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Unsupervised machine learning reveals risk stratifying glioblastoma tumor cells.
Leelatian N, Sinnaeve J, Mistry AM, Barone SM, Brockman AA, Diggins KE, Greenplate AR, Weaver KD, Thompson RC, Chambless LB, Mobley BC, Ihrie RA, Irish JM
(2020) Elife 9:
MeSH Terms: Algorithms, Glioblastoma, Humans, Pilot Projects, Tumor Cells, Cultured, Unsupervised Machine Learning
Show Abstract · Added July 1, 2020
A goal of cancer research is to reveal cell subsets linked to continuous clinical outcomes to generate new therapeutic and biomarker hypotheses. We introduce a machine learning algorithm, Risk Assessment Population IDentification (RAPID), that is unsupervised and automated, identifies phenotypically distinct cell populations, and determines whether these populations stratify patient survival. With a pilot mass cytometry dataset of 2 million cells from 28 glioblastomas, RAPID identified tumor cells whose abundance independently and continuously stratified patient survival. Statistical validation within the workflow included repeated runs of stochastic steps and cell subsampling. Biological validation used an orthogonal platform, immunohistochemistry, and a larger cohort of 73 glioblastoma patients to confirm the findings from the pilot cohort. RAPID was also validated to find known risk stratifying cells and features using published data from blood cancer. Thus, RAPID provides an automated, unsupervised approach for finding statistically and biologically significant cells using cytometry data from patient samples.
© 2020, Leelatian et al.
3 Communities
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6 MeSH Terms
Laryngotracheal Mucosal Surface Expression of Candidate Biomarkers in Idiopathic Subglottic Stenosis.
Liu MM, Motz KM, Murphy MK, Yin LX, Ding D, Gelbard A, Hillel AT
(2021) Laryngoscope 131: 342-349
MeSH Terms: Adult, Aged, Biomarkers, Dilatation, Disease Progression, Endoscopy, Female, Fibrosis, Humans, Laryngeal Mucosa, Laryngostenosis, Larynx, Male, Membrane Proteins, Middle Aged, Pilot Projects, Predictive Value of Tests, Respiratory Function Tests, Trachea, Transcriptome
Show Abstract · Added July 30, 2020
OBJECTIVES - Idiopathic subglottic stenosis (iSGS) is an inflammatory process leading to fibrosis and narrowing of the laryngotracheal airway. There is variability in patient response to surgical intervention, but the mechanisms underlying this variability are unknown. In this pilot study, we measure expression of candidate targets at the mucosal surface of the subglottis in iSGS patients. We aim to identify putative biomarkers for iSGS that provide insights into the molecular basis of disease progression, yield a gene signature for the disease, and/or predict a response to therapy.
STUDY DESIGN - In vitro comparative study of human cells.
METHODS - Levels of candidate transcripts and proteins were measured in healthy and stenotic laryngotracheal tissue specimens taken from the mucosal surface in 16 iSGS patients undergoing endoscopic balloon dilation. Pre- and post-operative pulmonary function test and patient reported voice and breathing outcomes were also assessed. Unsupervised clustering was used to define patient subgroups based on expression profile.
RESULTS - Pulmonary function and voice and breathing outcome metrics demonstrated significant post-operative improvement. Transcript levels of αSMA, CCL2, COL1A1, COL3A1, FN1, IFNG, and TGFB1 and protein levels of CCL2, IFNG, and IL-6 were significantly upregulated in stenotic as compared to healthy tissues. Marked heterogeneity was observed in the patterns of expression of candidate markers across individuals and tissue types. Patient subgroups defined by expression profile did not show a statistically significant difference in dilation interval.
CONCLUSION - Pro-inflammatory and pro-fibrotic pathways are significantly upregulated along the mucosal surface of stenotic laryngotracheal tissues, and CCL2 and IFNG merit further investigation as potential iSGS biomarkers.
LEVEL OF EVIDENCE - 4 Laryngoscope, 131:342-349, 2021.
© 2020 The American Laryngological, Rhinological and Otological Society, Inc.
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20 MeSH Terms
Primary prevention of venous thromboembolism with apixaban for multiple myeloma patients receiving immunomodulatory agents.
Cornell RF, Goldhaber SZ, Engelhardt BG, Moslehi J, Jagasia M, Harrell S, Rubinstein SM, Hall R, Wyatt H, Piazza G
(2020) Br J Haematol 190: 555-561
MeSH Terms: Aged, Comorbidity, Consolidation Chemotherapy, Factor Xa Inhibitors, Female, Hemorrhage, Humans, Immunologic Factors, Lenalidomide, Maintenance Chemotherapy, Male, Middle Aged, Multiple Myeloma, Myocardial Infarction, Pilot Projects, Proof of Concept Study, Prospective Studies, Pulmonary Embolism, Pyrazoles, Pyridones, Stroke, Thalidomide, Thrombophilia, Venous Thromboembolism, Venous Thrombosis
Show Abstract · Added May 29, 2020
Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well-tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single-arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non-major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six-month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non-major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low-dose apixaban was safe and well-tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low-dose apixaban as a standard primary prevention anti-thrombotic strategy for patients with MM receiving IMiDs.
© 2020 British Society for Haematology and John Wiley & Sons Ltd.
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25 MeSH Terms
Nicotinic treatment of post-chemotherapy subjective cognitive impairment: a pilot study.
Vega JN, Albert KM, Mayer IA, Taylor WD, Newhouse PA
(2019) J Cancer Surviv 13: 673-686
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Cancer Survivors, Cognition, Cognitive Dysfunction, Female, Humans, Male, Middle Aged, Neoplasms, Nicotine, Pilot Projects, Quality of Life, Self Report, Survivors, Transdermal Patch
Show Abstract · Added March 3, 2020
PURPOSE - Persistent chemotherapy-related cognitive impairment (pCRCI) is commonly reported following cancer treatment and negatively affects quality of life; however, there is currently no pharmacological treatment indicated for pCRCI. This pilot study obtained preliminary data regarding the use of transdermal nicotine patches as a therapeutic strategy for women with pCRCI to (1) reduce subjective cognitive complaints and (2) enhance objective cognitive performance in breast, colon, lymphoma, or ovarian cancer survivors with pCRCI.
METHODS - Participants were randomized to either placebo (n = 11) or transdermal nicotine (n = 11) for 6 weeks, followed by 2 weeks of treatment withdrawal for a total of 8 weeks. Participants were assessed using both subjective and objective measures of cognitive functioning at five visits before, during, and after treatment.
RESULTS - Over the course of the study, women in both groups improved substantially in severity of self-reported cognitive complaints measured by Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairments regardless of treatment arm. Additionally, objective cognitive performance measures improved in both groups; however, there was no significant difference in improvement between groups.
CONCLUSIONS - Due to a large placebo response, we were unable to determine if a drug effect was present. However, we did observe substantial improvement in self-reported cognitive symptoms, likely resulting from factors related to participation in the trial rather than specific drug treatment effects.
TRIAL REGISTRATION - The study was registered with clinicaltrials.gov (trial registration: NCT02312943).
IMPLICATIONS FOR CANCER SURVIVORS - These results suggest that women with pCRCI can exhibit improvement in subjective cognition, with attention paid to symptoms and close follow-up over a short period of time.
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18 MeSH Terms
Endothelial-Dependent Vasomotor Dysfunction in Infants After Cardiopulmonary Bypass.
Krispinsky LT, Stark RJ, Parra DA, Luan L, Bichell DP, Pietsch JB, Lamb FS
(2020) Pediatr Crit Care Med 21: 42-49
MeSH Terms: Acetylcholine, Biomarkers, Cardiac Surgical Procedures, Cardiopulmonary Bypass, Cardiovascular Diseases, Child, Child, Preschool, Cytokines, Endothelium, Vascular, Heart Defects, Congenital, Humans, Infant, Microcirculation, Nitric Oxide, Pilot Projects, Postoperative Complications, Prospective Studies, Severity of Illness Index, Vascular Resistance, Vasodilator Agents, Vasomotor System
Show Abstract · Added July 2, 2019
OBJECTIVES - Cardiopulmonary bypass-induced endothelial dysfunction has been inferred by changes in pulmonary vascular resistance, alterations in circulating biomarkers, and postoperative capillary leak. Endothelial-dependent vasomotor dysfunction of the systemic vasculature has never been quantified in this setting. The objective of the present study was to quantify acute effects of cardiopulmonary bypass on endothelial vasomotor control and attempt to correlate these effects with postoperative cytokines, tissue edema, and clinical outcomes in infants.
DESIGN - Single-center prospective observational cohort pilot study.
SETTING - Pediatric cardiac ICU at a tertiary children's hospital.
PATIENTS - Children less than 1 year old requiring cardiopulmonary bypass for repair of a congenital heart lesion.
INTERVENTION - None.
MEASUREMENTS AND MAIN RESULTS - Laser Doppler perfusion monitoring was coupled with local iontophoresis of acetylcholine (endothelium-dependent vasodilator) or sodium nitroprusside (endothelium-independent vasodilator) to quantify endothelial-dependent vasomotor function in the cutaneous microcirculation. Measurements were obtained preoperatively, 2-4 hours, and 24 hours after separation from cardiopulmonary bypass. Fifteen patients completed all laser Doppler perfusion monitor (Perimed, Järfälla, Sweden) measurements. Comparing prebypass with 2-4 hours postbypass responses, there was a decrease in both peak perfusion (p = 0.0006) and area under the dose-response curve (p = 0.005) following acetylcholine, but no change in responses to sodium nitroprusside. Twenty-four hours after bypass responsiveness to acetylcholine improved, but typically remained depressed from baseline. Conserved endothelial function was associated with higher urine output during the first 48 postoperative hours (R = 0.43; p = 0.008).
CONCLUSIONS - Cutaneous endothelial dysfunction is present in infants immediately following cardiopulmonary bypass and recovers significantly in some patients within 24 hours postoperatively. Confirmation of an association between persistent endothelial-dependent vasomotor dysfunction and decreased urine output could have important clinical implications. Ongoing research will explore the pattern of endothelial-dependent vasomotor dysfunction after cardiopulmonary bypass and its relationship with biochemical markers of inflammation and clinical outcomes.
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21 MeSH Terms
Magnetization Transfer MRI of Breast Cancer in the Community Setting: Reproducibility and Preliminary Results in Neoadjuvant Therapy.
Virostko J, Sorace AG, Wu C, Ekrut D, Jarrett AM, Upadhyaya RM, Avery S, Patt D, Goodgame B, Yankeelov TE
(2019) Tomography 5: 44-52
MeSH Terms: Adult, Breast, Breast Neoplasms, Community Health Centers, Female, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Middle Aged, Neoadjuvant Therapy, Neoplasm, Residual, Pilot Projects, Reproducibility of Results, Treatment Outcome
Show Abstract · Added March 25, 2019
Repeatability and reproducibility of magnetization transfer magnetic resonance imaging of the breast, and the ability of this technique to assess the response of locally advanced breast cancer to neoadjuvant therapy (NAT), are determined. Reproducibility scans at 3 different 3 T scanners, including 2 scanners in community imaging centers, found a 16.3% difference (n = 3) in magnetization transfer ratio (MTR) in healthy breast fibroglandular tissue. Repeatability scans (n = 10) found a difference of ∼8.1% in the MTR measurement of fibroglandular tissue between the 2 measurements. Thus, MTR is repeatable and reproducible in the breast and can be integrated into community imaging clinics. Serial magnetization transfer magnetic resonance imaging performed at longitudinal time points during NAT indicated no significant change in average tumoral MTR during treatment. However, histogram analysis indicated an increase in the dispersion of MTR values of the tumor during NAT, as quantified by higher standard deviation ( = .005), higher full width at half maximum ( = .02), and lower kurtosis ( = .02). Patients' stratification into those with pathological complete response (pCR; n = 6) at the conclusion of NAT and those with residual disease (n = 9) showed wider distribution of tumor MTR values in patients who achieved pCR after 2-4 cycles of NAT, as quantified by higher standard deviation ( = .02), higher full width at half maximum ( = .03), and lower kurtosis ( = .03). Thus, MTR can be used as an imaging metric to assess response to breast NAT.
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14 MeSH Terms
Early urine electrolyte patterns in patients with acute heart failure.
Collins SP, Jenkins CA, Baughman A, Miller KF, Storrow AB, Han JH, Brown NJ, Liu D, Luther JM, McNaughton CD, Self WH, Peng D, Testani JM, Lindenfeld J
(2019) ESC Heart Fail 6: 80-88
MeSH Terms: Acute Disease, Aged, Biomarkers, Disease Progression, Diuretics, Female, Follow-Up Studies, Heart Failure, Humans, Male, Middle Aged, Pilot Projects, Prognosis, Prospective Studies, Sodium, Stroke Volume
Show Abstract · Added October 25, 2018
AIMS - We conducted a prospective study of emergency department (ED) patients with acute heart failure (AHF) to determine if worsening HF (WHF) could be predicted based on urinary electrolytes during the first 1-2 h of ED care. Loop diuretics are standard therapy for AHF patients. A subset of patients hospitalized for AHF will develop a blunted natriuretic response to loop diuretics, termed diuretic resistance, which often leads to WHF. Early detection of diuretic resistance could facilitate escalation of therapy and prevention of WHF.
METHODS AND RESULTS - Patients were eligible if they had an ED AHF diagnosis, had not yet received intravenous diuretics, had a systolic blood pressure > 90 mmHg, and were not on dialysis. Urine electrolytes and urine output were collected at 1, 2, 4, and 6 h after diuretic administration. Worsening HF was defined as clinically persistent or WHF requiring escalation of diuretics or administration of intravenous vasoactives after the ED stay. Of the 61 patients who qualified in this pilot study, there were 10 (16.3%) patients who fulfilled our definition of WHF. At 1 h after diuretic administration, patients who developed WHF were more likely to have low urinary sodium (9.5 vs. 43.0 mmol; P < 0.001) and decreased urine sodium concentration (48 vs. 80 mmol/L; P = 0.004) than patients without WHF. All patients with WHF had a total urine sodium of <35.4 mmol at 1 h (100% sensitivity and 60% specificity).
CONCLUSIONS - One hour after diuretic administration, a urine sodium excretion of <35.4 mmol was highly suggestive of the development of WHF. These relationships require further testing to determine if early intervention with alternative agents can prevent WHF.
© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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16 MeSH Terms
Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA in New-Onset Type 1 Diabetes.
Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ, Type 1 Diabetes TrialNet ATG-GCSF Study Group
(2018) Diabetes Care 41: 1917-1925
MeSH Terms: Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin A, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult
Show Abstract · Added May 2, 2019
OBJECTIVE - A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that ) low-dose ATG/GCSF or ) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).
RESEARCH DESIGN AND METHODS - A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided value < 0.025.
RESULTS - The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) ( = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo ( = 0.031). HbA was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, = 0.002 and 0.011, respectively.
CONCLUSIONS - Low-dose ATG slowed decline of C-peptide and reduced HbA in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.
© 2018 by the American Diabetes Association.
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MeSH Terms
A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.
Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J
(2018) Eur Respir J 51:
MeSH Terms: Adult, Aged, Angiotensin-Converting Enzyme 2, Animals, Biomarkers, Cytokines, Female, Gene Expression, Humans, Hypertension, Pulmonary, Male, Middle Aged, Peptidyl-Dipeptidase A, Pilot Projects, Proof of Concept Study, Proto-Oncogene Proteins, Pulmonary Artery, Receptors, G-Protein-Coupled, Superoxide Dismutase, Swine, Vascular Resistance
Show Abstract · Added March 26, 2019
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Copyright ©ERS 2018.
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3 Members
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21 MeSH Terms
The Combined Utility of Ex Vivo IFN-γ Release Enzyme-Linked ImmunoSpot Assay and In Vivo Skin Testing in Patients with Antibiotic-Associated Severe Cutaneous Adverse Reactions.
Trubiano JA, Strautins K, Redwood AJ, Pavlos R, Konvinse KC, Aung AK, Slavin MA, Thursky KA, Grayson ML, Phillips EJ
(2018) J Allergy Clin Immunol Pract 6: 1287-1296.e1
MeSH Terms: Adult, Aged, Aged, 80 and over, Anti-Bacterial Agents, Drug Eruptions, Enzyme-Linked Immunospot Assay, Female, Humans, Interferon-gamma, Leukocytes, Mononuclear, Male, Middle Aged, Pilot Projects, Skin Tests, Young Adult
Show Abstract · Added March 30, 2020
BACKGROUND - For severe cutaneous adverse reactions (SCARs) associated with multiple antibiotics dosed concurrently, clinical causality is challenging and diagnostic approaches are limited, leading to constricted future antibiotic choices.
OBJECTIVE - To examine the combined utility of in vivo and ex vivo diagnostic approaches at assigning drug causality in a cohort of patients with antibiotic-associated (AA)-SCARs.
METHODS - Patients with AA-SCARs were prospectively recruited between April 2015 and February 2017. In vivo testing (patch testing or delayed intradermal testing) was performed to the implicated antibiotic(s) at the highest nonirritating concentration and read at 24 hours through 1 week. Ex vivo testing used patient peripheral blood mononuclear cells (PBMCs) stimulated with a range of pharmacologically relevant concentrations of implicated antibiotics to measure dose-dependent IFN-γ release from CD4+ and CD8+ T cells via an enzyme-linked immunoSpot assay.
RESULTS - In 19 patients with AA-SCARs, combined in vivo and ex vivo testing assigned antibiotic causality in 15 (79%) patients. Ten patients (53%) with AA-SCARs were positive on IFN-γ release enzyme-linked immunoSpot assay, with an overall reported sensitivity of 52% (95% CI, 29-76) and specificity of 100% (95% CI, 79-100), with improved sensitivity noted in acute (within 1 day to 6 weeks after SCAR onset) testing (75%) and in patients with higher phenotypic scores (59%). There was increased use of narrow-spectrum beta-lactams and antibiotics from within the implicated class following testing in patients with a positive ex vivo or in vivo test result.
CONCLUSIONS - We demonstrate the potential utility of combined in vivo and ex vivo testing in patients with AA-SCARs to assign drug causality with high specificity.
Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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