Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes

Background: Prostate cancer (PC) is a heterogenous multifocal disease ranging from indolent to lethal states. For improved treatment-stratification, reliable approaches are needed to faithfully differentiate between high- and low-risk tumors and to predict therapy response at diagnosis. Methods: A metabolomic approach based on high resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) analysis was applied on intact biopsies samples (n = 111) obtained from patients (n = 31) treated by prostatectomy, and combined with advanced multi- and univariate statistical analysis methods to identify metabolomic profiles reflecting tumor differentiation (Gleason scores and the International Society of Urological Pathology (ISUP) grade) and subtypes based on tumor immunoreactivity for Ki67 (cell proliferation) and prostate specific antigen (PSA, marker for androgen receptor activity). Results: Validated metabolic profiles were obtained that clearly distinguished cancer tissues from benign prostate tissues. Subsequently, metabolic signatures were identified that further divided cancer tissues into two clinically relevant groups, namely ISUP Grade 2 (n = 29) and ISUP Grade 3 (n = 17) tumors. Furthermore, metabolic profiles associated with different tumor subtypes were identified. Tumors with low Ki67 and high PSA (subtype A, n = 21) displayed metabolite patterns significantly different from tumors with high Ki67 and low PSA (subtype B, n = 28). In total, seven metabolites; choline, peak for combined phosphocholine/glycerophosphocholine metabolites (PC + GPC), glycine, creatine, combined signal of glutamate/glutamine (Glx), taurine and lactate, showed significant alterations between PC subtypes A and B. Conclusions: The metabolic profiles of intact biopsies obtained by our non-invasive HR MAS NMR approach together with advanced chemometric tools reliably identified PC and specifically differentiated highly aggressive tumors from less aggressive ones. Thus, this approach has proven the potential of exploiting cancer-specific metabolites in clinical settings for obtaining personalized treatment strategies in PC

Metabolomics of Interstitial Fluid, Plasma and Urine in Patients with Arterial Hypertension: New Insights into the Underlying Mechanisms

There is growing evidence that lymphatic system plays a pivotal role in the pathogenesis of hypertension. Here, for the first time, the metabolome of interstitial fluid is analyzed in patients with arterial hypertension. Due to ethical issues to obtain human interstitial fluid samples, this study included only oncological patients after axillary lymph node dissection (ALND). These patients were matched into hypertensive (n = 29) and normotensive (n = 35) groups with similar oncological status. Simultaneous evaluation of interstitial fluid, plasma, and urine was obtained by combining high-resolution proton nuclear magnetic resonance (1H NMR) spectroscopy with chemometric analysis. Orthogonal partial least squares discriminant analysis (OPLS-DA) provided a clear differentiation between the hypertension and normotensive group, with the discrimination visible in each biofluid. In interstitial fluid nine potential metabolomic biomarkers for hypertension could be identified (creatinine, proline, pyroglutamine, glycine, alanine, 1-methylhistidine, the lysyl group of albumin, threonine, lipids), seven distinct markers in plasma (creatinine, mannose, isobutyrate, glycine, alanine, lactate, acetate, ornithine), and seven respectively in urine (methylmalonate, citrulline, phenylacetylglycine, fumarate, citrate, 1-methylnicotinamide, trans-aconitate). Biomarkers in plasma and urine allowed for the identification of specific biochemical pathways involved in hypertension, as previously suggested. Analysis of the interstitial fluid metabolome provided additional biomarkers compared to plasma or urine. Those biomarkers reflected primarily alterations in the metabolism of lipids and amino acids, and indicated increased levels of oxidative stress/inflammation in patients with hypertension.Special Issue: Primary and Secondary Hypertension: Novelty in Diagnosis and Treatment</p

Lymphoscintigraphic alterations in lower limbs in women with lipedema in comparison to women with overweight/obesity

Introduction: Lipedema is a bilateral enlargement of the legs due to abnormal depositions of subcutaneous fat. Recent studies using lymphoscintigraphy documented that lipedema associates with lymphatic alterations. It is still not known, whether non-lipedema obesity also leads to similar lymphoscintigraphic changes within lower legs. Clinically, both, lipedema and obesity may progress to secondary lymphedema. The aim of the study was to evaluate lymphoscintigraphy of lower limbs in women with lipedema in comparison to overweight/obese women. Methods: 51 women (in the mean age of 43.3 ± 13.56) with the diagnosis of lipedema and 31 women (in the mean age of 44.7 ± 13.48) with overweight/obesity were enrolled into the study. Women in both study groups had no clinical signs of lymphedema. The groups were matched by mean volume of their legs, calculated using the formula for a truncated cone. Lymphoscintigraphy was evaluated in every women qualitatively. Body composition parameters were assessed using bioelectric impedance analysis (BIA). Results: Lymphoscintigraphic alterations within lower extremities were similar in both, lipedema and overweight/obese groups and were present in majority of women in both study groups. The most common lymphoscintigraphic alteration in both groups were additional lymphatic vessels (in the lipedema group observed in 76.5% of patients and in the overweight/obesity group – in 93.5%). Visualization of popliteal lymph nodes and dermal backflow were observed respectively in 33% and in 5.9% in the group with lipedema and in 45.2% and in 9.7% in the overweight/obesity group. There were significant relationships between severity of lymphoscintigraphic alterations and weight, lean body mass (LBM), total body water (TBW), volume of both legs and thigh circumference in the lipedema group. Such relationships were absent in the overweight/obesity group. Discussion: Our study indicates that lymphatic alterations are present before development to clinically visible secondary lymphedema in both conditions, lipedema and overweight/obesity. In majority of women from both study groups they indicate rather an overload of the lymphatic system than insufficiency. Lymphoscintigraphic alterations are similar in both groups, therefore, lymphoscintigraphy is not a diagnostic tool that might distinguish lipedema fro

Additional file 1 of Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes

Additional file 1: Table S1. Metabolites identified by 1H HR MAS NMR in prostate tissue samples

Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status

Background: Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses. Methods: Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (H-1 HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by H-1/P-31 NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort. Results: The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and alpha-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in beta-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress. Conclusions: Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients

Disability and emotional symptoms in women with lipedema : a comparison with overweight/obese women

Background: Lipedema is characterized by the painful abnormal deposition of adipose tissue in the lower limbs and is often misdiagnosed as obesity. Considering the numerous bothersome physical symptoms of lipedema, women with lipedema may have greater disability and emotional problems than women with lifestyle-induced obesity. Objectives: Our study aims to assess disability, anxiety and depression symptoms in women with lipedema compared to women with overweight/obesity. Material and methods: Women with lipedema (n = 45, with a mean age of 41 years) and women who are overweight/obese (n = 43, with a mean age of 44.95 years) were asked to complete the following questionnaires: The World Health Organization Disability Assessment Schedule (WHO-DAS II), Beck's Depression Inventory - II (BDI-II), and The Hospital Anxiety and Depression Scale (HADS). Results: Despite the higher BMI in the overweight/obesity group, the group with lipedema was more disabled in numerous domains of the WHO-DAS II questionnaire, including Life activities - domestic, work and school responsibilities and Participation in society When the influence of BMI was adjusted, a difference in the domain of Mobility was also present. The study groups did not differ in anxiety and depression symptoms. Conclusions: We showed that behavioral impairment was the main factor affecting functioning in women with lipedema. Emotional symptoms did not differentiate the study groups. Leg volumes and adipose tissue pain intensity were associated with greater disability in women with lipedema, and should be considered in managing women with this condition and in future research estimating the effectiveness of lipedema treatment

Disability and emotional symptoms in women with lipedema : a comparison with overweight/obese women

Background: Lipedema is characterized by the painful abnormal deposition of adipose tissue in the lower limbs and is often misdiagnosed as obesity. Considering the numerous bothersome physical symptoms of lipedema, women with lipedema may have greater disability and emotional problems than women with lifestyle-induced obesity. Objectives: Our study aims to assess disability, anxiety and depression symptoms in women with lipedema compared to women with overweight/obesity. Material and methods: Women with lipedema (n = 45, with a mean age of 41 years) and women who are overweight/obese (n = 43, with a mean age of 44.95 years) were asked to complete the following questionnaires: The World Health Organization Disability Assessment Schedule (WHO-DAS II), Beck's Depression Inventory - II (BDI-II), and The Hospital Anxiety and Depression Scale (HADS). Results: Despite the higher BMI in the overweight/obesity group, the group with lipedema was more disabled in numerous domains of the WHO-DAS II questionnaire, including Life activities - domestic, work and school responsibilities and Participation in society When the influence of BMI was adjusted, a difference in the domain of Mobility was also present. The study groups did not differ in anxiety and depression symptoms. Conclusions: We showed that behavioral impairment was the main factor affecting functioning in women with lipedema. Emotional symptoms did not differentiate the study groups. Leg volumes and adipose tissue pain intensity were associated with greater disability in women with lipedema, and should be considered in managing women with this condition and in future research estimating the effectiveness of lipedema treatment