tbuckley/cabot-search huggingface dataset:
Hexafil: Individualized or guideline-concordant G-CSF usage—Is there a bridge?
Authors: Hans Tesch, DeLi Tilly Chang, Bertram Ottillinger
Journal: Journal of Clinical Oncology (2013)

e20563 Background: G-CSF is frequently used to prevent/treat chemotherapy (CT)-induced neutropenia (CIN) in cancer patients. The non-interventional observational study HEXAFIL on the use of biosimilar filgrastim (EP-2006) was conducted to provide further insight into G-CSF usage with respect to guidelines (EORTC, ASCO) in Germany. Methods: Patients who signed informed consents were enrolled. Data were documented for up to 3 consecutive G-CSF-supported CT-cycles. Rates of modified CT-treatments (dose modification/discontinuation of drug) were calculated by the number and percentage of patients affected; data presented are based on the first CT-cycle. In/Exclusion criteria: www.germanctr.de . Results: A total of 709 breast cancer patients were included in this interim analysis (9/2012). Only 2.0% of all patients experienced febrile neutropenia (FN) and 8.7% neutropenic complications. A majority of patients received primary (49.4%, PP) or secondary prophylaxis (33.6%, SP) with the biosimilar G-CSF. However, 17.1% were treated interventional (TX). Median G-CSF treatment duration was 4d with median start on day 6 after CT. Of all documented patients, 96.3% received CT without modifications; in 3.0% of the patients dose of CT was modified and in 0.8% CT drug was discontinued. To investigate potential effects of guideline-concordant G-CSF treatment the following populations were selected: patients with FN-risk &gt; 20% and (1) G-CSF initiation &lt; day 5 after CT (ie, “guideline-concordant” GL; N=104) or (2) G-CSF initiation starting &gt; day 6 after CT (ie, “individualized” IND; N=169). As expected, IND-patients experienced FN twice as often as GL-patients (4.1% vs 1.9%). Moreover, CT treatment had to be modified in 6.5% of IND-patients compared with only 1.0% of GL-patients. Conclusions: A total of 96.3% of all analyzed patients receiving biosimilar G-CSF-supported CT-cycles had no modification to their CT-regimen. Data indicate that IND-patients showed a higher rate of CT disturbances/FNs and, as a consequence, should “cross the bridge” to potentially benefit from guideline-concordant treatment. However, further data are required to detail the impact of individualized G-CSF treatment. Clinical trial information: DRKS00000313.
Distinct Contributions of Whisker Sensory Cortex and Tongue-Jaw Motor Cortex in a Goal-Directed Sensorimotor Transformation
Authors: Johannes M. Mayrhofer, Sami El-Boustani, Georgios Foustoukos, Matthieu Auffret, Keita Tamura, Carl C.H. Petersen
Journal: Neuron (2019)

The neural circuits underlying goal-directed sensorimotor transformations in the mammalian brain are incompletely understood. Here, we compared the role of primary tongue-jaw motor cortex (tjM1) and primary whisker sensory cortex (wS1) in head-restrained mice trained to lick a reward spout in response to whisker deflection. Two-photon microscopy combined with microprisms allowed imaging of neuronal network activity across cortical layers in transgenic mice expressing a genetically encoded calcium indicator. Early-phase activity in wS1 encoded the whisker sensory stimulus and was necessary for detection of whisker stimuli. Activity in tjM1 encoded licking direction during task execution and was necessary for contralateral licking. Pre-stimulus activity in tjM1, but not wS1, was predictive of lick direction and contributed causally to small preparatory jaw movements. Our data reveal a shift in coding scheme from wS1 to tjM1, consistent with the hypothesis that these areas represent cortical start and end points for this goal-directed sensorimotor transformation.
LOXL2 Upregulates Phosphorylation of Ezrin to Promote Cytoskeletal Reorganization and Tumor Cell Invasion
Authors: Xiu-Hui Zhan, Ji-Wei Jiao, Hai-Feng Zhang, Xiu-E Xu, Jian-Zhong He, Run-Liu Li, Hai-Ying Zou, Zhi-Yong Wu, Shao-Hong Wang, Jian-Yi Wu, Lian-Di Liao, Juan-Juan Wang, Yin-Wei Cheng, Kai Zhang, Gera Neufeld, Li-Yan Xu, En-Min Li
Journal: Cancer Research (2019)

Lysyl oxidase-like 2 (LOXL2), a copper-dependent enzyme of the lysyl oxidase family and its nonsecreted, catalytically dead spliced isoform L2Δ13, enhance cell migration and invasion, stimulate filopodia formation, modulate the expression of cytoskeletal genes, and promote tumor development and metastasis in vivo. We previously showed that LOXL2 reorganizes the actin cytoskeleton in esophageal squamous cell carcinoma (ESCC) cells, however, the underlying molecular mechanisms were not identified. Here, using interactome analysis, we identified ezrin (EZR), fascin (FSCN1), heat shock protein beta-1 (HSPB1), and tropomodulin-3 (TMOD3) as actin-binding proteins that associate with cytoplasmic LOXL2, as well as with its L2Δ13 variant. High levels of LOXL2 and L2Δ13 and their cytoskeletal partners correlated with poor clinical outcome in patients with ESCC. To better understand the significance of these interactions, we focused on the interaction of LOXL2 with ezrin. Phosphorylation of ezrin at T567 was greatly reduced following depletion of LOXL2 and was enhanced following LOXL2/L2Δ13 reexpression. Furthermore, LOXL2 depletion inhibited the ability of ezrin to promote tumor progression. These results suggest that LOXL2-induced ezrin phosphorylation, which also requires PKCα, is critical for LOXL2-induced cytoskeletal reorganization that subsequently promotes tumor cell invasion and metastasis in ESCC. In summary, we have characterized a novel molecular mechanism that mediates, in part, the protumorigenic activity of LOXL2. These findings may enable the future development of therapeutic agents targeting cytoplasmic LOXL2. SIGNIFICANCE: LOXL2 and its spliced isoform L2Δ13 promote cytoskeletal reorganization and invasion of esophageal cancer cells by interacting with cytoplasmic actin-binding proteins such as ezrin.
The Immunoscore: Colon Cancer and Beyond
Authors: Helen K. Angell, Daniela Bruni, J. Carl Barrett, Ronald Herbst, Jérôme Galon
Journal: Clinical Cancer Research (2019)

Tumors evolve in close interaction with their microenvironment, which encompasses a continual tension between the developing tumor and the host immune system. Clinical trials have shown that appropriate enhancement of a tumor immune response can lead to long-lasting clinical responses and patient benefit. Understanding the contribution of the immune contexture, in addition to the molecular subtype across different tumor indications, is a significant knowledge gap with limited sagacity to drive rational immunotherapy combinations. To better inform clinical studies, we must first strive to understand the multifaceted elements of the tumor-immune interaction, the spatiotemporal interplay of numerous different immune cell types, in conjunction with an understanding of the oncogenic drivers and mutations that may lead to presentation of neoepitopes and could drive changes within the tumor microenvironment. In this review, we discuss the Immunoscore and its probable universal characteristic. The overlay of immune quantification with the molecular segments of disease and how this may benefit identification of patients at high risk of tumor recurrence will be discussed. The Immunoscore may translate to provide a tumor agnostic method to define immune fitness of a given tumor and predict and stratify patients who will benefit from certain therapies (in particular immune therapies) and, ultimately, help save the lives of patients with cancer.
Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study
Authors: Steven D Nathan, Jürgen Behr, Harold R Collard, Vincent Cottin, Marius M Hoeper, Fernando J Martinez, Tamera J Corte, Anne M Keogh, Hanno Leuchte, Nesrin Mogulkoc, Silvia Ulrich, Wim A Wuyts, Zhen Yao, Francis Boateng, Athol U Wells
Journal: The Lancet Respiratory Medicine (2019)
Analysis of new N descriptors on prognosis of esophageal cancer with positive lymph nodes in a Chinese population.
Authors: Yaping Xu
Journal: Journal of Clinical Oncology (2012)

e14678 Background: The 7 th edition of the American Joint Committee on Cancer / Union International Against Cancer (AJCC/UICC) TNM staining system for esophageal cancer (EC) has been published. N descriptors are now divided into N0, N1, N2 and N3. In this study, we aimed to validate the prognostic ability of the new N staging system in patients with resectable EC and positive lymph nodes, and evaluate whether the new N staging system can help the decision-making for postoperative adjuvant therapy in this population. Methods: From 2002 to 2008, patients with stage T1-4N1-3M0 EC who underwent esophagectomy were retrospectively analyzed. EC was classified according to the new N staging system. Kaplan-Meier method and Cox regression analysis were employed to compare overall survival (OS). Results: A total of545 patients met the inclusion criteria: 346 (63.5%) received esophagectomy alone, 199 (36.5%) received esophagectomy and adjuvant radiotherapy, and 36.1% (197/545) received esophagectomy and adjuvant chemotherapy. Univariate analysis and multivariate analysis revealed significant difference in OS among patients with EC at different N stages (p&lt;0.001). Significant difference in OS was also present among patients receiving radiotherapy (p&lt;0.001) and those undergoing chemotherapy (p&lt;0.001). Subgroup analysis indicated that postoperative adjuvant therapy did not significantly affect the OS among patients with EC at different N stages. Conclusions: Our results validated the prognostic ability of new N staging system. N descriptor is an independent prognostic factor in patients with resectable EC who were positive for lymph nodes. Further studies are required to clarify the role of new N staging system in the decision-making for postoperative adjuvant therapy in this population.
Photothermal-pH-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy with negligible skin phototoxicity
Authors: Dapeng Chen, Yunyun Tang, Jiawei Zhu, Jiaojiao Zhang, Xuejiao Song, Wenjun Wang, Jinjun Shao, Wei Huang, Peng Chen, Xiaochen Dong
Journal: Biomaterials (2019)
Abstract 16712: Aortic Stiffness is Associated With Coronary Artery Intimal Thickening in Pediatric Heart Transplant Recipients
Authors: Anita T Cote, Martin C Hosking, Christine Voss, George G Sandor, Kevin C Harris
Journal: Circulation (2017)

Introduction: Pediatric heart transplant patients (HTx) are at risk for cardiac allograft vasculopathy (CAV), a leading cause of graft failure and mortality. CAV is diagnosed by selective coronary ...
Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils
Authors: Akira Takeda, Maija Hollmén, Denis Dermadi, Junliang Pan, Kevin Francis Brulois, Riina Kaukonen, Tapio Lönnberg, Pia Boström, Ilkka Koskivuo, Heikki Irjala, Masayuki Miyasaka, Marko Salmi, Eugene C. Butcher, Sirpa Jalkanen
Journal: Immunity (2019)
Author Correction: Microbiota therapy acts via a regulatory T cell MyD88/RORγt pathway to suppress food allergy
Authors: Azza Abdel-Gadir, Emmanuel Stephen-Victor, Georg K. Gerber, Magali Noval Rivas, Sen Wang, Hani Harb, Leighanne Wang, Ning Li, Elena Crestani, Sara Spielman, William Secor, Heather Biehl, Nicholas DiBenedetto, Xiaoxi Dong, Dale T. Umetsu, Lynn Bry, Rima Rachid, Talal A. Chatila
Journal: Nature Medicine (2019)
Development and Testing of Improved Models to Predict Payment Using Centers for Medicare &amp; Medicaid Services Claims Data
Authors: Harlan M. Krumholz, Frederick Warner, Andreas Coppi, Elizabeth W. Triche, Shu-Xia Li, Shiwani Mahajan, Yixin Li, Susannah M. Bernheim, Jacqueline Grady, Karen Dorsey, Nihar R. Desai, Zhenqiu Lin, Sharon-Lise T. Normand
Journal: JAMA Network Open (2019)

Predicting payments for particular conditions or populations is essential for research, benchmarking, public reporting, and calculations for population-based programs. Centers for Medicare & Medicaid Services (CMS) models often group codes into disease categories, but using single, rather than grouped, diagnostic codes and leveraging present on admission (POA) codes may enhance these models.To determine whether changes to the candidate variables in CMS models would improve risk models predicting patient total payment within 30 days of hospitalization for acute myocardial infarction (AMI), heart failure (HF), and pneumonia.This comparative effectiveness research study used data from Medicare fee-for-service hospitalizations for AMI, HF, and pneumonia at acute care hospitals from July 1, 2013, through September 30, 2015. Payments across multiple care settings, services, and supplies were included and adjusted for geographic and policy variations, corrected for inflation, and winsorized. The same data source was used but varied for the candidate variables and their selection, and the method used by CMS for public reporting that used grouped codes was compared with variations that used POA codes and single diagnostic codes. Combinations of use of POA codes, separation of index admission diagnoses from those in the previous 12 months, and use of individual International Classification of Diseases, Ninth Revision, Clinical Modification codes instead of grouped diagnostic categories were tested. Data analysis was performed from December 4, 2017, to June 10, 2019.The models' goodness of fit was compared using root mean square error (RMSE) and the McFadden pseudo R2.Among the 1 943 049 total hospitalizations of the study participants, 343 116 admissions were for AMI (52.5% male; 37.4% aged ≤74 years), 677 044 for HF (45.5% male; 25.9% aged ≤74 years), and 922 889 for pneumonia (46.4% male; 28.2% aged ≤74 years). The mean (SD) 30-day payment was $23 103 ($18 221) for AMI, $16 365 ($12 527) for HF, and $17 097 ($12 087) for pneumonia. Each incremental model change improved the pseudo R2 and RMSE. Incorporating all 3 changes improved the pseudo R2 of the patient-level models from 0.077 to 0.129 for AMI, from 0.042 to 0.129 for HF, and from 0.114 to 0.237 for pneumonia. Parallel improvements in RMSE were found for all 3 conditions.Leveraging POA codes, separating index from previous diagnoses, and using single diagnostic codes improved payment models. Better models can potentially improve research, benchmarking, public reporting, and calculations for population-based programs.
Plant-Microbe Interactions Facing Environmental Challenge
Authors: Yu Ti Cheng, Li Zhang, Sheng Yang He
Journal: Cell Host & Microbe (2019)

In the past four decades, tremendous progress has been made in understanding how plants respond to microbial colonization and how microbial pathogens and symbionts reprogram plant cellular processes. In contrast, our knowledge of how environmental conditions impact plant-microbe interactions is less understood at the mechanistic level, as most molecular studies are performed under simple and static laboratory conditions. In this review, we highlight research that begins to shed light on the mechanisms by which environmental conditions influence diverse plant-pathogen, plant-symbiont, and plant-microbiota interactions. There is a great need to increase efforts in this important area of research in order to reach a systems-level understanding of plant-microbe interactions that are more reflective of what occurs in nature. In the past four decades, tremendous progress has been made in understanding how plants respond to microbial colonization and how microbial pathogens and symbionts reprogram plant cellular processes. In contrast, our knowledge of how environmental conditions impact plant-microbe interactions is less understood at the mechanistic level, as most molecular studies are performed under simple and static laboratory conditions. In this review, we highlight research that begins to shed light on the mechanisms by which environmental conditions influence diverse plant-pathogen, plant-symbiont, and plant-microbiota interactions. There is a great need to increase efforts in this important area of research in order to reach a systems-level understanding of plant-microbe interactions that are more reflective of what occurs in nature.
Getting to the heart of the matter in a multisystem disorder: Erdheim–Chester disease
Authors: Andrea Buono, Ilaria Bassi, Caterina Santolamazza, Antonella Moreo, Patrizia Pedrotti, Alice Sacco, Nuccia Morici, Cristina Giannattasio, Fabrizio Oliva, Enrico Ammirati
Journal: The Lancet (2019)
Machine Learning to Predict the Likelihood of Acute Myocardial Infarction
Authors: Martin P. Than, John W. Pickering, Yader Sandoval, Anoop S.V. Shah, Athanasios Tsanas, Fred S. Apple, Stefan Blankenberg, Louise Cullen, Christian Mueller, Johannes T. Neumann, Raphael Twerenbold, Dirk Westermann, Agim Beshiri, Nicholas L. Mills, Peter M George, A Mark Richards, Richard W Troughton, Sally J Aldous, Andrew R Chapman, Atul Anand, Jaimi Greenslade, William Parsonage, Jasper Boeddinghaus, Karin Wildi, Thomas Nestelberger, Patrick Badertscher, Shaoqing Du, Janel Huang, Stephen W Smith, Nils A Sörensen, Francisco Ojeda
Journal: Circulation (2019)

Variations in cardiac troponin concentrations by age, sex, and time between samples in patients with suspected myocardial infarction are not currently accounted for in diagnostic approaches. We aimed to combine these variables through machine learning to improve the assessment of risk for individual patients.A machine learning algorithm (myocardial-ischemic-injury-index [MI3]) incorporating age, sex, and paired high-sensitivity cardiac troponin I concentrations, was trained on 3013 patients and tested on 7998 patients with suspected myocardial infarction. MI3 uses gradient boosting to compute a value (0-100) reflecting an individual's likelihood of a diagnosis of type 1 myocardial infarction and estimates the sensitivity, negative predictive value, specificity and positive predictive value for that individual. Assessment was by calibration and area under the receiver operating characteristic curve. Secondary analysis evaluated example MI3 thresholds from the training set that identified patients as low risk (99% sensitivity) and high risk (75% positive predictive value), and performance at these thresholds was compared in the test set to the 99th percentile and European Society of Cardiology rule-out pathways.Myocardial infarction occurred in 404 (13.4%) patients in the training set and 849 (10.6%) patients in the test set. MI3 was well calibrated with a very high area under the receiver operating characteristic curve of 0.963 [0.956-0.971] in the test set and similar performance in early and late presenters. Example MI3 thresholds identifying low- and high-risk patients in the training set were 1.6 and 49.7, respectively. In the test set, MI3 values were <1.6 in 69.5% with a negative predictive value of 99.7% (99.5-99.8%) and sensitivity of 97.8% (96.7-98.7%), and were ≥49.7 in 10.6% with a positive predictive value of 71.8% (68.9-75.0%) and specificity of 96.7% (96.3-97.1%). Using these thresholds, MI3 performed better than the European Society of Cardiology 0/3-hour pathway (sensitivity, 82.5% [74.5-88.8%]; specificity, 92.2% [90.7-93.5%]) and the 99th percentile at any time point (sensitivity, 89.6% [87.4-91.6%]); specificity, 89.3% [88.6-90.0%]).Using machine learning, MI3 provides an individualized and objective assessment of the likelihood of myocardial infarction, which can be used to identify low- and high-risk patients who may benefit from earlier clinical decisions.URL: https://www.anzctr.org.au. Unique identifier: ACTRN12616001441404.
In vitro screening of anticancer drug penetration into tumor tissue: taxanes
Authors: Alastair H. Kyle, Lynsey A. Huxham, Devon M. Yeoman, Andrew I. Minchinton
Journal: Cancer Research (2005)

5936  The failure of many anticancer drugs to control the growth of solid cancers may stem in part from inadequate delivery to tumour regions distant from vasculature. In this study we use a novel, effect-based assay that employs multilayered cell culture (MCC), a tissue-engineered disc grown from tumour cells on a permeable membrane. MCCs are similar to multicellular spheroids but their planar nature permits flux through the cultures to be more easily measured. Like spheroids they exhibit a gradient in proliferation but since MCCs grow as discs, this gradient forms as a mirror image from either side towards the middle. In this study, we exploit this symmetry by exposing MCCs to drugs from one side and then comparing their effect on the exposed side versus the far side of the cultures. This approach circumvents issues that normally arise from the biochemical gradients that occur with distance into tissue (e.g. changing intrinsic sensitivity of cells to drugs with depth into tissue). In this study we have compared the tissue penetration of the microtubule targeting agents paclitaxel and docetaxel. The distribution of drug effect within the cultures was assessed 2 days after exposure via immunodetection of S-phase cells using bromodeoxyuridine. Using an automated computer analysis routine, the effect of the drugs in the first three cell layers located on either edge of the cultures relative to controls was then assessed. Paclitaxel exhibited better tissue penetration, exerting a more equal effect within the cultures, than docetaxel. Over the concentration range studied, 0.03 - 3 μM, paclitaxel exhibited a ∼3-fold gradient in drug concentration across the MCCs while docetaxel was greater than 10-fold. As expected, docetaxel exhibited a greater effect on the side directly exposed to drug as compared with paclitaxel, but showed less effect on the far sides. This was consistent with its higher rate of cellular uptake relative to paclitaxel leading to increased consumption by the first layers of cells and resulting in less drug reaching further into the tissue. Only at concentrations greater than 1 μM was docetaxel able to exert an equal effect on both sides. Interestingly, MCC growth-delay, as measured by thickness, was similar for both drugs. Results obtained with the MCCs will be compared with xenograft experiments in which S-phase cells are mapped in relation to tumour vasculature. This model could be applied as a screening system for the discovery of biologically active drugs, which exhibit desirable penetration properties. This research is supported by the Canadian Institutes for Health Research and the Michael Smith Foundation for Health Research.
Abstract 18026: Pro-angiogenic Dual Gene Therapy in Chronic Diabetic Hindlimb Ischemia with Ultrasound Mediated Delivery of miR-126 and VEGF Plasmid DNA
Authors: Wei J Cao, Pratiek N Matkar, Hao H Chen, Yu J Kim, Dmitriy Rudenko, Michael Kuliszewski, Howard Leong-Poi
Journal: Circulation (2014)

Background: MicroRNA (miR)-126 is an endothelial cell specific microRNA that regulates angiogenesis by blocking Sprouty-related protein (SPRED1) and phosphoinositol-3 kinase (PI3K) two endogenous i...