scholarly journals Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

2016 ◽  
Vol 6 (4) ◽  
pp. 439-447 ◽  
Author(s):  
Jarrod W. Barnes ◽  
Adriano R. Tonelli ◽  
Gustavo A. Heresi ◽  
Jennie E. Newman ◽  
Noël E. Mellor ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Precision Medicine ◽  
Relevant Literature ◽  
Vascular Diseases ◽  
Peripheral Circulation ◽  
Response To Therapy ◽  
Protein Glycosylation ◽  
Exhaled Breath ◽  
Peripheral Vasculature ◽  
Novel Methods

Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

Roundtable Discussion of the Impact of the 4th World Symposium on Pulmonary Hypertension

2009 ◽  
Vol 8 (2) ◽  
pp. 89-94
Author(s):  
Robyn J. Barst ◽  
Marc Humbert ◽  
Ivan M. Robbins ◽  
Lewis J. Rubin ◽  
Robyn J. Park
Keyword(s):  
New York ◽  
Pulmonary Hypertension ◽  
Vascular Diseases ◽  
Assistant Professor ◽  
Associate Professor ◽  
Future Research ◽  
Columbia University ◽  
School Of Medicine ◽  
Maryland School ◽  
The Impact

A discussion among attendees of the 4th World Symposium on Pulmonary Hypertension took place to share “an insider's look” into the current and future research and treatment implications in pulmonary hypertension. Myung H. Park, MD, guest editor of this issue of Advances in Pulmonary Hypertension, Assistant Professor of Medicine and Director, Pulmonary Vascular Diseases Program, Division of Cardiology, University of Maryland School of Medicine, Baltimore, moderated the discussion. Participants included Robyn Barst, MD, Professor Emerita, Columbia University, New York; Marc Humbert, MD, PhD, Universite Paris-Sud, French Referal Center for Pulmonary Hypertension, Hopital Antoine-Beclere, Assistance Publique Hopitaux de Paris, Clamart, France; Ivan Robbins, MD, Associate Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and Lewis J. Rubin, MD, Clinical Professor, Department of Medicine, University of California, San Diego.

Novel Methods for Assessment of Right Heart Structure and Function in Pulmonary Hypertension

2012 ◽  
Vol 39 (3) ◽  
pp. 685-701 ◽  
Author(s):  
Gautam K. Singh ◽  
Philip T. Levy ◽  
Mark R. Holland ◽  
Aaron Hamvas
Keyword(s):  
Pulmonary Hypertension ◽  
Structure And Function ◽  
Right Heart ◽  
Novel Methods ◽  
And Function

Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Natalia Bogatcheva ◽  
Sarvesh Chelvanambi ◽  
Xingjuan Chen ◽  
Alexander Obukhov ◽  
Matthias Clauss
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Arterial Disease ◽  
Statin Treatment ◽  
Systemic Circulation ◽  
Vascular Pathology ◽  
Systemic Hypertension ◽  
Dependent Manner ◽  
Specific Expression

Introduction: HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation. Hypothesis: Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin. Methods: Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner. Results: Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment. Conclusions: Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.

scholarly journals Complex Tumor Spheroids, a Tissue-Mimicking Tumor Model, for Drug Discovery and Precision Medicine

2021 ◽  
pp. 247255522110383
Author(s):  
Gurmeet Kaur ◽  
David M. Evans ◽  
Beverly A. Teicher ◽  
Nathan P. Coussens
Keyword(s):  
Drug Discovery ◽  
Precision Medicine ◽  
Cell Lines ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cell Types ◽  
Response To Therapy ◽  
Cancer Drug ◽  
Malignant Cells ◽  
Pancreatic Cell

Malignant tumors are complex tissues composed of malignant cells, vascular cells, structural mesenchymal cells including pericytes and carcinoma-associated fibroblasts, infiltrating immune cells, and others, collectively called the tumor stroma. The number of stromal cells in a tumor is often much greater than the number of malignant cells. The physical associations among all these cell types are critical to tumor growth, survival, and response to therapy. Most cell-based screens for cancer drug discovery and precision medicine validation use malignant cells in isolation as monolayers, embedded in a matrix, or as spheroids in suspension. Medium- and high-throughput screening with multiple cell lines requires a scalable, reproducible, robust cell-based assay. Complex spheroids include malignant cells and two normal cell types, human umbilical vein endothelial cells and highly plastic mesenchymal stem cells, which rapidly adapt to the malignant cell microenvironment. The patient-derived pancreatic adenocarcinoma cell line, K24384-001-R, was used to explore complex spheroid structure and response to anticancer agents in a 96-well format. We describe the development of the complex spheroid assay as well as the growth and structure of complex spheroids over time. Subsequently, we demonstrate successful assay miniaturization to a 384-well format and robust performance in a high-throughput screen. Implementation of the complex spheroid assay was further demonstrated with 10 well-established pancreatic cell lines. By incorporating both human stromal and tumor components, complex spheroids might provide an improved model for tumor response in vivo.

scholarly journals Explainable Transformer-Based Neural Network forthe Prediction of Survival Outcomes in Non-SmallCell Lung Cancer (NSCLC)

2021 ◽  
Author(s):  
Gustavo Arango ◽  
Elly Kipkogei ◽  
Etai Jacob ◽  
Ioannis Kagiampakis ◽  
Arijit Patra
Keyword(s):  
Immune System ◽  
Precision Medicine ◽  
Cancer Patients ◽  
Patient Survival ◽  
Response To Therapy ◽  
Survival Models ◽  
Attractive Alternative ◽  
Survival Prediction ◽  
Molecular Features ◽  
Clinical Measurements

In this paper, we introduce the Clinical Transformer - a recasting of the widely used transformer architecture as a method for precision medicine to model relations between molecular and clinical measurements, and the survival of cancer patients. Although the emergence of immunotherapy offers a new hope for cancer patients with dramatic and durable responses having been reported, only a subset of patients demonstrate benefit. Such treatments do not directly target the tumor but recruit the patient immune system to fight the disease. Therefore, the response to therapy is more complicated to understand as it is affected by the patients physical condition, immune system fitness and the tumor. As in text, where the semantics of a word is dependent on the context of the sentence it belongs to, in immuno-therapy a biomarker may have limited meaning if measured independent of other clinical or molecular features. Hence, we hypothesize that the transformer-inspired model may potentially enable effective modelling of the semantics of different biomarkers with respect to patient survival time. Herein, we demonstrate that this approach can offer an attractive alternative to the survival models utilized incurrent practices as follows: (1) We formulate an embedding strategy applied to molecular and clinical data obtained from the patients. (2) We propose a customized objective function to predict patient survival. (3) We show the applicability of our proposed method to bioinformatics and precision medicine. Applying the clinical transformer to several immuno-oncology clinical studies, we demonstrate how the clinical transformer outperforms other linear and non-linear methods used in current practice for survival prediction. We also show that when initializing the weights of a domain-specific transformer by the weights of a cross-domain transformer, we further improve the predictions. Lastly, we show how the attention mechanism successfully captures some of the known biology behind these therapies

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