-
1.
Dynamic personalized risk prediction in chronic heart failure patients: a longitudinal, clinical investigation of 92 biomarkers (Bio-SHiFT study).
Klimczak-Tomaniak, D, de Bakker, M, Bouwens, E, Akkerhuis, KM, Baart, S, Rizopoulos, D, Mouthaan, H, van Ramshorst, J, Germans, T, Constantinescu, A, et al
Scientific reports. 2022;(1):2795
Abstract
The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .
-
2.
Machine Learning Application in a Phase I Clinical Trial Allows for the Identification of Clinical-Biomolecular Markers Significantly Associated With Toxicity.
Bedon, L, Cecchin, E, Fabbiani, E, Dal Bo, M, Buonadonna, A, Polano, M, Toffoli, G
Clinical pharmacology and therapeutics. 2022;(3):686-696
Abstract
Machine learning (ML) algorithms have been used to forecast clinical outcomes or drug adverse effects by analyzing different data sets such as electronic health records, diagnostic data, and molecular data. However, ML implementation in phase I clinical trial is still an unexplored strategy that implies challenges such as the selection of the best development strategy when dealing with limited sample size. In the attempt to better define prechemotherapy baseline clinical and biomolecular predictors of drug toxicity, we trained and compared five ML algorithms starting from clinical, blood biochemistry, and genotype data derived from a previous phase Ib study aimed to define the maximum tolerated dose of irinotecan (FOLFIRI (folinic acid, fluorouracil, and irinotecan) plus bevacizumab regimen) in patients with metastatic colorectal cancer. During cross-validation the Random Forest algorithm achieved the best performance with a mean Matthews correlation coefficient of 0.549 and a mean accuracy of 80.4%; the best predictors of dose-limiting toxicity at baseline were hemoglobin, serum glutamic oxaloacetic transaminase (SGOT), and albumin. The feasibility of a prediction model prototype was in principle assessed using the two distinct dose escalation cohorts, where in the validation cohort the model scored a Matthews correlation coefficient of 0.59 and an accuracy of 82.0%. Moreover, we found a strong relationship between SGOT and irinotecan pharmacokinetics, suggesting its role as surrogates' estimators of the irinotecan metabolism equilibrium. In conclusion, the potential application of ML techniques to phase I study could provide clinicians with early prediction tools useful both to ameliorate the management of clinical trials and to make more adequate treatment decisions.
-
3.
Baseline Diabetes Knowledge Assessment Amongst Adults With Type 1 and Type 2 Diabetes Receiving Eye Care at a Tertiary Ophthalmic Centre in Canada.
Sivachandran, N, Ahmad, A, Qian, J, Moinul, P, Barbosa, J, Farrokhyar, F, Chaudhary, V
Canadian journal of diabetes. 2021;(1):22-26
Abstract
OBJECTIVES The aim of this work was to assess the current state of baseline knowledge of diabetes and diabetic retinopathy (DR) in new patients referred to a tertiary retina service from their primary eye care provider. METHODS This single-centre, prospective, observational study included patients presenting to the retina clinic at the Hamilton Regional Eye Institute, a major tertiary referral centre, for their initial consultation for diabetes- or DR-associated complications. Upon recruitment into the study, patients were asked to complete a 35-item questionnaire regarding diabetes and associated complications. All data were coded and analyzed using statistical software. RESULTS A total of 98 patients participated in the study, which included 50 men and 48 women. Seventy-eight patients (79.6%) were Caucasian. We found that 56.1% (n=55) of the patients did not know the meaning of "HbA1C" (glycated hemoglobin) and only 26.5% of patients sampled were aware of their DR status. Bivariate analysis revealed that patients who had postsecondary education (p<0.001) or those who had education on complications of diabetes (p<0.05) were more likely to know their DR status. More importantly, it was found that 56.1% of patients expressed interest in a future diabetes seminar. CONCLUSIONS It is evident that a significant proportion of patients do not have adequate knowledge of diabetes or DR, and this is related to their level of education and lack of being taught about diabetes complications. Our findings may guide prevention initiatives by primary eye care providers and promote increased awareness about diabetes and DR for prevention of disease complications, including blindness.
-
4.
Nutritional markers and proteome in patients undergoing treatment for pulmonary tuberculosis differ by geographic region.
Jarsberg, LG, Kedia, K, Wendler, J, Wright, AT, Piehowski, PD, Gritsenko, MA, Shi, T, Lewinsohn, DM, Sigal, GB, Weiner, MH, et al
PloS one. 2021;(5):e0250586
Abstract
INTRODUCTION Contemporary phase 2 TB disease treatment clinical trials have found that microbiologic treatment responses differ between African versus non-African regions, the reasons for which remain unclear. Understanding host and disease phenotypes that may vary by region is important for optimizing curative treatments. METHODS We characterized clinical features and the serum proteome of phase 2 TB clinical trial participants undergoing treatment for smear positive, culture-confirmed TB, comparing host serum protein expression in clinical trial participants enrolled in African and Non-African regions. Serum samples were collected from 289 participants enrolled in the Centers for Disease Control and Prevention TBTC Study 29 (NCT00694629) at time of enrollment and at the end of the intensive phase (after 40 doses of TB treatment). RESULTS After a peptide level proteome analysis utilizing a unique liquid chromatography IM-MS platform (LC-IM-MS) and subsequent statistical analysis, a total of 183 core proteins demonstrated significant differences at both baseline and at week 8 timepoints between participants enrolled from African and non-African regions. The majority of the differentially expressed proteins were upregulated in participants from the African region, and included acute phase proteins, mediators of inflammation, as well as coagulation and complement pathways. Downregulated proteins in the African population were primarily linked to nutritional status and lipid metabolism pathways. CONCLUSIONS We have identified differentially expressed nutrition and lipid pathway proteins by geographic region in TB patients undergoing treatment for pulmonary tuberculosis, which appear to be associated with differential treatment responses. Future TB clinical trials should collect expanded measures of nutritional status and further evaluate the relationship between nutrition and microbiologic treatment response.
-
5.
Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2.
Dorling, JL, van Vliet, S, Huffman, KM, Kraus, WE, Bhapkar, M, Pieper, CF, Stewart, T, Das, SK, Racette, SB, Roberts, SB, et al
Nutrition reviews. 2021;(1):98-113
-
-
Free full text
-
Abstract
Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.
-
6.
PIVKA-II: A biomarker for diagnosing and monitoring patients with pancreatic adenocarcinoma.
Tartaglione, S, Mancini, P, Viggiani, V, Chirletti, P, Angeloni, A, Anastasi, E
PloS one. 2021;(5):e0251656
Abstract
BACKGROUND Pancreatic adenocarcinoma (PDAC) is an incurable cancer without adequate tumor markers. Our previous study has showed a better diagnostic performance of Protein Induced by Vitamin K Absence II (PIVKA-II) compared to currently used PDAC biomarkers. To corroborate our previous data with a larger sample size and to assess a possible role of PIVKA-II in predicting surgical success. Additionally, to further evaluate the hypothesis of a direct PIVKA-II production by PDAC cells, we examined PIVKA-II tissue expression in a case of PDAC using immunofluorescence. METHODS We enrolled 76 newly diagnosed PDAC patients and selected 11 patients to determine PIVKA-II levels also after surgical resection. An immunofluorescence (IF) study of PIVKA-II tissue expression was carried out in one of them. PIVKA-II serum values were measured by chemiluminescent enzyme immunoassay method (CLEIA) on LUMIPULSE G1200 (Fujirebio-Europe, Belgium). RESULTS PIVKA-II serum levels were above the cut-off at baseline in 71 patients (94%) with a median value of 464 mAU/Ml (range 27-40783 mAU/mL); the sensitivity and specificity were 78.67% and 90.67% respectively. Patients with pre-operative PIVKA-II positivity showed a significant decrease (P < 0.015) of median PIVKA-II serum concentrations after surgery: 820 (91-40783) mAU/mL at diagnosis vs 123 (31-4666) mAU/mL post-operatively. IF assay on PDAC sections demonstrated PIVKA-II expression in cancer cells. CONCLUSION These data are the first showing a decreased PIVKA-II serum levels after surgery in PDAC patients and reporting PIVKA-II expression in PDAC tissue. Further studies are needed to confirm these findings and to determine PIVKA-II usefulness in diagnosing and monitoring PDAC patients.
-
7.
Urinary excretion of amino acids and their advanced glycation end-products (AGEs) in adult kidney transplant recipients with emphasis on lysine: furosine excretion is associated with cardiovascular and all-cause mortality.
Baskal, S, Post, A, Kremer, D, Bollenbach, A, Bakker, SJL, Tsikas, D
Amino acids. 2021;(11):1679-1693
-
-
Free full text
-
Abstract
Arginine (Arg) and lysine (Lys) moieties of proteins undergo various post-translational modifications (PTM) including enzymatic NG- and Nε-methylation and non-enzymatic NG- and Nε-glycation. In a large cohort of stable kidney transplant recipients (KTR, n = 686), high plasma and low urinary concentrations of asymmetric dimethylarginine (ADMA), an abundant PTM metabolite of Arg, were associated with cardiovascular and all-cause mortality. Thus, the prediction of the same biomarker regarding mortality may depend on the biological sample. In another large cohort of stable KTR (n = 555), higher plasma concentrations of Nε-carboxymethyl-lysine (CML) and Nε-carboxyethyl-lysine (CEL), two advanced glycation end-products (AGEs) of Lys, were associated with higher cardiovascular mortality. Yet, the associations of urinary AGEs with mortality are unknown. In the present study, we measured 24 h urinary excretion of Lys, CML, and furosine in 630 KTR and 41 healthy kidney donors before and after donation. Our result indicate that lower urinary CML and lower furosine excretion rates are associated with higher mortality in KTR, thus resembling the associations of ADMA. Lower furosine excretion rates were also associated with higher cardiovascular mortality. The 24 h urinary excretion rate of amino acids and their metabolites decreased post-donation (varying as little as - 24% for CEL, and as much as - 62% for ADMA). For most amino acids, the excretion rate was lower in KTR than in donors pre-donation [except for S-(1-carboxyethyl)-L-cysteine (CEC) and NG-carboxyethylarginine (CEA)]. Simultaneous GC-MS measurement of free amino acids, their PTM metabolites and AGEs in urine is a non-invasive approach in kidney transplantation.
-
8.
Soluble Klotho Is Decreased in Children With Type 1 Diabetes and Correlated With Metabolic Control.
Zubkiewicz-Kucharska, A, Wikiera, B, Noczyńska, A
Frontiers in endocrinology. 2021;:709564
Abstract
UNLABELLED Klotho concentration may be considered as a prognostic factor in the development of chronic complications of diabetes. Moreover, decrease in sKlotho concentration may contribute to beta cell apoptosis and type 1 diabetes development. The aim of this study was to evaluate if sKlotho protein concentration in children with type 1 diabetes (T1D) and its correlation with classical risk factors of chronic complications of diabetes: dysglycemia and endothelial dysfunction. MATERIAL AND METHODS In a cross-section single center study the levels of soluble Klotho protein in 80 T1D (37 boys) and 34 healthy children (controls, 15 boys). Micro- and macroangiopathy were excluded and renal function was normal in all participants. Serum sKlotho, sICAM-1, sVCAM-1 and E-selectin levels were measured. RESULTS The concentration of sKlotho was lower in T1D than in the controls (2041.9 ± 1017.6 pg/mL vs. 2790.3 ± 1423.9 pg/mL, p=0.0113). sICAM-1, sVCAM-1 and E-selectin concentrations were comparable in patients and controls. In T1D, sKlotho was not correlated with the duration of diabetes. Klotho and E-selectin were correlated with HbA1c (r=-0.31, P=0.0066 and r=0.25, P=0.0351, respectively), but not with AVBG and blood glucose SD. Correlations of sKlotho with total cholesterol (r=0.31, P=0.0129), HDL-cholesterol (r=0.43, P=0.0011) and LDL-cholesterol (r=0.28, P=0.0412), but not with triglycerides, were found. Likewise, Klotho was not correlated with sICAM-1, sVCAM-1, and E-selectin concentrations. CONCLUSIONS This study reports the significantly lower level of s-Klotho in children with type 1 diabetes, correlated with HbA1c and HDL cholesterol, but not with the adhesion molecules concentrations nor the duration of the disease. Negative correlation between the levels of HbA1c and soluble Klotho may suggest its possible involvement in the development of chronic diabetes complications.
-
9.
Insulin Secretion Predicts the Response to Antidiabetic Therapy in Patients With New-onset Diabetes.
Abdelgani, S, Puckett, C, Adams, J, Triplitt, C, DeFronzo, RA, Abdul-Ghani, M
The Journal of clinical endocrinology and metabolism. 2021;(12):3497-3504
-
-
Free full text
-
Abstract
CONTEXT The results of the present study demonstrate that beta cell function in newly diagnosed T2DM patients is the key predictor of response to glucose lowering medications and provides a practical tool (C-Pep120 /C-Pep0) to guide the choice of glucose lowering agent. OBJECTIVE This work aims to identify predictors for individualization of antidiabetic therapy in patients with new-onset type 2 diabetes mellitus (T2DM). METHODS A total of 261 drug-naive participants in the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT) study, with new-onset diabetes, were randomly assigned in a single-center study to receive 1) metformin followed by glipizide and then insulin glargine on failure to achieve glycated hemoglobin A1c (HbA1c) less than 6.5%, or 2) initial triple therapy with metformin/pioglitazone/exenatide. Each patient received a 75-g oral glucose tolerance test (OGTT) prior to start of therapy. Factors that predicted response to therapy were identified using the area under the receiver operating characteristic curve method. RESULTS Thirty-nine patients started and maintained the treatment goal (HbA1c < 6.5%) on metformin only, and did not require intensification of antihyperglycemic therapy; 54 patients required addition of glipizide to metformin; and 47 patients required insulin addition to metformin plus glipizide for glucose control. The plasma C-peptide concentration (C-Pep)120/C-Pep0 ratio during the OGTT was the strongest predictor of response to therapy. Patients with a ratio less than 1.78 were more likely to require insulin for glucose control, whereas patients with a ratio greater than 2.65 were more likely to achieve glucose control with metformin monotherapy. In patients started on initial triple therapy, the HbA1c decreased independently of the C-Pep120/C-Pep0 ratio. CONCLUSION The increase in C-Pep above fasting following glucose load predicts the response to antihyperglycemic therapy in patients with new-onset diabetes. C-Pep120/C-Pep0 provides a useful tool for the individualization of antihyperglycemic therapy in patients with new-onset T2DM.
-
10.
Safety and disease monitoring biomarkers in Duchenne muscular dystrophy: results from a Phase II trial.
Wagner, KR, Guglieri, M, Ramaiah, SK, Charnas, L, Marraffino, S, Binks, M, Vaidya, VS, Palmer, J, Goldstein, R, Muntoni, F
Biomarkers in medicine. 2021;(15):1389-1396
Abstract
Aim: Evaluate the utility of glutamate dehydrogenase (GLDH) and cardiac troponin I as safety biomarkers, and creatine kinase and muscle injury panel as muscle health biomarkers in Duchenne muscular dystrophy. Patients & methods: Data were collected during a Phase II trial of domagrozumab. Results: GLDH was a more specific biomarker for liver injury than alanine aminotransferase. Cardiac troponin I elevations were variable and not sustained, limiting its applicability as a biomarker. Muscle injury panel biomarkers were no more informative than creatine kinase as a muscle health biomarker. Conclusion: Results support the use of GLDH as a specific biomarker for liver injury in patients with Duchenne muscular dystrophy. Clinical trial registration: ClinicalTrials.gov, NCT02310763.