Publications by authors named "Daniela Weber"

138 Publications

Do low molecular weight antioxidants contribute to the Protection against oxidative damage? The interrelation between oxidative stress and low molecular weight antioxidants based on data from the MARK-AGE study.

Arch Biochem Biophys 2021 Oct 16;713:109061. Epub 2021 Oct 16.

Dept of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv, 6997801, Israel; Holon Institute of Technology, Holon, 5810201, Israel. Electronic address:

A redox steady state is important in maintaining vital cellular functions and is therefore homeostatically controlled by a number of antioxidative agents, the most important of which are enzymes. Oxidative Stress (OS) is associated with (or/and caused by) excessive production of damaging reactive oxygen and/or nitrogen species (ROS, RNS), which play a role in many pathologies. Because OS is a risk factor for many diseases, much effort (and money) is devoted to early diagnosis and treatment of OS. The desired benefit of the "identify (OS) and treat (by low molecular weight antioxidants, LMWA)" approach is to enable selective treatment of patients under OS. The present work aims at gaining understanding of the benefit of the antioxidants based on interrelationship between the concentration of different OS biomarkers and LMWA. Both the concentrations of a variety of biomarkers and of LMWA were previously determined and some analyses have been published by the MARK-AGE team. For the sake of simplicity, we assume that the concentration of an OS biomarker is a linear function of the concentration of a LMWA (if the association is due to causal relationship). A negative slope of this dependence (and sign of the correlation coefficient) can be intuitively expected for an antioxidant, a positive slope indicates that the LMWA is pro-oxidative, whereas extrapolation of the OS biomarker to [LMWA] = 0 is an approximation of the concentration of the OS biomarker in the absence of the LMWA. Using this strategy, we studied the effects of 12 LMWA (including tocopherols, carotenoids and ascorbic acid) on the OS status, as observed with 8 biomarkers of oxidative damage (including malondialdehyde, protein carbonyls, 3-nitrotyrosine). The results of this communication show that in a cross-sectional study the LMWA contribute little to the redox state and that different "antioxidants" are very different, so that single LMWA treatment of OS is not scientifically justified assuming our simple model. In view of the difficulty of quantitating the OS and the very different effects of various LMWA, the use of the "identify and treat" approach is questionable.
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http://dx.doi.org/10.1016/j.abb.2021.109061DOI Listing
October 2021

Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease.

Transplant Cell Ther 2021 Aug 30. Epub 2021 Aug 30.

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3α were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD.
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http://dx.doi.org/10.1016/j.jtct.2021.08.021DOI Listing
August 2021

An investigation of the diagnostic, predictive, and prognostic impacts of three colonic biopsy grading systems for acute graft versus host disease.

PLoS One 2021 26;16(8):e0256543. Epub 2021 Aug 26.

Institute of Pathology, University Medical Center Mainz, Mainz, Germany.

Acute graft versus host disease (aGvHD) is an important, life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). To investigate the value of multiple simultaneous colon biopsies in improving diagnostic accuracy in patients with aGvHD, we retrospectively analyzed 157 patients after alloHSCT. The biopsies were evaluated individually using three established histological grading systems (Lerner, Sale, and Melson). The maximum, minimum, median, and mean histological aGvHD grades were calculated for each patient, and the results were correlated with the Glucksberg grade of clinical manifestation of GvHD, steroid therapy status, and outcome. We found that multiple colon biopsies enhanced diagnostic sensitivity. Moreover, higher histological grades correlated with steroid therapy initiation and refractoriness; the latter particularly occurred when advanced damage was present in all samples and healthy colon mucosa was reduced or absent. On multivariate analysis, the minimal Lerner and Glucksberg grades for intestinal aGvHD were significantly associated with steroid treatment failure. Ninety-nine patients died. The median survival was 285 days after the biopsies were taken. Fifteen patients died from relapse of their underling disorder and 84 from other causes, mostly infection (53 patients) and GvHD (14 patients). Multivariate analysis revealed a significant association between none-relapse mortality and the mean Lerner grade, minimum Melson grade, Glucksberg organ stage, and platelet counts. Thus, we found the Lerner system to be superior to the other grading methods in most instances and histologic evaluation of multiple simultaneously obtained biopsies from the colon to result in a higher diagnostic yield, which helps plan systemic steroid treatment while predicting treatment response and outcome.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256543PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389423PMC
August 2021

Altered Adiponectin Response in Older Women Following Dextrose and High-Fat Dietary Challenges.

Mol Nutr Food Res 2021 09 4;65(17):e2100487. Epub 2021 Aug 4.

Department of Nutrition and Gerontology, German Institute of Human Nutrition, Potsdam - Rehbrücke, Nuthetal, Germany.

Scope: Despite its beneficial properties, higher adiponectin concentrations are paradoxically associated with mortality in advanced age. Several mechanisms are being discussed. However, little is known about postprandial regulation of adiponectin in older adults. We assessed age-specific differences of the adiponectin response to different test meals considering potential determinants.

Methods And Results: Older (n = 20) and younger (n = 22) women are randomized to a dextrose (DEX) or high-fat (HF) dietary challenge. Postprandial adiponectin and fibroblast growth factor 21 (FGF21) concentrations are measured before and 60, 120, 240 min after ingestion. We assessed postprandial changes and group differences using linear mixed models controlled for possible determinants. In younger women, postprandial adiponectin remains stable after both test meals. In contrast, adiponectin increases following DEX and decreases after HF in older women, irrespective of control variables. Postprandial adiponectin is positively associated with malondialdehyde and inversely associated with interleukin-6 following DEX and also negatively associated with metabolic parameters after both test meals. In older women, elevated postprandial FGF21 concentrations are associated with a higher adiponectin response (β = 30.7, 95% CI 10.6-50.8, p = 0.007).

Conclusions: Adiponectin response is associated with type of dietary challenge, age, and FGF21 response. Age-group differences are partly attributable to metabolic parameters and oxidative stress.
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http://dx.doi.org/10.1002/mnfr.202100487DOI Listing
September 2021

"This Graft-vs.-Host Disease Determines My Life. That's It."-A Qualitative Analysis of the Experiences and Needs of Allogenic Hematopoietic Stem Cells Transplantation Survivors in Germany.

Front Public Health 2021 1;9:687675. Epub 2021 Jul 1.

Department for Epidemiology and Preventive Medicine, Division of Medical Sociology, University of Regensburg, Regensburg, Germany.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment modality for many patients affected by hematologic malignancies. However, it can cause debilitating long-term effects. Understanding the impact of alloHSCT on all aspects of the patients' life is required for optimal survivorship management. To explore in-depth HSCT-survivors' experiences and needs post-transplant. Partners were included to provide further information on survivors' needs and how care could be improved in this area. We conducted semi-structured face-to-face and phone interviews with alloHSCT-survivors and their partners referred to a survivorship clinic in Germany. Theoretical sampling was used to recruit participants. Data were analyzed using framework analysis. Thirty-two survivors (consent rate: 100%, response rate: 100%) and eighteen partners (consent rate: 84%, response rate: 72%) participated. Survivors were aged between 25 and 68 years (Median: 48, IQR: 25.3) and partners were aged between 26 and 64 years (Median: 54, IQR: 16, SD: 12.8). The themes emerging from the data involved survivors' needs included (i) the diversity of long-term treatment side-effects; and (ii) time post discharge as a dynamic process with individual peaks of burden. Survivors and their partners also suggested strategies for mitigating these unmet needs, i.e., (iii) transparent communication and patient empowerment; and (iv) improvement in continuity of care system and help with claiming social benefits as cornerstones of optimal survivorship care. To our knowledge, this is one of the first qualitative studies focused on the views of German alloHSCT-survivors on the long-term effects of alloHSCT and the first study integrating the view of their partners. Healthcare providers could better support survivors with managing their symptoms and adhering to their prescribed care by ensuring comprehensive, transparent communication that helps increase survivors' understanding and involvement in their care. Further efforts should be made to provide patient-centered, continuous survivorship care that involves additional support with navigating the healthcare and social service system. Intervention studies are required to test the effectiveness of the suggested strategies.
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http://dx.doi.org/10.3389/fpubh.2021.687675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280766PMC
August 2021

Special issue on 'Biomarkers of Oxidative Stress, Aging and Nutrition in Human Studies'.

Redox Biol 2021 09 25;45:102059. Epub 2021 Jun 25.

Department of Molecular Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Nuthetal, Germany.

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http://dx.doi.org/10.1016/j.redox.2021.102059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282506PMC
September 2021

Parametric Imaging of Contrast-Enhanced Ultrasound (CEUS) for the Evaluation of Acute Gastrointestinal Graft-Versus-Host Disease.

Cells 2021 05 3;10(5). Epub 2021 May 3.

Department of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, 93053 Regensburg, Germany.

In recent years contrast-enhanced ultrasound (CEUS) has been an emerging diagnostic modality for the detection of acute gastrointestinal (GI) graft-versus-host disease (GvHD) in patients after allogeneic stem cell transplantation. However, broad clinical usage has been partially limited by its high dependence on the expertise of an experienced examiner. Thus, the aim of this study was to facilitate detection of acute GI GvHD by implementing false color-coded parametric imaging of CEUS. As such, two inexperienced examiners with basic knowledge in abdominal and vascular ultrasound analyzed parametric images obtained from patients with clinical suspicion for acute GvHD in a blinded fashion. As diagnostic gold standard, histopathological GvHD severity score on intestinal biopsies obtained from lower GI tract endoscopy was performed. The evaluation of parametric images by the two inexperienced ultrasound examiners in patients with histological confirmation of acute GI GvHD was successful in 17 out of 19 patients (89%) as opposed to analysis of combined B-mode ultrasound, strain elastography, and CEUS by an experienced examiner, which was successful in 18 out of 19 of the patients (95%). Therefore, CEUS with parametric imaging of the intestine was technically feasible and has the potential to become a valuable diagnostic tool for rapid and widely accessible detection of acute GvHD in clinical practice.
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http://dx.doi.org/10.3390/cells10051092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147630PMC
May 2021

Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation - A single center retrospective efficacy analysis.

Vaccine 2021 07 25;39(33):4742-4750. Epub 2021 May 25.

Dept. of Internal Medicine III, University Hospital Regensburg, Franz-Joseph-Strauss-Allee 11, 93053 Regensburg, Germany. Electronic address:

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6-70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients' characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.052DOI Listing
July 2021

Prolonged suppression of butyrate producing bacteria is associated with acute gastrointestinal graft-versus-host disease and transplant related mortality after allogeneic stem cell transplantation.

Clin Infect Dis 2021 May 27. Epub 2021 May 27.

Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany.

Background: Butyrogenic bacteria play an important role in gut microbiome homeostasis and intestinal epithelial integrity. Previous studies have demonstrated an association between administration of short chain fatty acids like butyrate and protection from acute graft-versus-host disease (aGvHD) after allogeneic stem cell transplantation (ASCT).

Methods: Here we examined the abundance and butyrogenic capacity of butyrate producing bacteria in 28 healthy donors and 201 patients after ASCT. We prospectively collected serial stool samples and performed PCR analysis of the butyrate producing bacterial enzyme butyryl-CoA:acetate CoA-transferase (BCoAT) in fecal nucleic acid extracts.

Results: Our data demonstrate a strong and prolonged suppression of butyrogenic bacteria early in the course of ASCT. In a multivariable analysis, early use of broad-spectrum antibiotics before day 0 (d 0, day of transplantation) was identified as independent factor associated with low BCoAT copies (odds ratio 0.370 (0.175-0.783), p=0.009). Diminished butyrogens correlated with other biomarkers of microbial diversity such as low 3-indoxyl sulfate (3-IS) levels, reduced abundance of Clostridiales and low inverse Simpson and effective Shannon indices (p<0.001, respectively). Low BCoAT copies at GvHD-onset correlated with GI-GvHD severity (p=0.002) and were associated with significantly higher GvHD associated mortality (p=0.040). Furthermore, low BCoAT copies at d 30 were associated with significantly higher transplant related mortality (p=0.017).

Conclusions: Our results are consistent with the hypothesis that alterations in the microbiome play an important role in GvHD pathogenesis and that microbial parameters such as BCoAT might serve as biomarkers to identify patients at high risk for developing lethal GI-GvHD.
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http://dx.doi.org/10.1093/cid/ciab500DOI Listing
May 2021

Age, sex and BMI influence on copper, zinc and their major serum carrier proteins in a large European population including Nonagenarian Offspring from MARK-AGE study.

J Gerontol A Biol Sci Med Sci 2021 May 13. Epub 2021 May 13.

Translational Research Center of Nutrition and Ageing, IRCCS INRCA, Ancona, Italy.

The analysis of copper (Cu) and zinc (Zn) along with their major serum carriers, albumin (Alb) and ceruloplasmin (Cp), could provide information on the capacity of humans to maintain homeostasis of metals (metallostasis). However, their relationship with aging, sex, BMI, as well as with nutritional and inflammatory markers was never investigated in a large-scale study. Here, we report results from the European large-scale cross-sectional study MARK-AGE in which Cu, Zn, Alb, Cp as well as nutritional and inflammatory parameters were determined in 2424 age-stratified subjects (35-75 years) including the general population (RASIG), nonagenarian offspring (GO), a well-studied genetic model of longevity, and spouses of GO (SGO). In RASIG, Cu to Zn ratio and Cp to Alb ratio were higher in women than in men. Both ratios increased with aging because Cu and Cp increased and Alb and Zn decreased. Cu, Zn, Alb and Cp were found associated with several inflammatory as well as nutritional biomarkers.GO showed higher Zn levels and higher Zn to Alb ratio compared to RASIG, but we did not observe significant differences with SGO, likely as a consequence of the low sample size of SGO and the shared environment. Our results show that aging, sex, BMI and GO status are characterized by different levels of Cu, Zn and their serum carrier proteins. These data and their relationship with inflammatory biomarkers support the concept that loss of metallostasis is a characteristic of inflammaging.
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http://dx.doi.org/10.1093/gerona/glab134DOI Listing
May 2021

Redox biomarkers in dietary interventions and nutritional observation studies - From new insights to old problems.

Redox Biol 2021 05 3;41:101922. Epub 2021 Mar 3.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558, Nuthetal, Germany; Food4Future (F4F), c/o Leibniz Institute of Vegetable and Ornamental Crops (IGZ), Theodor-Echtermeyer-Weg 1, 14979, Grossbeeren, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, 14558, Nuthetal, Germany. Electronic address:

Purpose: The purpose of this review is to give an overview on recently published articles investigating the associations of diet and dietary interventions with biomarkers of oxidative stress with special emphasis on different categories of redox biomarkers.

Findings: Intervention and observational studies both in healthy participants and patients that investigated associations of dietary habits, foodstuffs or isolated nutrients with biomarkers of oxidative stress were included in this review. Recently published observation studies confirm the inverse association between fruit and vegetable intake and oxidative stress markers. Studies investigating the effect of vitamin D and vitamin E, magnesium, zinc, chromium, selenium, probiotic supplementation and several phytochemicals reported consistent changes in redox biomarkers. Of 88 articles included in this review, only seven studies measured biomarkers from the three categories: oxidative damage, endogenous antioxidants, and exogenous antioxidants. Many studies rely on controversial assays for total antioxidant capacity, thus there is potential in many studies to improve biomarker repertoire to cover all three categories of biomarkers and to turn away from such assays.
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http://dx.doi.org/10.1016/j.redox.2021.101922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020480PMC
May 2021

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

Geroscience 2021 06 18;43(3):1317-1329. Epub 2021 Feb 18.

German Institute for Human Nutrition, Potsdam, Germany.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.
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http://dx.doi.org/10.1007/s11357-021-00334-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190217PMC
June 2021

Abatacept as salvage therapy in chronic graft-versus-host disease-a retrospective analysis.

Ann Hematol 2021 Mar 30;100(3):779-787. Epub 2021 Jan 30.

Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.

The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health's (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55-393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required.
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http://dx.doi.org/10.1007/s00277-021-04434-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914235PMC
March 2021

Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts.

Cancers (Basel) 2021 Jan 23;13(3). Epub 2021 Jan 23.

Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria.

Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, -cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.
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http://dx.doi.org/10.3390/cancers13030434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865782PMC
January 2021

Potential Novel Biomarkers in Chronic Graft-Versus-Host Disease.

Front Immunol 2020 23;11:602547. Epub 2020 Dec 23.

Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.

Prognostic, diagnostic or predictive biomarkers are urgently needed for assessment of chronic graft-versus-host disease (cGvHD), a major risk for patients undergoing allogeneic hematopoietic stem cell transplantation. The main goal of this review generated within the COST Action EUROGRAFT "Integrated European Network on Chronic Graft Versus Host Disease" was to identify potential novel biomarkers for cGvHD besides the widely accepted molecular and cellular biomarkers. Thus, the focus was on cellular biomarkers, alloantibodies, glycomics, endothelial derived particles, extracellular vesicles, microbiome, epigenetic and neurologic changes in cGvHD patients. Both host-reactive antibodies in general, and particularly alloantibodies have been associated with cGvHD and require further consideration. Glycans attached to IgG modulate its activity and represent a promising predictive and/or stratification biomarker for cGVHD. Furthermore, epigenetic changes such as microRNAs and DNA methylation represent potential biomarkers for monitoring cGvHD patients and novel targets for developing new treatment approaches. Finally, the microbiome likely affects the pathophysiology of cGvHD; bacterial strains as well as microbial metabolites could display potential biomarkers for dysbiosis and risk for the development of cGvHD. In summary, although there are no validated biomarkers currently available for clinical use to better inform on the diagnosis, prognosis or prediction of outcome for cGvHD, many novel sources of potential markers have shown promise and warrant further investigation using well characterized, multi-center patient cohorts.
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http://dx.doi.org/10.3389/fimmu.2020.602547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786047PMC
June 2021

Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial.

Blood 2020 12;136(26):3041-3050

Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.
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http://dx.doi.org/10.1182/blood.2020005998DOI Listing
December 2020

Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication.

Blood Adv 2020 12;4(24):6342-6352

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.
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http://dx.doi.org/10.1182/bloodadvances.2020002673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757000PMC
December 2020

Targeting Mitochondria in Melanoma.

Biomolecules 2020 09 30;10(10). Epub 2020 Sep 30.

Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria.

Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer.
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http://dx.doi.org/10.3390/biom10101395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599575PMC
September 2020

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation.

Bone Marrow Transplant 2021 02 27;56(2):419-433. Epub 2020 Aug 27.

Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center of Regensburg, Regensburg, Germany.

The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person's vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day -16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day -2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann-Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients.
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http://dx.doi.org/10.1038/s41409-020-01031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870805PMC
February 2021

Cyclophosphamide for salvage therapy of chronic graft-versus-host disease: a retrospective analysis.

Ann Hematol 2020 Sep 26;99(9):2181-2190. Epub 2020 Jul 26.

Department of Hematology and Oncology, Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

We retrospectively analyzed the safety and efficacy of cyclophosphamide (cyclo) for salvage treatment of chronic graft-versus-host disease (cGvHD) and cGvHD-associated (glomerulo-)nephritis at our center between 01/2010 and 11/2019. We identified 13 patients (pts) receiving cyclo for treatment of moderate (3/13) and severe (6/13) steroid-refractory cGvHD, cGvHD-associated (glomerulo-)nephritis (3/13), or vasculitis-like CNS manifestation of cGvHD (1/13). Cyclo was started on median day 509 (range 42-8193) after cGvHD onset; the median duration of application was 153 days (range 14-486) with 2/13 currently continuing treatment. The National Institute of Health organ grading and the intensity of immunosuppression (IS) were assessed at cyclo start and repeated after 3, 6, and 12 months. Response assessment was stopped at the start of any additional new IS. The median time of follow up was 407 days (range 86-1534). Best response was 1/13 CR, 6/13 PR, 4/13 SD, 1/13 MR, and 1/13 PD (ORR 54%). Significant and durable response was observed especially in cGvHD-associated (glomerulo-)nephritis (3/3). Infectious complications > CTCAE grade III were observed in 3/12 pts. During cyclo therapy, none of the pts suffered from recurrence of underlying malignancy. Overall, cyclo was relatively well tolerated and showed responses in heavily pretreated patients but requires further evaluation within clinical trials.
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http://dx.doi.org/10.1007/s00277-020-04193-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419371PMC
September 2020

Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals.

J Clin Med 2020 Jul 1;9(7). Epub 2020 Jul 1.

Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany.

The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35-75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (-3.31% difference per increase in medication group), β-carotene (-11.44%), α-carotene (-8.50%) and positive associations with retinol (+2.26%), α-tocopherol/cholesterol (+2.89%) and γ-tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, α- and γ-tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients.
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http://dx.doi.org/10.3390/jcm9072072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408954PMC
July 2020

Comparative assessment of purified saponins as permeabilization agents during respirometry.

Biochim Biophys Acta Bioenerg 2020 10 26;1861(10):148251. Epub 2020 Jun 26.

Chair of Molecular Nutritional Medicine, TUM School of Life Sciences, Technical University of Munich, Freising, Germany; EKFZ - Else Kröner-Fresenius Center for Nutritional Medicine, Technical University of Munich, Freising, Germany. Electronic address:

Saponins are a diverse group of secondary plant metabolites, some of which display hemolytic toxicity due to plasma membrane permeabilization. This feature is employed in biological applications for transferring hydrophilic molecules through cell membranes. Widely used commercial saponins include digitonin and saponins from soap tree bark, both of which constitute complex mixtures of little definition. We assessed the permeabilization power of pure saponins towards cellular membranes in an effort to detect novel properties and to improve existing applications. In a respirometric assay, we characterized half-maximal permeabilization of the plasma membrane for different metabolites, of the mitochondrial outer membrane for cytochrome C and the full solubilization of mitochondrial inner membrane protein complexes. Beyond the complete list as repository for the field, we highlight several findings with direct applicability. First, we identified and validated α-chaconine as alternative permeabilization agent in respirometric assays of cultured cells and isolated synaptosomes, superior to digitonin in its tolerability for mitochondria. Second, we identified glycyrrhizic acid to form exceptionally small pores impermeable for adenosine diphosphate. Third, in a concentration dependent manner, tomatine proved to be able to selectively permeabilize the mitochondrial outer, but not inner membrane, allowing for novel states in which to determine cytochrome C oxidase activity. In summary, we provide a list of the permeabilization properties of 18 pure saponins. The identification of two saponins, namely tomatine and chaconine, with direct usability in improved or novel cell biological applications within this small subgroup demonstrates the tremendous potential for further functional screening of pure saponins.
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http://dx.doi.org/10.1016/j.bbabio.2020.148251DOI Listing
October 2020

Prospects of activity limitations among older adults in 23 low and middle income countries.

Sci Rep 2020 06 26;10(1):10442. Epub 2020 Jun 26.

Wittgenstein Centre (IIASA, VID/ÖAW, WU), International Institute for Applied Systems Analysis (IIASA), Schlossplatz 1, 2361, Laxenburg, Austria.

Increasing life expectancy and a growing share of older people around the world spotlight the issue of health during additional years of life. Research on trends of proportions of older people with activity limitations for low and middle income countries is sparse. We use data from the World Health Survey and the UN World Population Prospects to predict prevalence of activity limitations for 23 low and middle income countries for the upcoming 30 years. Our projections highlight huge variation in the proportion of older adults with limitations across investigated countries and this variation is not expected to diminish. However, these countries are facing considerable demographic changes and even though prevalence rates appear almost constant, absolute numbers are changing which require policy interventions. Furthermore, variations across countries reflect not only disparities in health conditions, but also differences in cultural peculiarities of reporting and historical perception of health.
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http://dx.doi.org/10.1038/s41598-020-67166-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319965PMC
June 2020

Arterial structure and function during and after long-duration spaceflight.

J Appl Physiol (1985) 2020 07 11;129(1):108-123. Epub 2020 Jun 11.

NASA Johnson Space Center, Houston, Texas.

Spaceflight missions expose astronauts to increased risk of oxidative stress and inflammatory damage that might accelerate the development of asymptomatic cardiovascular disease. The purpose of this investigation was to determine whether long-duration spaceflight (>4 mo) results in structural and functional changes in the carotid and brachial arteries. Common carotid artery (CCA) intima-media thickness (cIMT), CCA distensibility and stiffness, and brachial artery endothelium-dependent and -independent vasodilation were measured in 13 astronauts (10 men, 3 women) ~180 and 60 days before launch, during the mission on ~15, 60, and 160 days of spaceflight, and within 1 wk after landing. Biomarkers of oxidative stress and inflammation were measured at corresponding times in fasting blood samples and urine samples from 24- or 48-h pools. Biomarkers of oxidative stress and inflammation increased during spaceflight, but most returned to preflight levels within 1 wk of landing. Mean cIMT, CCA stiffness, and distensibility were not significantly different from preflight at any time. As a group, neither mean endothelium-dependent nor -independent vasodilation changed from preflight to postflight, but changes within individuals in endothelial function related to some biomarkers of oxidative stress. Whereas biomarkers of oxidative stress and inflammation are elevated during spaceflight, CCA and brachial artery structure and function were not changed by spaceflight. It is unclear whether future exploration missions, with an extended duration in altered gravity fields and higher radiation exposure, may be problematic. Carotid artery structure and stiffness did not change on average in astronauts during long-duration spaceflight (<12 mo), despite increased oxidative stress and inflammation. Most oxidative stress and inflammation biomarkers returned to preflight levels soon after landing. Brachial artery structure and function also were unchanged by spaceflight. In this group of healthy middle-aged male and female astronauts, spaceflight in low Earth orbit does not appear to increase long-term cardiovascular health risk.
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http://dx.doi.org/10.1152/japplphysiol.00550.2019DOI Listing
July 2020

Advanced glycation end products and protein carbonyl levels in plasma reveal sex-specific differences in Parkinson's and Alzheimer's disease.

Redox Biol 2020 07 18;34:101546. Epub 2020 May 18.

Department of Neurology, University Clinic Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Electronic address:

Neurodegenerative diseases (NDD) such as Alzheimer's (AD) and Parkinson's disease (PD) are distinct clinical entities, however, the aggregation of key neuronal proteins, presumably leading to neuronal demise appears to represent a common mechanism. It has become evident, that advanced glycation end products (AGEs) trigger the accumulation of such modified proteins, which eventually contributes to pathological aspect of NDDs. Increased levels of AGEs are found in amyloid plaques in AD brains and in both advanced and early PD (incidental Lewy body disease). The molecular mechanisms by which AGE dependent modifications may modulate the susceptibility towards NDDs, however, remain enigmatic and it is unclear, whether AGEs may serve as biomarker of NDD. In the present study, we examined AGEs (CML: Carboxymethyllysine and CEL: Carboxyethyllysine), markers of oxidative stress and micronutrients in the plasma of PD and AD patients and controls. As compared to healthy controls, AD females displayed lower levels of CEL while higher levels of CML were found in AD and PD patients. A somewhat similar pattern was observed for protein carbonyls (PC), revealing lower values exclusively in AD females, whereas AD males displayed significantly higher values compared to healthy controls and PD. Sex-specific differences were also observed for other relevant markers such as malondialdehyde, 3-nitrotyrosine, γ -tocopherols, retinol, plasma proteins and α-carotene, while α-tocopherols, β-carotene, lutein/zeaxanthin, β-cryptoxanthin and lycopene showed no relevant association. Taken together, our study suggests yet unappreciated differences of the distribution of AGEs among the sexes in NDD. We therefore suggest to make a clear distinction between sexes when analyzing oxidative (AGEs)-related stress and carbonyl-related stress and vitamins.
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http://dx.doi.org/10.1016/j.redox.2020.101546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251371PMC
July 2020

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Blood 2020 07;136(1):130-136

Department of Medicine, Weill Cornell Medical College, New York, NY.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.
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http://dx.doi.org/10.1182/blood.2019003369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332893PMC
July 2020

Model-Based Optimal AML Consolidation Treatment.

IEEE Trans Biomed Eng 2020 12 19;67(12):3296-3306. Epub 2020 Nov 19.

Objective: Neutropenia is an adverse event commonly arising during intensive chemotherapy of acute myeloid leukemia (AML). It is often associated with infectious complications. Mathematical modeling, simulation, and optimization of the treatment process would be a valuable tool to support clinical decision making, potentially resulting in less severe side effects and deeper remissions. However, until now, there has been no validated mathematical model available to simulate the effect of chemotherapy treatment on white blood cell (WBC) counts and leukemic cells simultaneously.

Methods: We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model combining a myelosuppression model considering endogenous granulocyte-colony stimulating factor (G-CSF), a PK model for cytarabine (Ara-C), a subcutaneous absorption model for exogenous G-CSF, and a two-compartment model for leukemic blasts. This model was fitted to data of 44 AML patients during consolidation therapy with a novel Ara-C plus G-CSF schedule from a phase II controlled clinical trial. Additionally, we were able to optimize treatment schedules with respect to disease progression, WBC nadirs, and the amount of Ara-C and G-CSF.

Results: The developed PK/PD model provided good prediction accuracies and an interpretation of the interaction between WBCs, G-CSF, and blasts. For 14 patients (those with available bone marrow blast counts), we achieved a median 4.2-fold higher WBC count at nadir, which is the most critical time during consolidation therapy. The simulation results showed that relative bone marrow blast counts remained below the clinically important threshold of 5%, with a median of 60% reduction in Ara-C.

Conclusion: These in silico findings demonstrate the benefits of optimized treatment schedules for AML patients.

Significance: Until 2017, no new drug had been approved for the treatment of AML, fostering the optimal use of currently available drugs.
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http://dx.doi.org/10.1109/TBME.2020.2982749DOI Listing
December 2020

Quantifying technical confounders in microbiome studies.

Cardiovasc Res 2021 02;117(3):863-875

Experimental and Clinical Research Center, a Cooperation of Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany.

Aims: Recent technical developments have allowed the study of the human microbiome to accelerate at an unprecedented pace. Methodological differences may have considerable impact on the results obtained. Thus, we investigated how different storage, isolation, and DNA extraction methods can influence the characterization of the intestinal microbiome, compared to the impact of true biological signals such as intraindividual variability, nutrition, health, and demographics.

Methods And Results: An observative cohort study in 27 healthy subjects was performed. Participants were instructed to collect stool samples twice spaced by a week, using six different methods (naive and Zymo DNA/RNA Shield on dry ice, OMNIgene GUT, RNALater, 95% ethanol, Zymo DNA/RNA Shield at room temperature). DNA extraction from all samples was performed comparatively using QIAamp Power Fecal and ZymoBIOMICS DNA Kits. 16S rRNA sequencing of the gut microbiota as well as qPCRs were performed on the isolated DNA. Metrics included alpha diversity as well as multivariate and univariate comparisons of samples, controlling for covariate patterns computationally. Interindividual differences explained 7.4% of overall microbiome variability, whereas the choice of DNA extraction method explained a further 5.7%. At phylum level, the tested kits differed in their recovery of Gram-positive bacteria, which is reflected in a significantly skewed enterotype distribution.

Conclusion: DNA extraction methods had the highest impact on observed microbiome variability, and were comparable to interindividual differences, thus may spuriously mimic the microbiome signatures of various health and nutrition factors. Conversely, collection methods had a relatively small influence on microbiome composition. The present study provides necessary insight into the technical variables which can lead to divergent results from seemingly similar study designs. We anticipate that these results will contribute to future efforts towards standardization of microbiome quantification procedures in clinical research.
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http://dx.doi.org/10.1093/cvr/cvaa128DOI Listing
February 2021

Plant resistance does not compromise parasitoid-based biocontrol of a strawberry pest.

Sci Rep 2020 04 3;10(1):5899. Epub 2020 Apr 3.

Department of Plant Protection Biology, Swedish University of Agricultural Sciences, Box 102, 23053, Alnarp, Sweden.

Plant nutritional  quality can influence interactions between herbivores and their parasitoids. While most previous work has focused on a limited set of secondary plant metabolites, the tri-trophic effects of overall phenotypic resistance have been understudied. Furthermore, the joint effects of secondary and primary metabolites on parasitoids are almost unexplored. In this study, we compared the performance and survival of the parasitoid species Asecodes parviclava Thompson on wild woodland strawberry (Fragaria vesca L.) genotypes showing variation in resistance against the parasitoid's host, the strawberry leaf beetle (Galerucella tenella L.). Additionally, we related the metabolic profiles of these plant genotypes to the tritrophic outcomes in order to identify primary and secondary metabolites involved in regulating plant potential to facilitate parasitism. We found that parasitoid performance was strongly affected by plant genotype, but those differences in plant resistance to the herbivore were not reflected in parasitoid survival. These findings could be explained in particular by a significant link between parasitoid survival and foliar carbohydrate levels, which appeared to be the most important compounds for parasitism success. The fact that plant quality strongly affects parasitism should be further explored and utilized in plant breeding programs for a synergistic application in sustainable pest management.
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http://dx.doi.org/10.1038/s41598-020-62698-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125231PMC
April 2020
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