Screening human lung cancer with predictive models of serum magnetic resonance spectroscopy metabolomics.

The current high mortality of human lung cancer stems largely from the lack of feasible, early disease detection tools. An effective test with serum metabolomics predictive models able to suggest patients harboring disease could expedite triage patient to specialized imaging assessment. Here, using a training-validation-testing-cohort design, we establish our high-resolution magic angle spinning (HRMAS) magnetic resonance spectroscopy (MRS)-based metabolomics predictive models to indicate lung cancer presence and patient survival using serum samples collected prior to their disease diagnoses. Studied serum samples were collected from 79 patients before (within 5.0 y) and at lung cancer diagnosis. Disease predictive models were established by comparing serum metabolomic patterns between our training cohorts: patients with lung cancer at time of diagnosis, and matched healthy controls. These predictive models were then applied to evaluate serum samples of our validation and testing cohorts, all collected from patients before their lung cancer diagnosis. Our study found that the predictive model yielded values for prior-to-detection serum samples to be intermediate between values for patients at time of diagnosis and for healthy controls; these intermediate values significantly differed from both groups, with an F1 score = 0.628 for cancer prediction. Furthermore, values from metabolomics predictive model measured from prior-to-diagnosis sera could significantly predict 5-y survival for patients with localized disease.

Antiviral CD8+ T-cell immune responses are impaired by cigarette smoke and in COPD.

BACKGROUND: Virus infections drive COPD exacerbations and progression. Antiviral immunity centres on the activation of virus-specific CD8+ T-cells by viral epitopes presented on major histocompatibility complex (MHC) class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialised intracellular protein degradation machine, which is induced by antiviral cytokines in infected cells. METHODS: We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome in vitro, ex vivo and in vivo using RNA and Western blot analyses. CD8+ T-cell activation was determined in co-culture assays with cigarette smoke-exposed influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of cigarette smoke on inflammatory antigen presentation in lung cells. IAV-specific CD8+ T-cell numbers were determined in patients' peripheral blood using tetramer technology. RESULTS: Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells in vitro, ex vivo and in vivo. In addition, cigarette smoke altered the peptide repertoire of antigens presented on MHC class I molecules under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8+ T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8+ T-cells compared to healthy controls and asthmatics. CONCLUSION: Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8+ T-cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections.

13 C NMR quantification of polyamine syntheses in rat prostate.

Currently, many prostate cancer patients, detected through the prostate specific antigen test, harbor organ-confined indolent disease that cannot be differentiated from aggressive cancer according to clinically and pathologically known measures. Spermine has been considered as an endogenous inhibitor for prostate-confined cancer growth and its expression has shown correlation with prostate cancer growth rates. If established clinically, measurements of spermine bio-synthesis rates in prostates may predict prostate cancer growth and patient outcomes. Using rat models, we tested the feasibility of quantifying spermine bio-synthesis rates with 13 C NMR. Male Copenhagen rats (10 weeks, n = 6) were injected with uniformly 13 C-labeled L-ornithine HCl, and were sacrificed in pairs at 10, 30, and 60 min after injection. Another two rats were injected with saline and sacrificed at 30 min as controls. Prostates were harvested and extracted with perchloric acid and the neutralized solutions were examined by 13 C NMR at 600 MHz. 13 C NMR revealed measurable ornithine, as well as putrescine-spermidine-spermine syntheses in rat prostates, allowing polyamine bio-synthetic and ornithine bio-catabolic rates to be calculated. Our study demonstrated the feasibility of 13 C NMR for measuring bio-synthesis rates of ornithine to spermine enzymatic reactions in rat prostates. The current study established a foundation upon which future investigations of protocols that differentiate prostate cancer growth rates according to the measure of ornithine to spermine bio-synthetic rates may be developed.

Differentiation of patients with and without prostate cancer using urine 1 H NMR metabolomics.

Prostate cancer (PCa) is one of the most prevalent cancers in men worldwide. For its detection, serum prostate-specific antigen (PSA) screening is commonly used, despite its lack of specificity, high false positive rate, and inability to discriminate indolent from aggressive PCa. Following increases in serum PSA levels, clinicians often conduct prostate biopsies with or without advanced imaging. Nuclear magnetic resonance (NMR)-based metabolomics has proven to be promising for advancing early-detection and elucidation of disease progression, through the discovery and characterization of novel biomarkers. This retrospective study of urine-NMR samples, from prostate biopsy patients with and without PCa, identified several metabolites involved in energy metabolism, amino acid metabolism, and the hippuric acid pathway. Of note, lactate and hippurate-key metabolites involved in cellular proliferation and microbiome effects, respectively-were significantly altered, unveiling widespread metabolomic modifications associated with PCa development. These findings support urine metabolomics profiling as a promising strategy to identify new clinical biomarkers for PCa detection and diagnosis.

Cognitive-behavioral therapy effects on alerting network activity and effective connectivity in panic disorder.

Given the particular relevance of arousal and alerting in panic disorder (PD), here the alerting network was investigated (1) contrasting patients with PD and healthy controls, (2) as a function of anxiety sensitivity constituting a dimensional measure of panic-related anxiety, and (3) as a possible correlate of treatment response. Using functional magnetic resonance imaging (fMRI), 45 out-patients with PD (f = 34) and 51 matched healthy controls were investigated for brain activation patterns and effective connectivity (Dynamic Causal Modeling, DCM) while performing the Attention Network Task (ANT). Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). Forty patients and 48 controls were re-scanned after a 6 weeks cognitive-behavioral treatment (CBT) or an equivalent waiting time, respectively. In the alerting condition, patients showed decreased activation in fronto-parietal pathways including the middle frontal gyrus and the superior parietal lobule (MFG, SPL). In addition, ASI scores were negatively correlated with connectivity emerging from the SPL, the SFB and the LC and going to the MFG in patients but not in healthy controls. CBT resulted in an increase in middle frontal and parietal activation along with increased connectivity going from the MFG to the SPL. This change in connectivity was positively correlated with reduction in ASI scores. There were no changes in controls. The present findings point to a pathological disintegration of the MFG in a fronto-parietal pathway in the alerting network in PD which was observed to be reversible by a successful CBT intervention.

Reversible magnetomechanical collapse: virtual touching and detachment of rigid inclusions in a soft elastic matrix.

Soft elastic composite materials containing particulate rigid inclusions in a soft elastic matrix are candidates for developing soft actuators or tunable damping devices. The possibility to reversibly drive the rigid inclusions within such a composite together to a close-to-touching state by an external stimulus would offer important benefits. Then, a significant tuning of the mechanical properties could be achieved due to the resulting mechanical hardening. For a long time, it has been argued whether a virtual touching of the embedded magnetic particles with subsequent detachment can actually be observed in real materials, and if so, whether the process is reversible. Here, we present experimental results that demonstrate this phenomenon in reality. Our system consists of two paramagnetic nickel particles embedded at finite initial distance in a soft elastic polymeric gel matrix. Magnetization in an external magnetic field tunes the magnetic attraction between the particles and drives the process. We quantify our experimental results by different theoretical tools, i.e., explicit analytical calculations in the framework of linear elasticity theory, a projection onto simplified dipole-spring models, as well as detailed finite-element simulations. From these different approaches, we conclude that in our case the cycle of virtual touching and detachment shows hysteretic behavior due to the mutual magnetization between the paramagnetic particles. Our results are important for the design and construction of reversibly tunable mechanical damping devices. Moreover, our projection on dipole-spring models allows the formal connection of our description to various related systems, e.g., magnetosome filaments in magnetotactic bacteria.

Applications of high-resolution magic angle spinning MRS in biomedical studies II-Human diseases.

High-resolution magic angle spinning (HRMAS) MRS is a powerful method for gaining insight into the physiological and pathological processes of cellular metabolism. Given its ability to obtain high-resolution spectra of non-liquid biological samples, while preserving tissue architecture for subsequent histopathological analysis, the technique has become invaluable for biochemical and biomedical studies. Using HRMAS MRS, alterations in measured metabolites, metabolic ratios, and metabolomic profiles present the possibility to improve identification and prognostication of various diseases and decipher the metabolomic impact of drug therapies. In this review, we evaluate HRMAS MRS results on human tissue specimens from malignancies and non-localized diseases reported in the literature since the inception of the technique in 1996. We present the diverse applications of the technique in understanding pathological processes of different anatomical origins, correlations with in vivo imaging, effectiveness of therapies, and progress in the HRMAS methodology.

Perception and prediction of apparent source width and listener envelopment in binaural spherical microphone array auralizations.

This article deals with the assessment and prediction of the reproduction quality when binaurally auralizing spherical microphone array data for room simulation applications. The auralization is perceptually assessed in a listening experiment using the two attributes, apparent source width (ASW) and listener envelopment (LEV), for spatial quality description, whereas the technical analysis employs a psychoacoustically motivated model for room acoustical perception (RAP) which is specifically designed to estimate ASW and LEV. Both analyses focus on the array configuration in terms of varying modal resolutions and its influence on the spatial reproduction quality. The auralizations comprise three simulated environments, i.e., free-field sound fields as well as a dry and a reverberant room. Ten different audio signals are used as test material. Perceptual results show that the array configuration strongly influences the perception of ASW and LEV which also depends on the reflection properties of the simulated room. The ASW and LEV predictions by the RAP model correlate well with the results from the listening experiment.

Microgels at the Water/Oil Interface: In Situ Observation of Structural Aging and Two-Dimensional Magnetic Bead Microrheology.

Stimuli-responsive microgels can be used as stabilizers for emulsions. However, the details of structure and the viscoelastic property of the microgel-laden interface are still not well-known. We synthesized fluorescently labeled microgels and used confocal microscopy to observe their arrangement at the water/oil interface. The microgels aggregated spontaneously at the interface, and the aggregated structure reorganized due to thermal motion. The structure of the interfacial layer formed by microgels depended on the microgel concentration at the interface. We suggest that the structure was controlled by the aggregation and adsorption of microgels at the interface. The interparticle separation between microgels at the interface decreased over time, implying a slow aging process of the microgels at the interface. Magnetic beads were introduced at the interface and used to trigger deformation of the microgel layer. Under compression and shear the microgels in the aggregated structure rearranged, leading to plastic deformation, and some elastic responses were also observed.

Buckling of paramagnetic chains in soft gels.

We study the magneto-elastic coupling behavior of paramagnetic chains in soft polymer gels exposed to external magnetic fields. To this end, a laser scanning confocal microscope is used to observe the morphology of the paramagnetic chains together with the deformation field of the surrounding gel network. The paramagnetic chains in soft polymer gels show rich morphological shape changes under oblique magnetic fields, in particular a pronounced buckling deformation. The details of the resulting morphological shapes depend on the length of the chain, the strength of the external magnetic field, and the modulus of the gel. Based on the observation that the magnetic chains are strongly coupled to the surrounding polymer network, a simplified model is developed to describe their buckling behavior. A coarse-grained molecular dynamics simulation model featuring an increased matrix stiffness on the surfaces of the particles leads to morphologies in agreement with the experimentally observed buckling effects.

The value of ADC, T2 signal intensity, and a combination of both parameters to assess Gleason score and primary Gleason grades in patients with known prostate cancer.

BACKGROUND: The ability to non-invasively analyze tumor aggressiveness is an important predictor for individual treatment stratification and patient outcome in prostate cancer (PCA). PURPOSE: To evaluate: (i) whether apparent diffusion coefficient (ADC), the T2 signal intensity (SI), and a combination of both parameters allow for an improved discrimination of Gleason Score (GS) ≥7 (intermediate and high risk) and GS <7 (low risk) in PCA; and (ii) whether ADC may distinguish between 3 + 4 and 4 + 3 PCA (primary Gleason grades [pGG]). MATERIAL AND METHODS: Prostatectomy specimens of 66 patients (mean age, 63 ± 5.6 years; 104 PCA foci) with a preceding multiparametric 1.5 T endorectal coil magnetic resonance imaging (MRI) were included. ADC (b values = 0, 100, 400, 800 s/mm(2)), standardized T2 (T2s), and the ADC/T2s ratio were tested for correlation with GS applying multivariate analysis. ADC cutoff values were calculated for prediction of GS and pGG, and logarithm of the odds (LOGIT) was used to express the probability for GS and pGG. Diagnostic accuracy was assessed by ROC analysis. RESULTS: We found an almost linear negative relationship of ADC for GS ≥7 (P = 0.002). The effect of ADC for GS ≥7 (adjusted odds ratio = 0.995) was almost identical for peripheral and transition zone PCA (P = 0.013 and P < 0.001, respectively). ADC showed an AUC of 78.9% for discrimination between GS <7 and GS ≥7. An ADC cutoff of <1.005 × 10(-3 )mm(2)/s indicated a GS ≥7 (90.5% sensitivity, 62.5% specificity). Within the group of GS = 7 PCA, an ADC > 0.762 × 10(-3 )mm(2)/s indicated a pGG of 3 (AUC = 69.6%). CONCLUSION: T2s and the ADC/T2s ratio do not provide additional information regarding prediction of GS. ADC values have a good discriminatory power to distinguish tumors with GS ≥7 from GS <7 and to predict pGG in GS = 7 PCA.

Modulation of prefrontal functioning in attention systems by NPSR1 gene variation.

Evidence has accumulated for a dysfunction of arousal and executive attention in anxiety. The neuropeptide S (NPS) system has been shown to play a pivotal role in the mediation of arousal and to be associated with anxiety/panic disorder. The present study aims at investigating the impact of functional neuropeptide S receptor (NPSR1) gene variation on neural attention patterns applying an imaging genetics approach. In an event-related functional magnetic resonance imaging (fMRI) setting, 47 healthy subjects (f=23) evenly pre-stratified for NPSR1 rs324981 A/T genotype were investigated for brain activation patterns while performing the Attention Network Task (ANT), simultaneously probing alerting and executive control functions. Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). In the alerting condition, NPSR1 TT homozygotes showed higher activations in the right prefrontal cortex and the locus coeruleus region as compared to A allele carriers. In the executive control condition, TT homozygotes displayed increased activations in fronto-parietal regions. Genotype-driven activation differences in the prefrontal cortex correlated with anxiety sensitivity, in both the alerting and the executive control system. The present results for the first time suggest NPSR1 gene variation to be associated with alterations of prefrontal functioning in the attentional functions alerting and executive control partly modulated by anxiety sensitivity. These findings may aid in unraveling the neurobiological underpinnings of distorted arousal and attention in anxiety and thereby possibly in the biomarker-guided development of preventive/therapeutic strategies targeting attention processes in anxiety disorders.

Differential imaging characteristics and dissemination potential of pilomyxoid astrocytomas versus pilocytic astrocytomas.

INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a rare WHO grade II tumor occurring most often in young children. PMA is associated with worse outcome as compared to the pathologically related pilocytic astrocytoma (PA). The radiological differentiation of PMAs from PAs is challenging. Furthermore, it is not completely clarified whether PMA is associated with a higher rate of cerebrospinal fluid (CSF) dissemination in the youngest pediatric population as compared to PA. The aim of our study was firstly to compare imaging features of these tumors and, secondly, to evaluate the occurrence of CSF dissemination. METHODS: The study population included 15 children with PMA and 32 children with PA. The initial MRI and CT scans from the time of the diagnosis were retrospectively analyzed according to standardized criteria and the findings compared between the two tumor types. Furthermore, we also compared the occurrence of imaging evidences of CSF dissemination. RESULTS: PMAs showed less frequently cystic components (p = 0.03) and never had large tumor cysts. Gadolinium enhancement of PMAs was more frequently homogeneous (p = 0.006). PMAs appeared to show more often intratumoral hemorrhages (p = 0.047). Within the subgroup of children <6 years of age, the PMA histology tended to have a larger effect on the occurrence of CSF dissemination than the age (p = 0.05 vs. 0.12). CONCLUSION: Some imaging features like enhancement pattern or presence of cysts or hemorrhage may help differentiating these low-grade gliomas. Our results confirm previous scarce data suggesting a higher rate of CSF dissemination in PMAs, even in the youngest patient population.

Tangential Flow Ultrafiltration Allows Purification and Concentration of Lauric Acid-/Albumin-Coated Particles for Improved Magnetic Treatment.

Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEON(LA-BSA), which were synthesized using excess albumin. For optimization of magnetic treatment applications, SPION suspensions need to be purified of excess surfactant and concentrated. Conventional methods for the purification and concentration of such ferrofluids often involve high shear stress and low purification rates for macromolecules, like albumin. In this work, removal of albumin by low shear stress tangential ultrafiltration and its influence on SEON(LA-BSA) particles was studied. Hydrodynamic size, surface properties and, consequently, colloidal stability of the nanoparticles remained unchanged by filtration or concentration up to four-fold (v/v). Thereby, the saturation magnetization of the suspension can be increased from 446.5 A/m up to 1667.9 A/m. In vitro analysis revealed that cellular uptake of SEON(LA-BSA) changed only marginally. The specific absorption rate (SAR) was not greatly affected by concentration. In contrast, the maximum temperature Tmax in magnetic hyperthermia is greatly enhanced from 44.4 °C up to 64.9 °C by the concentration of the particles up to 16.9 mg/mL total iron. Taken together, tangential ultrafiltration is feasible for purifying and concentrating complex hybrid coated SPION suspensions without negatively influencing specific particle characteristics. This enhances their potential for magnetic treatment.

Different storage conditions influence biocompatibility and physicochemical properties of iron oxide nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted increasing attention in many biomedical fields. In magnetic drug targeting SPIONs are injected into a tumour supplying artery and accumulated inside the tumour with a magnet. The effectiveness of this therapy is thus dependent on magnetic properties, stability and biocompatibility of the particles. A good knowledge of the effect of storage conditions on those parameters is of utmost importance for the translation of the therapy concept into the clinic and for reproducibility in preclinical studies. Here, core shell SPIONs with a hybrid coating consisting of lauric acid and albumin were stored at different temperatures from 4 to 45 °C over twelve weeks and periodically tested for their physicochemical properties over time. Surprisingly, even at the highest storage temperature we did not observe denaturation of the protein or colloidal instability. However, the saturation magnetisation decreased by maximally 28.8% with clear correlation to time and storage temperature. Furthermore, the biocompatibility was clearly affected, as cellular uptake of the SPIONs into human T-lymphoma cells was crucially dependent on the storage conditions. Taken together, the results show that the particle properties undergo significant changes over time depending on the way they are stored.

Treatment Efficiency of Free and Nanoparticle-Loaded Mitoxantrone for Magnetic Drug Targeting in Multicellular Tumor Spheroids.

Major problems of cancer treatment using systemic chemotherapy are severe side effects. Magnetic drug targeting (MDT) employing superparamagnetic iron oxide nanoparticles (SPION) loaded with chemotherapeutic agents may overcome this dilemma by increasing drug accumulation in the tumor and reducing toxic side effects in the healthy tissue. For translation of nanomedicine from bench to bedside, nanoparticle-mediated effects have to be studied carefully. In this study, we compare the effect of SPION, unloaded or loaded with the cytotoxic drug mitoxantrone (MTO) with the effect of free MTO, on the viability and proliferation of HT-29 cells within three-dimensional multicellular tumor spheroids. Fluorescence microscopy and flow cytometry showed that both free MTO, as well as SPION-loaded MTO (SPION(MTO)) are able to penetrate into tumor spheroids and thereby kill tumor cells, whereas unloaded SPION did not affect cellular viability. Since SPION(MTO) has herewith proven its effectivity also in complex multicellular tumor structures with its surrounding microenvironment, we conclude that it is a promising candidate for further use in magnetic drug targeting in vivo.

Ependymoblastoma of the brainstem: MRI findings and differential diagnosis.

Ependymoblastoma (EBL) is a rare malignant CNS tumor of early childhood, listed as a subgroup of primitive neuroectodermal tumors (PNET) in the 2007 WHO Classification of Tumours of the Central Nervous System. Histologically, EBL can be defined by multilayered, mitotically active "ependymoblastic" rosettes with central lumen as a histological hallmark. The prognosis seems to be far inferior to other embryonal CNS tumors, and known clinical and MRI characteristics of EBL are based on scattered case reports. We present and discuss two uncommon cases of histopathologically confirmed ependymoblastoma that both seem to originate from the brainstem.

Hypertrophic olivary degeneration with gadolinium enhancement after posterior fossa surgery in a child with medulloblastoma.

Hypertrophic olivary degeneration (HOD) is a rare transsynaptic form of degeneration occurring secondary to the disruption of the dentato-rubro-olivary pathway ("Guillain-Mollaret triangle"). HOD can be caused by ischemic, hemorrhagic, traumatic, or neoplastic lesions, and it can also occur following posterior fossa surgery. MRI characteristics of HOD include T2 signal increase and hypertrophy. To date, blood­brain barrier disruption has not been reported in HOD. Here, we present the first case of HOD with temporary gadolinium enhancement in a 10-year-old child 7 months after resection of a posterior fossa medulloblastoma. The recognition of gadolinium enhancement as a radiological feature of HOD may help to distinguish between this benign secondary condition and tumor recurrence.

An endolymphatic sac tumor with imaging features of aneurysmal bone cysts: differential diagnostic considerations.

BACKGROUND: Endolymphatic sac tumors (ELSTs) are rare, slow-growing tumors of the petrous bone. Despite the typical localisation, their radiological diagnosis can be challenging due to the variety of other tumors potentially showing similar features. CASE REPORT: We present a 16-year-old child with progressive hearing loss, vertigo, and tinnitus who had a large petrous bone lesion showing imaging features of both ELSTs and aneurysmal bone cysts (ABCs). The patient underwent preoperative embolization of the tumor-supplying vessels and subsequently a subtotal resection. Histological examination revealed an ELST. CONCLUSION: Despite the rarity of petrous bone ABCs, they should be considered as a differential diagnostic alternative of ELSTs due to their similar imaging appearance.

Ex Vivo High-Resolution Magic Angle Spinning (HRMAS) 1H NMR Spectroscopy for Early Prostate Cancer Detection.

The aim of our study was to assess ex vivo HRMAS (high-resolution magic angle spinning) 1H NMR spectroscopy as a diagnostic tool for early PCa detection by testing whether metabolomic alterations in prostate biopsy samples can predict future PCa diagnosis. In a primary prospective study (04/2006-10/2018), fresh biopsy samples of 351 prostate biopsy patients were NMR spectroscopically analyzed (Bruker 14.1 Tesla, Billerica, MA, USA) and histopathologically evaluated. Three groups of 16 patients were compared: group 1 and 2 represented patients whose NMR scanned biopsy was histobenign, but patients in group 1 were diagnosed with cancer before the end of the study period, whereas patients in group 2 remained histobenign. Group 3 included cancer patients. Single-metabolite concentrations and metabolomic profiles were not only able to separate histobenign and malignant prostate tissue but also to differentiate between samples of histobenign patients who received a PCa diagnosis in the following years and those who remained histobenign. Our results support the hypothesis that metabolomic alterations significantly precede histologically visible changes, making metabolomic information highly beneficial for early PCa detection. Thanks to its predictive power, metabolomic information can be very valuable for the individualization of PCa active surveillance strategies.