.02), 36 (p = 0.04), and 52 (p = 0.02). A clinically meaningful (≥5 points) reduction in NTX score over baseline was observed more frequently for the ALC vs. control arm (week 24, 41% vs. 34%; week 36, 41% vs. 28%; 1 year, 41% vs. 32%; 2 years, 40% vs. 34%). For both treatment groups 2 year NTX scores were significantly different compared to baseline (p &lt; 0.001). Conclusions: For both groups NTX scores were reduced with taxane-therapy and remained persistently low 2-years following treatment. Twenty-four weeks of ALC therapy resulted in significantly worse CIPN at weeks 24 36 and 52. Understanding the mechanism of this persistent effect may inform prevention and treatment strategies. Clinical trial information: NCT00775645.
Online quantitative monitoring of live cell engineered cartilage growth using diffuse fiber-optic Raman spectroscopy
Authors: Mads S. Bergholt, Michael B. Albro, Molly M. Stevens
Journal: Biomaterials (2017)

Tissue engineering (TE) has the potential to improve the outcome for patients with osteoarthritis (OA). The successful clinical translation of this technique as part of a therapy requires the ability to measure extracellular matrix (ECM) production of engineered tissues in vitro, in order to ensure quality control and improve the likelihood of tissue survival upon implantation. Conventional techniques for assessing the ECM content of engineered cartilage, such as biochemical assays and histological staining are inherently destructive. Raman spectroscopy, on the other hand, represents a non-invasive technique for in situ biochemical characterization. Here, we outline current roadblocks in translational Raman spectroscopy in TE and introduce a comprehensive workflow designed to non-destructively monitor and quantify ECM biomolecules in large (>3 mm), live cell TE constructs online. Diffuse near-infrared fiber-optic Raman spectra were measured from live cell cartilaginous TE constructs over a 56-day culturing period. We developed a multivariate curve resolution model that enabled quantitative biochemical analysis of the TE constructs. Raman spectroscopy was able to non-invasively quantify the ECM components and showed an excellent correlation with biochemical assays for measurement of collagen (R2 = 0.84) and glycosaminoglycans (GAGs) (R2 = 0.86). We further demonstrated the robustness of this technique for online prospective analysis of live cell TE constructs. The fiber-optic Raman spectroscopy strategy developed in this work offers the ability to non-destructively monitor construct growth online and can be adapted to a broad range of TE applications in regenerative medicine toward controlled clinical translation.
A multimodal spatiotemporal cardiac motion atlas from MR and ultrasound data
Authors: Esther Puyol-Antón, Matthew Sinclair, Bernhard Gerber, Mihaela Silvia Amzulescu, Hélène Langet, Mathieu De Craene, Paul Aljabar, Paolo Piro, Andrew P. King
Journal: Medical Image Analysis (2017)

Cardiac motion atlases provide a space of reference in which the motions of a cohort of subjects can be directly compared. Motion atlases can be used to learn descriptors that are linked to different pathologies and which can subsequently be used for diagnosis. To date, all such atlases have been formed and applied using data from the same modality. In this work we propose a framework to build a multimodal cardiac motion atlas from 3D magnetic resonance (MR) and 3D ultrasound (US) data. Such an atlas will benefit from the complementary motion features derived from the two modalities, and furthermore, it could be applied in clinics to detect cardiovascular disease using US data alone. The processing pipeline for the formation of the multimodal motion atlas initially involves spatial and temporal normalisation of subjects' cardiac geometry and motion. This step was accomplished following a similar pipeline to that proposed for single modality atlas formation. The main novelty of this paper lies in the use of a multi-view algorithm to simultaneously reduce the dimensionality of both the MR and US derived motion data in order to find a common space between both modalities to model their variability. Three different dimensionality reduction algorithms were investigated: principal component analysis, canonical correlation analysis and partial least squares regression (PLS). A leave-one-out cross validation on a multimodal data set of 50 volunteers was employed to quantify the accuracy of the three algorithms. Results show that PLS resulted in the lowest errors, with a reconstruction error of less than 2.3 mm for MR-derived motion data, and less than 2.5 mm for US-derived motion data. In addition, 1000 subjects from the UK Biobank database were used to build a large scale monomodal data set for a systematic validation of the proposed algorithms. Our results demonstrate the feasibility of using US data alone to analyse cardiac function based on a multimodal motion atlas.
An Intra-Hepatic TH2 Cytokine Predominance Promotes the Development of PBC-Induced Cirrhosis
Authors: L Golden-Mason, AM Kelly, O Traynor, G McEntee, JE Hegarty, C O'Farrelly
Journal: Endoscopy (2004)

The intra-hepatic cytokine imbalance resulting from chronic inflammation promotes fibrogenesis/cirrhosis. Liver pathology in Primary Biliary Cirrhosis (PBC) has been associated with a progressive shift to an inflammatory or Th1-dominant hepatic cytokine profile. However, murine fibrosis models suggest Th2 (anti-inflammatory) but not Th1-cytokines are fibrogenic. We therefore determined the Th1/Th2 hepatic cytokine profile associated with PBC-induced cirrhosis. Normal liver biopsies (n=14) were obtained from donor organs prior to liver transplantation. PBC cirrhotic liver (n=10) was obtained at time of liver transplantation for end-stage liver disease. Liver was snap-frozen, powdered, soluble protein extracted and cytokines measured by ELISA. Pro-inflammatory cytokines IL-12/IL-18 were significantly increased in PBC compared to normal liver (p<0.05). Th1 cytokines IFN-γ/IL-2 were also increased (p<0.05), suggesting a Th1 shift. However, a 10 fold increase was observed for the Th2/regulatory cytokine IL-10 in PBC liver (p<0.05). This increase in IL-10 reversed the IFN-γ:IL-10 ratio observed in normal liver, suggesting Th2 predominance in PBC. Of interest, anti-inflammatory cytokines IL-13/TGF-β, known fibrogenic agents, were significantly reduced in PBC-liver (p<0.05). Use of IL-10 as an anti-fibrogenic agent is currently being investigated, however, our results suggest that chronic overproduction of IL-10 may promote fibrosis. These findings have important implications for our understanding of the mechanisms involved in and the treatment of fibrosis/cirrhosis.
Towards 'Off-the-Shelf ' Universal Chimeric Antigen Receptor (CAR) T Cells: Mouse Anti-3rd Party Central Memory CD8 Veto Cells Prolong Functional Engraftment of Allogeneic Genetically Modified T Cells
Authors: Noga Or Geva, Rotem Gidron, Aloukick Kumar Singh, Rakefet Sidlik Muskatel, Yair Reisner
Journal: Blood (2016)
MicroRNAs control mRNA fate by compartmentalization based on 3′ UTR length in male germ cells
Authors: Ying Zhang, Chong Tang, Tian Yu, Ruirui Zhang, Huili Zheng, Wei Yan
Journal: Genome biology (2017)

Post-transcriptional regulation of gene expression can be achieved through the control of mRNA stability, cytoplasmic compartmentalization, 3' UTR length and translational efficacy. Spermiogenesis, a process through which haploid male germ cells differentiate into spermatozoa, represents an ideal model for studying post-transcriptional regulation in vivo because it involves a large number of transcripts that are physically sequestered in ribonucleoprotein particles (RNPs) and thus subjected to delayed translation. To explore how small RNAs regulate mRNA fate, we conducted RNA-Seq analyses to determine not only the levels of both mRNAs and small noncoding RNAs, but also their cytoplasmic compartmentalization during spermiogenesis.Among all small noncoding RNAs studied, miRNAs displayed the most dynamic changes in both abundance and subcytoplasmic localization. mRNAs with shorter 3' UTRs became increasingly enriched in RNPs from pachytene spermatocytes to round spermatids, and the enrichment of shorter 3' UTR mRNAs in RNPs coincided with newly synthesized miRNAs that target these mRNAs at sites closer to the stop codon. In contrast, the translocation of longer 3' UTR mRNAs from RNPs to polysomes correlated with the production of new miRNAs that target these mRNAs at sites distal to the stop codon.miRNAs appear to control cytoplasmic compartmentalization of mRNAs based on 3' UTR length. Our data suggest that transcripts with longer 3' UTRs tend to contain distal miRNA binding sites and are thus targeted to polysomes for translation followed by degradation. In contrast, those with shorter 3' UTRs only possess proximal miRNA binding sites, which, therefore, are targeted into RNPs for enrichment and delayed translation.
An estimation model for Oncotype Dx score using routine clinical and pathological parameters.
Authors: Rossana Esther Ruiz Mendoza, Fernando Namuche, Claudio J. Flores, Alfredo Aguilar, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2017)

548 Background: Oncotype Dx(ODX) prognosticates the risk of recurrence and predicts the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). However, its cost makes it prohibitive for many health care systems. Our objective is to develop a model using routine clinical and pathological parameters to estimate ODX high risk category to guide adjuvant chemotherapy decisions. Methods: We retrospectively reviewed ODX and pathology reports from 190 early BC patients (2014 to 2016) in a specialized cancer center. Variables were selected through a multiple linear regression model. Coefficients of statistically significant variables were used to build an equation. Its results were divided into 2 estimated risk categories. ODX RS was also divided into 2 categories; above or below 25 (cut-off in TAILORx and RxPONDER). The final locked model was independently validated in 57 patients. Results: Among the tested variables, tumor size (pT), progesterone receptor (PR), Ki67 and Elston-Ellis grade were significantly associated with ODX RS (Table 1). The linear predictor is: (0.2544 x pT) – (0.0739 x PR) + (0.0861 x Ki67) + (5.4232 x Elston grade). The threshold score for this equation was set on 13 (median value) to discriminate low and high estimated risks. The correct classification rate (CCR) for the training and validation sets was 60% and 56%, respectively. CCR for high risk was 72% and 87% in the training and validation sets, respectively. Conclusions: An equation based on readily available variables correctly classified more than half of cases. Although the overall CCR is modest, our equation is remarkably useful for high risk cases requiring chemotherapy. With further validation, our model could provide a clinically useful estimation of high risk at lower cost. [Table: see text]
Distinguishing aggressive versus nonaggressive prostate cancer using a novel prognostic proteomics biopsy test, ProMark.
Authors: Fred Saad, Michail Shipitsin, Sibgat Choudhury, Teresa Capela, Christina Ernst, Aeron Hurley, Clayton Small, Alexander Kaprelyants, Sadiq Hussain, Hua Chang, Eldar Giladi, James Dunyak, Louis Coupal, Thomas Nifong, Mathieu Latour, David Berman, Peter Blume-Jensen
Journal: Journal of Clinical Oncology (2014)

5090 Background: Current clinical and pathological parameters are insufficient for accurate prediction of progression risk for patients with biopsy Gleason grades 3+3 or 3+4. Reasons for this include biopsy sampling error and pathologist grading discordance, resulting in inaccurate prostate pathology assessment. Consequently, a majority of these patients are over-treated. We have established a novel proteomics-based test, ProMark for automated quantitative measurements of biomarkers from tumor epithelium of intact FFPE biopsy tissue. The test generates a personalized risk score predictive of prostate tumor pathology at the time of biopsy. Methods: A clinical biopsy simulation study using prostatectomy tissue (N=380) was designed to identify 12 biomarkers that can predict surgical Gleason score and lethal disease despite sampling error. Next, a clinical study of 381 biopsies with matched prostatectomy annotation was done to select the best marker subset predictive of prostate pathology. Subsequently, the locked model was validated in a separate blinded clinical study with centralized Gleason grading (N=274). Results: The Promark risk scores were strongly predictive of prostate tumor pathology, the primary study objective. The test was able to separate ‘favorable’ cases [surgical Gleason score 3+3 or 3+4; organ-confined (<=pT2)] from ‘non-favorable’ cases [non-organ-confined disease (≥T3a, N, or M) or surgical Gleason >=4+3] with an AUC of 0.68 (0.61-0.74;p<0.0001). At risk score <0.33 the specificity for prediction of favorable disease is 90% with a predictive value of 81%. At a risk score > 0.8, the predictive value for non-favorable disease is 77%. Importantly, ProMark provides improved personalized disease prediction relative to standard risk stratification systems, including NCCN and D’Amico. Conclusions: We have established a novel prognostic test, ProMark, for prostate cancer biopsies. The risk scores are generated independent of clinical and pathological parameters and correlate strongly with pathological outcome. The test could be useful as an aid in clinical decision making for stratification of patients into good and poor candidates for active surveillance.
Alectinib versus crizotinib in treatment-naive advanced <i>ALK</i>-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study.
Authors: Alice Tsang Shaw, Solange Peters, Tony Mok, Shirish M. Gadgeel, Jin Seok Ahn, Sai-Hong Ignatius Ou, Maurice Perol, Rafal Dziadziuszko, Dong-Wan Kim, Rafael Rosell, Ali Hassan Zeaiter, Ting Liu, Sophie Golding, Bogdana Balas, Johannes Noé, Peter N. Morcos, D. Ross Camidge
Journal: Journal of Clinical Oncology (2017)

LBA9008 Background: Alectinib, a TKI targeting ALK, has shown robust efficacy in crizotinib-naïve/resistant ALK+ NSCLC. J-ALEX showed superiority of alectinib 300mg BID vs crizotinib in Japanese pts with crizotinib-naïve ALK+ NSCLC (progression-free survival [PFS] HR 0.34, p&lt;0.0001). We report primary results from the ALEX study of first-line alectinib 600mg BID vs crizotinib in advanced ALK+ NSCLC (NCT02075840). Methods: This open-label randomized multicenter phase III study enrolled pts with stage IIIB/IV ALK+ NSCLC, determined by central IHC testing. Eligible pts had ECOG PS 0–2 and no prior systemic therapy for advanced NSCLC. Pts with asymptomatic CNS metastases were allowed. Pts (n=303) were randomized 1:1 to receive alectinib 600mg or crizotinib 250mg BID. Primary endpoint: Investigator (Inv)-assessed PFS (RECIST v1.1), with systematic CNS imaging in all pts. Secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression (TTP), objective response rate (ORR), overall survival (OS) and safety. Results: At the primary data cut-off (9 Feb 2017), alectinib demonstrated statistically significant superiority vs crizotinib, reducing risk of progression/death by 53% (HR 0.47, 95% CI 0.34–0.65, p&lt;0.0001); alectinib median PFS was not reached (95% CI 17.7–NE) vs crizotinib 11.1 months (95% CI 9.1–13.1). Key secondary endpoints showed superiority for alectinib vs crizotinib, respectively: IRC PFS, HR 0.50 (95% CI 0.36–0.70; p&lt;0.0001); median PFS 25.7 months (95% CI 19.9–NE) vs 10.4 months (95% CI 7.7–14.6); CNS TTP, cause-specific HR of CNS progression 0.16 (95% CI 0.10–0.28; p&lt;0.0001); ORR (Inv) 83% (95% CI 76–89) vs 76% (95% CI 68–82), p=0.09; OS, based on 25% events, HR 0.76 (95% CI 0.48–1.20; p=0.24). Grade 3/4 AEs were less frequent with alectinib, 41%, vs 50% with crizotinib; fatal AEs occurred in 3% vs 5%, respectively. Rates of AEs leading to discontinuation, dose reduction and interruption were lower with alectinib. Conclusions: Alectinib showed superior efficacy and favorable tolerability compared with crizotinib. ALEX results support alectinib as a new standard of care for treatment-naïve ALK+ NSCLC. Funding: F. Hoffmann-La Roche Clinical trial information: NCT02075840.
Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor
Authors: Kevin Litchfield, Max Levy, Giulia Orlando, Chey Loveday, Philip J Law, Gabriele Migliorini, Amy Holroyd, Peter Broderick, Robert Karlsson, Trine B Haugen, Wenche Kristiansen, Jérémie Nsengimana, Kerry Fenwick, Ioannis Assiotis, ZSofia Kote-Jarai, Alison M Dunning, Kenneth Muir, Julian Peto, Rosalind Eeles, Douglas F Easton, Darshna Dudakia, Nick Orr, Nora Pashayan, D Timothy Bishop, Alison Reid, Robert A Huddart, Janet Shipley, Tom Grotmol, Fredrik Wiklund, Richard S Houlston, Clare Turnbull
Journal: Nature Genetics (2017)
The Value of Tissue Polymerase Chain Reaction Testing for the Diagnosis of Tissue-Invasive Cytomegalovirus Disease Following Allogeneic Hematopoietic Cell Transplantation
Authors: Armin Rashidi, Kiran R Vij, Richard S Buller, Kristine M Wylie, Gregory A Storch, John F DiPersio
Journal: Blood (2016)
Global Remodeling of the Vascular Stem Cell Niche in Bone Marrow of Diabetic Patients
Authors: Gaia Spinetti, Daniela Cordella, Orazio Fortunato, Elena Sangalli, Sergio Losa, Ambra Gotti, Franco Carnelli, Francesco Rosa, Stefano Riboldi, Fausto Sessa, Elisa Avolio, Antonio Paolo Beltrami, Constanza Emanueli, Paolo Madeddu
Journal: Circulation Research (2012)

Rationale: The impact of diabetes mellitus on bone marrow (BM) structure is incompletely understood. Objective: Investigate the effect of type-2 diabetes mellitus (T2DM) on BM microvascular and hematopoietic cell composition in patients without vascular complications. Methods and Results: Bone samples were obtained from T2DM patients and nondiabetic controls (C) during hip replacement surgery and from T2DM patients undergoing amputation for critical limb ischemia. BM composition was assessed by histomorphometry, immunostaining, and flow cytometry. Expressional studies were performed on CD34 pos immunosorted BM progenitor cells (PCs). Diabetes mellitus causes a reduction of hematopoietic tissue, fat deposition, and microvascular rarefaction, especially when associated with critical limb ischemia. Immunohistochemistry documented increased apoptosis and reduced abundance of CD34 pos -PCs in diabetic groups. Likewise, flow cytometry showed scarcity of BM PCs in T2DM and T2DM+critical limb ischemia compared with C, but similar levels of mature hematopoietic cells. Activation of apoptosis in CD34 pos -PCs was associated with upregulation and nuclear localization of the proapoptotic factor FOXO3a and induction of FOXO3a targets, p21 and p27 kip1 . Moreover, microRNA-155, which regulates cell survival through inhibition of FOXO3a, was downregulated in diabetic CD34 pos -PCs and inversely correlated with FOXO3a levels. The effect of diabetes mellitus on anatomic and molecular end points was confirmed when considering background covariates. Furthermore, exposure of healthy CD34 pos -PCs to high glucose reproduced the transcriptional changes induced by diabetes mellitus, with this effect being reversed by forced expression of microRNA-155. Conclusions: We provide new anatomic and molecular evidence for the damaging effect of diabetes mellitus on human BM, comprising microvascular rarefaction and shortage of PCs attributable to activation of proapoptotic pathway.
Network Meta-analysis in Mental Health Research—Reply
Authors: Andre Russowsky Brunoni, Wagner Gattaz, Anna Chaimani
Journal: JAMA Psychiatry (2017)

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Infant Lymphoblastic Leukemia: A Single Center Experience
Authors: Selin Aytac, Inci Yaman Bajin, Barış Kuşkonmaz, Duygu Uckan-Cetinkaya, Ilhan Altan, Sule Unal, Betül Tavil, Fatma Gumruk, A. Murat Tuncer, Mualla Cetin
Journal: Blood (2016)
Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of a Single-Dose Oral Solution of Dabigatran Given after Standard Anticoagulant Therapy in Children (Two Age Groups: 1-&lt;2 and 2-&lt;12 Years Old), with Venous Thromboembolism
Authors: Jacqueline ML Halton, Manuela Albisetti, Matteo Luciani, Fenglei Huang, Branislav Biss, Martina Brueckmann, Savion Gropper, Hugo Maas, Igor Tartakovsky, Lesley G Mitchell
Journal: Blood (2016)